Pyrimidine As Consituent of Naturally Bioactive Compounds

CHEMISTRY & BIODIVERSITY Vol.
2 (2005)
REVIEW
Pyrimidine as Constituent of Natural Biologically Active Compounds
by Irene M. Lagoja
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, B-3000 Leuven
(phone: 32 16 337397; fax: 32 16 337340; e-mail: irene.lagoja@rega.kuleuven.ac.be)
This review describes the various manifestations of the pyrimidine system (alkylated, glycosylated, benzoannelated.). These comprise pyrimidine nucleosides as well as alkaloids and antibiotics some of them have
been discovered and isolated from natural sources already long time ago, others have been reported very
recently. A short overview on pyrimidine syntheses (prebiotic synthesis, biosynthesis, and metabolism) is given.
The biological activities of most of the pyrimidine analogs are briefly described, and, in some cases, syntheses are
formulated.
Contents
1. Introduction
2. The Nucleic Bases
2.1. General Aspects of the Chemical Pyrimidine Syntheses
3. The Prebiotic Synthesis of Pyrimidines
4. Biosynthesis and Catabolism of Pyrimidines
5. The Unglycosylated Pyrimidine in Natural Products
5.1. Pyrimidine-Containing Amino Acids
5.2. Vitamines
5.3. Nonglycosylated Pyrimidine Antibiotics
5.4. Pyrimidine and Quinazoline Alkaloids
5.5. Pyrimidine-Containing Toxins
6. Glycosylated Pyrimidines
6.1. Pyrimidine Nucleic Acid Building Blocks
6.2. Pyrimidine Nucleoside Modifications Found in DNA and RNA
6.3. Naturally Occurring Pyrimidine O-Nucleosides
6.4. Glycosylated Pyrimidine Antibiotics
6.5. Pyrimidine Diphosphate Derivatives
1. Introduction
Nitrogen-containing heterocyclic compounds featured prominently in early studies
of chemistry, and they were closely associated with the development of organic
chemistry, which was concerned with the study of materials isolated from living sources,
whilst inorganic chemistry dealed with the study of inanimate materials.
2005 Verlag Helvetica Chimica Acta AG, Zrich
CHEMISTRY & BIODIVERSITY Vol. 2 (2005)
The manifestation of the purine system in natural products has been reviewed
recently [1]. Over the years, the pyrimidine system turned out to be an important
pharmacophor, interacting with the synthesis and function of nucleic acids (e.g., the
cytostaticum fluorouracil (1) [2] or the HIV drug zidovudine (2) [3]). Ultrashort-acting
barbiturates such as thiopental sodium 3 (Pentothal) [4] are often used as general
anesthetics, whereas methylphenobarbital (4) [5] still is in use as antiepilepticum. Some
diaminopyrimidines, such as pyrimethamine (5) [6] or trimethoprim (6) [7] are
powerful antimalaria drugs. Used in combination with sulfonamides, 6 is also a potent
antibacteriostaticum, whereas minoxidil (7) [8] is used as antihypertensivum.
Sulfadiazine (8) [9] is one of the chemotherapeutics containing a pyrimidine moiety.
O
N
O
CH3
HN
O
HO
O
O
N3
O
H3C
HN
N
H
C2H5
C6H5
N
H
OCH3
H3CO
Cl
OCH3
NH2
N
N
H5C2
NH2
N
NH2
H2N
NH2
NH2
N
N SO2
H
NH2
Due to long-lasting interest in pyrimidine derivatives as potential drugs, the

syntheses of this heterocyclic ring system has been excessively reviewed [10]. This
review should provide an overview over naturally occurring pyrimidine derivatives with
a brief description of their biological activities. Therewith, it should be demonstrated
how manifold and diverse the function of this heterocyclic system is for the construction
of naturally occurring compounds.
2. The Nucleic Bases

As early as 1776, a purine derivative (uric acid (9)) was isolated in pure form, from
urinary calculi (stones) by Scheele [11]. Pyrimidines (m-diazine) were known as
breakdown products of uric acid at a very early date in the history of organic chemistry.
The first pyrimidine derivative (alloxan (10)) to be isolated was obtained in 1818 by
Brugnatelli [12], oxidizing uric acid with HNO3 [13].
In the early 1870s, Miescher [14] examined used bandages obtained from a hospital
caring for the wounded of the Crimean War, and, eventually, he discovered a substance
containing both phosphorous and nitrogen, made up of apparently large molecules, in
the nuclei of white blood cells found in pus. He named it nuclein because it seemed to
come from the cell nuclei. After being able to separate nuclein into a protein and an
O
H
N
N
H
urinary calculi
O
O
NH
O
N
H
HN
NH
O
10
C. W. Scheele
L. Brugnatelli
acid compound, the term nucleic acid was coined [15]. Systematic study of the ring
system really began with the work of Pinner [16], who first applied the name
pyrimidine (combination of the words pyridine and amidine) to the unsubstituted
parent body. He was the first to point out the structural similarity of pyrimidines to
benzene, pyridine, and s-triazine, and, accordingly, depicted the ring system in the form
of a regular hexagon [17].
In this period, the first pyrimidines could be isolated from natural sources by A.
Kossel (Fig. 1), and their structures were established by synthesis.
Fig. 1. A. Kossel
In 1910, Kossel received the Nobel Prize for Medicine in recognition of the
contributions to our knowledge of cell chemistry made through his work on proteins,
including the nucleic substances. Thymine (11) was isolated from hydrolyzates of
bovine thymus or spleen in 1893 [18], but only eight years later it was obtained
synthetically. Cytosine (12) was isolated 1894 from hydrolysis of calf thymus [19] and,
by 1903, its structure was known [20]. Uracil (13) was first isolated from the hydrolysis
of herring sperm in 1900 [21], shortly afterwards it was obtained from bovine thymus or
spleen, and from wheat germ. Its structure was established by synthesis in 1901. In 1905
orotic acid (14) was isolated from the whey of cows milk [22], shortly after the first
synthesis was achieved. But only in 1930, the identity of the natural and synthetic orotic
acid could be verified [23]. 5-Methylcytosine (15) was synthesized in 1901, and its
isolation from hydrolyzates of tubercule bacilli was reported in 1925 [24]. However,
this turned out to be incorrect and, only about 1950, it was isolated by hydrolysis of the
deoxyribonucleotide fractions from thymus, wheat germ, and other sources [25].

CH3
O
O
HN
NH
O
11
NH2
HN
O
HN
NH
12
13
NH2
NH
HO
N
H
14
H3C
N
N
H
15
2.1. General Aspects of the Chemical Pyrimidine Syntheses

A very large number of pyrimidine syntheses has been described [10] [26]. Mainly,
they can be classified into three types, according to the fundamental nature of the
fragments, which combine together to form the pyrimidine nucleus (Fig. 2).
Fig. 2. Types of pyrimidine synthesis
The most common pyrimidine syntheses are those belonging to Type 1. The
cyclization usually involves a double condensation with elimination of H2O, alcohol, or
hydrogen halide between amino, and carbonyl, carboxylic acid, carboxylic ester, acid
chloride, or enol ether groups, or condensation by addition of amino to CN groups or to
polarized double bonds without an elimination reaction. In the earliest recorded
example, Grimaux [27] condensed urea with malonic acid in the presence of phosphoryl
chloride and obtained barbituric acid, but the sodium alkoxide catalyzed reaction of a
malonic ester with urea is the common process [28]. The application of this process,
especially with esters of dialkylmalonic acids, can be exemplified by the preparation of
barbiturate drugs [29]. The most common variant of Type 2 is exemplified in Scheme 1,
in which the eliminated group, A, may be EtO [30], OH [31], SH [32], or NH2 [33].
Scheme 1
The required aminomethylidene intermediate 17 may be obtained from the

corresponding ethoxymethylidene compound 16 with NH3 , but it can also result from
reaction of an imino ether, amide, or amidine with the reactive methylidene compound
preliminary to cyclization with the same reagent. The success of the cyclization to 18
depends on the nucleophilic character of the aminomethylidene group, or its derived
anion, which will be increased if X is CN rather than CO2Et. Similarly, aminomethylidene compounds react with an isocyanate [34], yielding a ureide, which cyclizes
in a succeeding stage. b-Amino acids [35] or b-amino ketones [36] may be employed
similarly to obtain dihydropyrimidines, ring closure being effected with AcCl, HCl, or
Ac2O. The earliest recorded pyrimidine synthesis, i.e., the synthesis of cyanalkine [37]
on heating propanenitrile with K, may be classified under Type 2 reactions.
Type 3 reactions, the insertion of a single C-atom between the N-atoms of a 1,3diamine 19 to obtain hydrogenated pyrimidine 20 may be achieved by a number of
conventional processes, for instance, treatment with Et2CO3 [38], phosgene [39], or
aldehydes [40] (Scheme 2).
Scheme 2
These basic synthetic principles of pyrimidine syntheses have been applied to all of
the modern approaches of these heterocyclic compounds.
During the last years, the introduction of 2H-, 13C-, and 15N-labeled oligonucleotide
building blocks became paramount for structure elucidation of RNA and DNA
molecules. Therefore, with the help of specific 15N and 13C labeling, key information on
local interactions such as H-bonding [41], protonation [42], hydration [43], ligand
interactions [44], and stacking [45] on large oligomers can be provided. An overview
over the used synthetic strategies has been published recently [46].
3. The Prebiotic Synthesis of Pyrimidines

An array of experimental findings [47] suggests that the simple molecules required
for the origin of life may have been available on the primitive earth [48]. The isolation
of purines and pyrimidines (one-fifth of the purine concentration) from the Murchison
meteorite [49] has been cited as evidence that these substances might have been
present in a prebiotic environment [50]. The first prebiotic pyrimidine synthesis based
on a cyano compound was the synthesis of cytosine (12) from cyanoacetylene (prop-2ynenitrile; 21) and cyanate (22) [51] (Scheme 3). Since cytosine (12) is readily hydrolyzed
to uracil (13), this pyrimidine also can be provided. The reactants are considered
Scheme 3
prebiotic, since they are produced in electric discharge experiments [52]. Alternatively,
cyanoacetylene (21) may be obtained by heating HCN and acetylene [53], while
cyanate (22) may also be obtained by hydrolysis of cyanogen [54].
However, the rapid hydrolysis of cyanoacetylene (21) and cyanate (22) leading to
HCOO and MeCN (23) would have limited their possible concentration in a primitive
earth environment (Scheme 4). Using a drying lagoon model of prebiotic synthesis
means that the reacting species both are non-volatile and soluble. With this estimation,
the yield of pyrimidine synthesis significantly increased [55].
Scheme 4
Another pathway starts from 2-formylacetonitrile (24), the first hydrolysis product
of 21 [56]. Addition of guanine (25) leads to the intermediate 26, which can undergo
ring closure to yield 2,4-diaminopyrimidine 27 (Scheme 5). Via partial hydrolysis,
cytosine (12) and uracil (13) are obtained.
Scheme 5
Starting from b-alanine (28) and urea (29) [57], both products of the hydrolysis of
HCN oligomers [58], offers another possible pathway for the formation of dihydrouracil (30), which can undergo photochemical dehydrogenation to uracil (13)
(Scheme 6). Various catalysts such as montmorrillonite clays [59] enhance the
dehydrogenation step.
Scheme 6
Starting from diaminofumaronitrile (31), formation of 5-hydroxyuracil (32) [60]

can be achieved (Scheme 7). This assumption is also consistent with the proposal that
the tetramer of HCN (cis- or trans-isomer) is the key intermediate in the formation of
HCN [61] oligomers and the biomolecules from the hydrolysis of these oligomers. It is
significant that as well purines and pyrimidines as amino acids, the principal Ncontaining building blocks for the formation of nucleic acids and proteins, may be
obtained by hydrolysis of HCN oligomers.
Scheme 7
4. Biosynthesis and Catabolism of Pyrimidines

In contrast to the de novo purine synthesis, pyrimidines are not built up from the
corresponding ribose-phosphate. The de novo biosynthetic pathway [62] is comprised
of five enzymes that produce UMP [63] (Scheme 8).
Aspartate transcarbamoylase (EC 2.1.3.2) is the first enzyme committed only to
pyrimidine biosynthesis and is responsible for the formation of carbamoylaspartate
from aspartate and carbamoylphosphate [64]. The other biosynthetic pathway enzymes
are dihydroorotase (EC 1.3.3.1), orotate phosphoribosyltransferase (EC 2.4.2.10), and
Scheme 8
orotidine 5'-monophosphate (OMP) decarboxylase (EC 4.1.1.23). Inhibitors of the

enzymes of these pathways may be effective as drugs for treatment of cancer,
inflammatory disorders, or various infections [65]. The biosynthesis [66] starts with the
formation of N-carbamoylaspartate (33) from carbamoyl phosphate and aspartate as
the speed-controlling step of this synthesis. Note that the synthesis of carbamoyl
phosphate occurs in the cytoplasm, with glutamine as amino donor. (In comparison,
urea synthesis takes place in the mitochondrion where the amino donor for carbamoyl
phosphate is ammonia.) After removing H2O, ring closure leads to 34, and oxidation
yields orotic acid 14, which is converted with PRPP to OMP (35). Decarboxylation
leads to UMP (36), and finally, via UDP (37), UTP (38) is obtained, which can be
converted to CTP (39).
Catabolism [67] of the pyrimidines occurs by hydrolytic ring opening between N(3)
and C(4) (Scheme 9). Since, during the synthesis of uridine (13) from orotic acid (14),
CO2 has been released, alanine instead of aspartate is formed. Ammonia is metabolized
to urea in the urea cycle and released [68].
Scheme 9
NH2
N
O
N
H
O
NH4
HN
HN
O
Cytosine
NH2
CH3 NH4
N
H
N
H
Thymine
Uracil
Ring reduction
5-Methylcytosine
NADP
NADP
O
HN
O
Carnosine
or
Anserine
N
H
NADPH + H
NADPH + H
Excreted
CH3
O
HN
N
H
N
H
1. Ring opens
2. CO2 + NH4
released
H2N CH2 CH2 CO2H
H2N CH2 CH CO2H
CH3
-Alanine
-Aminoisobutyrate Excreted
From the seedlings of Albizzia julibrissin (Fig. 3) the non-proteinogenic amino acid
albizzine ( 2-amino-3-ureidopropanoic acid; 43) could be isolated and identified as
the main product of the uracil catabolism [69].
First, uracil (13) is transformed into isobarbituric acid (40) by a microsomal
hydroxylase (Scheme 10). Enzymatic amination leads to the toxic intermediate 5aminouracil (41), which is converted into 5-amino-5,6-dihydrouracil (42) by dihydrouracil dehydrogenase (EC 1.3.1.21). Finally, the ring is opened to albizzine (43) by
Fig. 3. Albizzia julibrissin

Scheme 10
dehydropyrimidinase (EC 3.5.2.2). b-Ureidopropionase releases NH3 and CO2 to give

2,3-diaminopropanoic acid (44) as the final product.
5. The Unglycosylated Pyrimidine in Natural Products

The free purines and their simple derivatives have been found much more
frequently in nature than the pyrimidines. Of the nucleic acid pyrimidines, only uracil
(13) [70] and hydrouracil ( 5,6-dihydropyrimidine-2,4(1H,3H)-dione; 30), isolated
from beef spleen [71], have been found in the free form.
O
HN
NH
HN
NH
13
30
5.1. Pyrimidine-Containing Amino Acids

Among the 800 natural amino acids of (R)- or (S)-configuration reported in the
literature, many are heterocyclic. In 1959, a non-proteinogenic l-a-amino acid,
willardiine (45), was isolated from the seeds of Acacia willardiana [72] and later from
other species of Acacia [73]. Extracts prepared from the seeds of the Leguminosae
have revealed, in a number of species of Lathyrus, the presence of a compound giving a
vivid orange-red reaction with ninhydrin [74].
10
CO2H
H2N
N
H
NH
O
45
CO2H
H2N
NH2
Lathyrus tingitanus
46
Acacia willardiana
The extracts of L. tingitanus appeared to contain the highest concentration of this

compound, also a non-proteinogenic l-a-amino acid, with the proposed name lathyrine
(tingitanine; 46) [75]. Willardiine (45) either can be synthesized [76] by a Shaw
synthesis (completion of the ring with a N1 fragment access to uracil or thiouracil
derivatives [77]) of the acetal 47, which is hydrolyzed to the aldehyde 48, followed by a
Strecker synthesis (KCN, NH3, and NH4Cl), or by condensation of ethyl formylacetate
(49) with the ureido acid 50, which is the most direct route [78] (Scheme 11). Synthetic
derivatives thereof ((S)-5-fluorowillardiine) have recently been described as compounds binding to functionally active AMPA receptors, revealing genuine allosteric
interaction with agonist binding sites [79].
Scheme 11
Also for the synthesis of lathyrine (tingitanine; 46), two different approaches can be
considered. Either starting from the corresponding 2-amino-4-methylpyrimidine
derivative 51, an azalacton synthesis can be carried out [80], or, starting from the
corresponding halogeno compound 52, the amino acid side chain is introduced [81]
(Scheme 12).
11
Scheme 12
In the first pathway, 2-aminopyrimidine-4-carboxylic acid (53), which was earlier

identified as a substrate of the enzyme lathyrine synthase [82] and has shown to be
present in seeds of Lathyrus tingitanus, is used as key intermediate.
Other unusual amino acids could be isolated from bacterial siderophores [83]
(ironcarriers, produced from aerobe organisms under iron deficit).
Ectoine (54) and hydroxyectoine (55) [84] possess a 3,4,5,6-tetrahydropyrimidine
moiety; in nature they mostly can be found as betaines. These secondary amino acids
act as agonists or antagonists for the receptors of peptidic molecules [85]. The
hydrogenated pyrimidine moiety of 54 and 55 can be found in manzacidin derivatives
86 described in Sect. 5.4.3.
N
OH
H
H
CO2H
54
H
CO2H
55
5.2. Vitamines
Vitamin B1 (aneurin, thiamine; 56), the antineuritic or anti-beriberi vitamin [86], a
H2O soluble substance, belongs to the vitamin B complex. It was first isolated from rice
bran by Jansen and Donath in 1926 [87], and has since been obtained from yeast and
other sources.
Thiamine (56) is known only in the form of its salts. The N-atom in the thiazole ring
has a charge of 1. This N-atom serves as an important electron sink in thiamine
pyrophosphate mediated reactions.
The biochemically active derivative of thiamine is the pyrophosphate ester of
thiamine, thiamine pyrophosphate (57), which is involved in a number of important
metabolic processes, including decarboxylation of a-oxoglutaric acid in the citric acid
12

O
OH
P
H3C
N
N
NH2
OH
N
Cl
H3C
NH2
N
Cl
CH3
OH
OH
CH3
56
57
cycle and the conversion of alanine, via pyruvic acid to acetyl coenzyme A [88]. The
total synthesis of thiamine (56) in 1937 verified the proposed structure [89].
5.3. Nonglycosylated Pyrimidine Antibiotics
5.3.1. Bacimethrin and Related Compounds. The simplest pyrimidine antibiotic is
bacimethrin ( 4-amino-5-(hydroxymethyl)-2-methoxypyrimidine; 58) [90], a naturally occurring thiamine antimetabolite [91], which was isolated in 1961 from Bacillus
megatherium.
NH2
NH2
HO
HO
N
N
OCH3
58
CH3
59
NH2
NH2
HO
Bacillus megatherium
N
H
60
N
H
61
Bacimethrin (58) is active against several yeasts and bacteria in vitro as well against
staphylococcal infections in vivo. Furthermore, some anticarcinoma activity in mice has
been reported [92]. Interesting is the close structural similarity [93] of 58 with
toxopyrimidine (59) [94], which is the pyrimidine part of aneurin (56), with 5(hydroxymethyl)cytosine (60) [95], which is replacing cytosine in the DNA of Tbacteriophages, and with 5-methylcytosine (61), which could be found in plant and
animal DNA but not in viral and bacterial DNA [24] [96]. Starting from 2methylisourea (62) and 2-(ethoxymethylidene)malononitrile (63), condensation in
alkaline medium yields 4-amino-2-methoxypyrimidine-5-carbonitrile (64), which can
easily be reduced to bacimethrin (58) [97] (Scheme 13).
Condensation of 2-(aminomethylidene)malononitrile (65) with ethyl acetimidate
(66) in EtOH/EtONa, leads to 4-amino-2-methylpyrimidine-5-carbonitrile (67), which
can be reduced to toxopyrimidine (59) [98] (Scheme 14).
Starting from 2-ethylisothiourea (68), 5-(hydroxymethyl)cytosine (60) can be
prepared in an analogous way [99] (Scheme 15).
5.3.2. Sparsomycin Derivatives. Sparsomycin (69a), an inhibitor of the protein
biosynthesis (peptidyl transferase activity of 70S and 80S on their isolated large
13
Scheme 13
Scheme 14
Scheme 15
subunits), is one of the few antibiotics that can inhibit protein synthesis in bacteria,
archaea, and eucarya. Moreover, the antibiotic and some of its derivatives selectively
act on several different human tumors [100]. However, there are no reports regarding
normalization of the phenotype of oncogene-transformed cells [101]. The mode of
action of the drug is unusual and different from those of the 4-aminohexose pyrimidine
nucleoside antibiotics discussed in Sect. 6.4.1. First, the antibiotic is incapable of binding
to ribosomes in the absence of donor substrate (peptidyl-tRNA or its truncated
derivatives); it seems to lack an affinity for ribosomal elements per se. Second, the
binding of the antibiotic and the donor substrate are synergistic; the drug stimulates the
binding of the donor substrate to the ribosome and fixes it in the d site of the PTC.
O
HN
O
N
H
H
CH3
OH
O
N
H H
O
R
Sparsomycin (69a)
R = MeS
Sparoxomycin A1 (69b) R = (R)-MeS(O)
Sparoxomycin A2 (69c) R = (S)-MeS(O)
As a peptidyl transferase drug [102], sparsomycin (69a) interferes with the peptide
bond formation, a central process in protein biosynthesis, which takes place on the large
ribosomal subunit. It is implied that sparsomycin (69a) recognizes a universally
conserved structural motif in the peptidyl transferase center that may involve
14
components from ribosomal protein and/or rRNA. Because this motif is likely to be
involved in binding of the 3'-terminal adenosine of the P/P'-site I, it is possible to infer
that one mechanism by which the drug acts is by stabilizing this interaction and,
thereby, inhibiting the movement of the 3'-end of the tRNA during elongation [103].
Sparsomycin (69a) is a metabolite of Streptomyces sparsogenes or Streptomyces
cuspidosporus, it only differs in the oxidation level at the S-atom from sparoxomycin
A1 (69b) and A2 (69c), new inducers of the flat reversion of NRK cells transformed by
temperature-sensitive Rous sarcoma virus, which have been isolated from a culture
broth of mycelium of Streptomyces sparsogenes SN-2325 [104].
The stereoselective synthesis has been described by Nakajima et al. [105]. Key step
of this synthesis is the stereoselective oxidation of the sulfide 70 to the chiral sulfoxide
71 under asymmetric conditions (Scheme 16). After deprotection of the amino group
and sulfenylation to the dithioacetal mono-oxide 72, coupling to 73 with b-(6methyluracil)acrylic acid was achieved with 1,3-dicyclohexylcarbodiimide (DCC) and
1-hydroxy-7-azabenzotriazole (HOAt). Deprotection of the MOM group leads to
sparsomycin (69a), whereas oxidation of the sulfide yields a mixture of MOMprotected sparoxomycins 74b/74c, which, after deprotection to 69b/69c, can be
separated by HPLC.
Scheme 16
5.3.3. The Bleomycin Glycopeptides. Bleomycin (75) and related glycopeptides

[106] are a family of antibiotics isolated from Streptomyces verticillus, which have
15
remarkable structural features that form the basis of a unique mode of antitumor
action. In clinic, bleomycin (75) is often used because of its rapid attack on solid forms
of tumor, and because of being one of the very few anticancer drugs not attacking bone
marrow. Bleomycin (75) is able to break single-stranded DNA in the tumor and
prevent repair. At the molecular level, its mode of action is fairly well understood
[107].
O
NH2
NH2
H
N
H
N
NH2
O
N
O
H2N
CH3 N
H
O
H
N
O
CH3 HO
O
R
S
NH
CH3
R
S
N
S
Bleomycin (75)
OH
O
Phleomycin (76)
N
H
O
OH
CH3
H
N
H H
N
O
HO
HO
O
O
O
OH
OH
OH
NH2
Bleomycin Derivatives found in nature:

A1
R = MeS(O)(CH2)3NH
A2
Demethyl-A2
A2'-a
A2'-b
R = Me2S(CH2)3NH
R = MeS(CH2)3NH
R = H2N(CH2)4NH
R = H2N(CH2)3NH
A2'-c
R=
H
N
N
A5 R = H2N(CH2)4NH(CH2)2NH
A6 R = H2N(CH2)3NH(CH2)4NH(CH2)3NH
B2' R = NH2
NH
B2 R = H2NCNH(CH2)4NH
(CH2)2NH
In action, bleomycin (75) combines with Fe2 ion via the five N-atoms shown in
Fig. 4. To the sixth Fe valence, O2 is bound, which is converted to O . and is retained in
the Fe-binding cage.
This activated complex oxidizes the H-atom at C(4) of the deoxyribose moiety in
the DNA, leading to a cascade reaction oxidatively cleaving the bond between C(3')
Fig. 4. Coordination of M (Cu2, Fe2 ) and O2 by bleomycin (75)
16
and C(4'). It is assumed that the anticancer effect of bleomycins is mainly due to the
appearance of 9-(3-oxoprop-1-enyl)guanine [108]. The bleomycin family of compounds contains a number of analogs that differ only in the terminal amine substituent,
whereas in the group of phleomycins (76), one of the double bonds in the bithiazole
portion is hydrogenated.
5.4. Pyrimidine and Quinazoline Alkaloids
5.4.1. Heteromines from Heterostemma brownii. In 1997, the isolation of three new
pyrimidines, heteromines F, G, and H (77a 77c, resp.) from the aerial parts of
Heterostemma brownii Hay has been reported. In Taipei folk medicine, this plant is
used for the treatment of cancer. Heteromines are shown to be cytotoxic in several
cancer cell lines [109].
H
OCH3
O
CH 3
N
R
CH3
Heteromine F (77a) R = Me2N

G (77b) R = MeNH
H (77c) R = NH2
Heterostemma brownii
5.4.2. Alkaloids from Crambe crambe. From a Mediterranean sponge, some

cytotoxic compounds 78 [110] bearing 2-aminopyrimidine moieties could be isolated.
Crambescin B (78b) has a IC50 value of 1 mg/ml vs. L1210 murine leukemia cells and is
10 20-times less cytotoxic than crambescidin 816 against these cells.
Based on the fragmentation pattern of the FAB mass spectrum [111], the originally
proposed structures of crambescin B (78b) and C1 (78c) [112] could be revised.
Alkylation of the dianion of methyl acetoacetate (79) with oxirane (80) affords 81,
which, after protection of the primary alcohol function, can undergo Knoevenagel
condensation to introduce the apolar side chain of 82 (Scheme 17).
Due to a couple of unwanted side reactions, guanidine cannot directly be condensed
to yield dihydropyrimidine derivatives. Therefore, a two-step route involving the
addition of the less basic O-methylisourea (83) has been employed. If the OH function
of 84 (OTBDMS) is converted to a leaving group X, the bicyclic pyrimidine moiety 85
of crambescin A (79a) can be obtained as well.
5.4.3. Manzacidin Alkaloids. A number of alkaloids containing an ester-linked
pyrrole and pyrimidine moiety have been isolated from marine sponges. The three
17
NH2
N
(CH2)9-12CH3
NH
(CH2)4
O
N
NH2
H
Crambescin A (78a)
Crambe crambe
NH2
HN
O
NH2
HN
(CH2)7CH3
NH
(CH2)7
HO
O
NH2
N
(CH2)7CH3
NH
(CH2)7
O
N
NH2
H
Crambescin B (78b)
Crambescin C1 (78c)
Scheme 17
bromopyrrole-containing derivatives manzacidin A C (86a 86c, resp.) were isolated

from the Okinawan sponge Hymeniacidon sp. [113], whereas manzacidin D (86d) was
found in the living fossil Astrosclera willeyana [114].
Starting from ethyl glyoxylate 87, oxathiazinanes 88 can be obtained in a single
throughput [115]. After protection with Boc2O, the carbamate 89 obtained is treated
with NaN3 to give the ring-opened product 90, which was sequentially reduced, and
afterwards the resulted amine was acylated to generate formamide 91 (Scheme 18).
Using POCl3 and 2,6-di(tert-butyl)-4-methylpyridine allows formation of the tetrahy-
18

O
N
HO
R1
R2
O
O
Hymeniacidon sp.
H
N
X
1
Manzacidin A (86a) R = R = H, X = Br
Manzacidin B (86b) R1 = OH, R2 = H, X = Br
Manzacidin C (86c) R1 = R2 = H, X = Br (9-epi)
Manzacidin D (86d) R1 = H, R2 = Me, X = H
Astrosclera willeyana
Scheme 18
a) ClSO2NCO, HCO2H (3 : 1 mixture of C(6)-epimers). b) 2 mol-% Rh2(OAc)4 , PhI(OAc)2 , MgO, CH2Cl2 . c)

Boc2O, pyridine (C5H5N). d) NaN3 , DMF. e) H2 Pd-C, then N-formyl-1H-[1,2,3]-benzotriazole. f) POCl3 , 2,6-(tBu2 ), 4-Me C5H5N. g) 8m HCl, DME, 608. h) NaH, DMF, 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloroethanone.
dropyrimidine 92 without attendant epimerization at C(4). After deprotection to 93,

acylation with the pyrrole derivative yields the desired manzacidins (86).
As often seen in the structure of marine natural products, a plausible biosynthetic
pathway involving (R)- or (S)-isonitrile intermediates also can be presumed [116]. The
obtained a-substituted a-amino acids [117] enable the asymmetric Strecker synthesis to
be a widely useful method also allowing the smooth preparation of manzacidins. Also in
this approach, an acyclic 1,3-diamino precursor with the right configuration undergoes
ring closure with a C1 donor to give the tetrahydropyrimidine derivative.
Another approach uses an isothiourea-iodocyclization strategy to directly form the
heterocyclic core inducing stereoselectivity at the quaternary center [118]. Glycine tertbutyl ester hydrochloride (94) was protected as its benzophenone imine derivative 95
(Scheme 19). After alkylation, the Schiff base of the resulted benzophenone imine 96
was selectively deprotected to 97, leaving the acid sensitive gem-disubstituted olefin
untouched. After introduction of the isothiourea moiety, 98 was suitable for the key
19
iodocyclization with IBr in CH2Cl2 , to give the corresponding tetrahydropyrimidine

derivative 99 in excellent yield and diastereoselectivity (Scheme is exemplified for the
synthesis of manzacidin A).
Scheme 19
Attempts at the conversion of the iodide by displacement with benzoate as model

for the bromopyrrole carboxylate led to the formation of an unexpected intramolecular
cyclization product 100, whereas Ag-salt-promoted solvolysis afforded alcohol 93,
suitable for ester condensation with the pyrrole derivatives (Scheme 20).
Scheme 20
5.4.4. Variolin-Type Alkaloids. Certain secondary metabolites of marine organisms

are nontraditional guanidine-based alkaloids 101, which possess a broad spectrum of
powerful biological activities, in general, the guanidine moiety can be found in the guise
of 2-aminoimidazol [119] or 2-aminopyrimidine rings [120].
CH3
H2N
OH
N
N
H2N
OH
N
N
OH
OCH3
N
H2N
Kirkpatrickia varialosa
Variolin A (101a)
N
N
N
H2N
H2N
Variolin B (101b) Variolin D (101c)
20
In 1994, Blunt, Munro, and co-workers reported the structure elucidation of the
variolins (101), a class of novel alkaloids from the rare, difficult-to-access Antarctic
sponge Kirkpatrickia varialosa [121]. Variolins (101) are the first examples of either
terrestrial or marine natural products with a pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine
system. These alkaloids were isolated after the examination of extracts, which were
shown to be active against P388 murine leukemia cells. Subsequently, variolin B (101b)
was found to be the most active in tests, which included antiviral activity (Herpes
simplex type I, polio type I) [122]. Since then, several synthetic strategies have been
developed to build up the heterocyclic core [123]. The formation of the annulated 2aminopyrimidine ring by way of a tandem aza-Wittig/carbodiamide-mediated cyclization [124] is described in Scheme 21.
Scheme 21
a) PhCH(Me)NCO, THF, r.t. b) Br2 , pyridine, 08. c) (2-Ethoxyvinyl)trimethyltin, DMF, PdCl2(PPh3 )2 .

d) Dimethylformamide di(tert-butyl) acetal, DMF, 808. e) H2N(CNH)NH2 HCl, K2CO3 , MeOCH2CH2OH,
reflux. f) Ph2O, 2608. g) Trifluoromethanesulfonic acid (TfOH), r.t.
Starting from the iminophosphorane 102, an aza-Wittig reaction with a-methylbenzyl isocyanate provides the tricyclic pyrimidopyrrolopyridine 103 the central core
21
of variolin (101) in almost quantitative yield (Scheme 21). After bromination of the
pyrrole ring C(5) to 104, conversion of the Br substituent to an Ac group, used as C2
moiety for the construction of the pyrimidine ring, is achieved by coupling with (aethoxyvinyl)trimethyltin in the presence of dichlorobis(triphenylphosphine)palladium.
Treatment of 105 with dimethylformamide di(tert-butyl)acetal in DMF provides the
corresponding enaminone 106. Reaction of 106 with guanidine hydrochloride in 2methoxyethanol in the presence of anhydrous K2CO3 leads to the formation of the
north-east 2-aminopyrimidine ring and concomitant ester hydrolysis to 107. Treatment
of 107 in Ph2O at 2608 not only leads to decarboxylation but also to O-methyl
deprotection to give 108. N-Deprotection with neat triflic acid finally yields Variolin B
(101b).
Closely related to the variolins (101) are meridianins (109), isolated from the
tunicate Aplidium meridianum (Ascidiae, Polyclinidae family), an Ascidian collected in
the South Atlantic [125].
Their structures can be described as a brominated and/or hydroxylated indole

nucleus linked with a 2-aminopyrimidine at C(3). They can also be considered as
guanidine-based alkaloids in which the guanidine moiety is found in the guise of a 2aminopyrimidine ring.
Meridianin D (109d) showed cytotoxicity [123] [126] toward LMM3 (murine
mamarian adenocarcinoma cell line) with an IC50 value of 33.9 mm. However, only
weak antitumor activities against a variety of tumor cell lines could be found [127].
Meridianins (except meridianin G (109g)) were found to inhibit CDKs, GSK-3, PKA,
and other protein kinases in the low micromolar range. Especially meridianin B and E
(109b and 109e, resp.) turned out to be the most potent derivatives [128].
Synthesis can be achieved by Pd-catalyzed cross-coupling reaction of 1H-indole-3boronic acid with 2,4-dichloropyrimidines [129]. 6-Bromo-1-tosyl-1H-indole (110) is
converted to 3,6-dibromo-1-tosyl-1H-indole (111), which was treated with t-BuLi in
THF at 788, followed by addition of (MeO)3B and aqueous workup, to give 6-bromo1-tosyl-1H-indole-3-boronic acid (112; Scheme 22). Pd-Catalyzed cross-coupling of 112
with 2-amino-4-chloropyrimidine (113) to 114, followed by alkaline deprotection,
yields meridianin D (109d).
An Antarctic sponge, Psammopemma sp., has yielded psammopemmins A C
(115a 115c, resp.), containing the novel 4'-amino-2'-bromopyrimidine-5-yl moiety
[130], which is currently unique in natural products chemistry. Synthesis and biological
properties have not been reported yet.
5.4.5. Quinazoline Alkaloids. Benzo-annelated pyrimidines, quinazolines, can be
isolated from a number of plants, microorganisms, and animals. The first known
22

Scheme 22
Br
N
OH
NH2
NH
R1
R2
Psammopemma sp. (sand sponge)
Psammopemmin A (115a) R1 = R2 = H
B (115b) R1 = H, R 2 = Br
C (115c) R1 = Br, R2 = H
quinazoline alkaloid was vasicine (peganine; 116) isolated in 1888 from Adhatoda
vasica, a plant being used in Indian indigenous medicine for centuries [131].
This review is restricted to the simple quinazoline skeleton, which is quite rare in
nature [132], and does not include fused derivatives such as pyrroloquinazolines or
pyridoquinazolines [133]. Most of the simple quinazolinone alkaloids 117 124 are
isolated from leaves of the plant known in Bengali as Ash-shoura. It is used in the
Ayurvedic medicine as a febrifuge and as an antihelmetic. The botanical name of the

O
NH
Me
Me
Me
118
117
119
O
NH
Ph
121
O
OMe
NH
N
N
Ph
N
Me
122
R
Ph
Glycosmis pentaphylla Correa

123
O
NH
Me
Ph
N
H
120
Glycosmis arborea Correa
Ph
23
Br
124 R = H, MeO
N
H
125
Tunicate Pyura sacciformis

(Pyuridae)
plant is stated as Glycosmis pentaphylla Correa, which is found in the Eastern and the
Western Ghats, Orissa, and the Malayan peninsula, whereas the closely related
Glycosmis arborea occurs widely throughout India. The difference between the two
species is evident from the botanical characteristics [134].
Glycosmicine (117) [135], glycorine (118) [135], arborine (119) [136], glycosminine
(120) [135], glycophymine (121) [137], glycophymoline (122) [138], and glycosine
(123) [139] could be isolated from Glycosmis Correa species, whereas 7-bromoquinazoline-2,4(1H,3H)-dione (125) was isolated from the tunicate Pyura sacciformis
(Pyuridae) [140]. The latter represents the first brominated quinazolinedione from a
natural source. From the seed husk extracts of the Mexican Zanthoxylum arborescens
(Rose), two more closely related 1-methyl-3-(2-phenylethyl)quinazoline-2,4(1H,3H)diones 124 could be isolated [141].
Kametani et al. [142] have developed a synthetic procedure based on the formation
of sulfonamide anhydrides 127 by reaction of anthranilic acids 126 with SOCl2 and the
subsequent in situ generation of the corresponding iminoketene 128 (Scheme 23).
Addition of the latter to an imine, or a primary or secondary amide affords the
24

Scheme 23
quinazoline derivatives. Glycorine (118), arborine (119), and glycosminine (120) have
been prepared according to this procedure.
Analytical data, the mass-fragmentation pattern, and the formation of glycophymine (121) by demethylation of arborine (119) suggested that glycophymine (121) was
either identical to glycosminine (120) or to the tautomeric 2-benzylquinazolin-4-one
121. Later, the prevalence of the thermodynamically more stable isomer 120 was
confirmed by UV, IR, and 1H-NMR data, and chemical investigations [143]. The
quinazolinedione glycosmicine (117) can be obtained by oxidation of glycorine (118)
[135b] [144]. Glycophymoline (122) can be seen as an enol-ether of glycosminine (120)
and is obtained by treatment of the latter with dimethyl sulfate [138]. The structure for
glycosine (123) has been confirmed by synthesis [139] from isatoic anhydride (129),
which, on treatment with aqueous NH3 , yields the anthranilide 130 (Scheme 24).
Methylation with MeI in a sealed tube leads to the N-methylanthranilamide (131),
which undergoes ring closure to glycosine (123) upon heating with PhCH2COOH and
P2O5 .
Scheme 24
A similar strategy was adapted for the synthesis of the alkaloids 124 of
Zanthoxylum arborescens [141]. Starting from N-methylisatoic anhydride (129a) and
(2-phenylethyl)amine, the corresponding benzamide derivative 132 was obtained,
which, after acylation with ClCO2Me to 133 could undergo ring closure to give the
desired quinazoline derivatives 124 (Scheme 25).
Starting from 4-bromoanthranilic acid (126), reaction with NaOCN leads to 134,
which, in alkaline medium, undergoes ring closure to the brominated quinazolinedione
derivative 125 [144] (Scheme 26).
5.4.6. Benzopyrimidines with Antimalarial Properties. Two interconvertible alkaloids, febrifugine (135) and isofebrifugine (136), could be isolated in small yields from
Dichroa febrifuga (Saxifragaceae [145]; Chinese name: Chang Shan), and Hydrangea
umbellate (Saxifragaceae) [146].
25
Scheme 25
Scheme 26
OH
O
N
N
N
H
135
N
O
OH
N
N
H
136
Dichroa febrifuga
Dichroa febrifuga is an ingredient in a traditional Chinese herbal effective against

malaria, and febrifugine (135), the first alkaloid other than those of the Cinchona group
appears to be primarily responsible [147].
The plane structure of 135 and 136 was first proposed in the 1950s, based on Bakers
synthetic work [148]. The relative configuration of 135 was corrected in 1973 [149], and
finally the absolute configurations of 135 and 136 were established in 1999 [150].
Kobayashi et al. [150] showed by a SnII-catalyzed asymmetric aldol reaction, followed
by a lanthanide-catalyzed aqueous three component reaction, that the previously
26
reported configuration of febrifugine (135) and isofebrifugine (136) were not (2'S,3'R)
and (2'R,3'R) as reported previously, but (2'R,3'S) and (2'S,3'S), respectively.
These repeated errors and corrections have caused much confusion in the study of
the relationship between the structure and antimalarial activity. Currently, medical and
synthetic studies [151] of febrifugine (135) are in progress.
With respect to green chemistry, an interesting synthesis [152] of ()-febrifugine
(135) by making use of a yeast reduction of a Cbz-protected piperidin-3-one derivative
137 [153] as the key asymmetric reaction is shown. The reaction of dl-137 with bakers
yeast and sucrose in EtOH and H2O afforded cis-piperidin-3-ol (138) with high
selectivity (Scheme 27). The intramolecular bromoetherification of 138 with Nbromosuccinimide (NBS) afforded hexahydrofuro[3,2-b]pyridine 139. After preparation of the MeO derivative 140, deacetalization, followed by coupling reaction with
quinazolin-4(3H)-one, afforded Cbz-protected isofebrifugine 141, which, after deprotection to 142, could be converted to febrifugine (135).
Scheme 27
a) N-Bromosuccinimide (NBS), MeCN, r.t. b) i. t-BuOK, THF, 08; ii. NBS, MeOH, r.t. c) i. H, MeCN, r.t.;
ii) quinazolin-4(3H)-one, K2CO3 , DMF, r.t.; d) H2 , 20% Pd(OH)2/C, MeOH. e) H2O, 808, H.
5.5. Pyrimidine-Containing Toxins

5.5.1. Hepatotoxins. In 1992, Moore and co-workers [154] described the isolation
and characterization of the hepatotoxin cylindrospermopsin (143) produced by the
fresh water blue-green alga Cylindrospermopsis raciborskii.
This compound produced by algal blooms in drinking water has implied a severe
outbreak of hepatoenteritis in tropical Australia.
7-Epicylindrospermopsin (144), which is also toxic, has been isolated from the
cyanobacterium Aphanizomenon ovalisporum collected from Lake Kinneret in Israel
[155]. It has been postulated that cylindrospermopsin probably exerts its toxic effects
O3SO
H3C
27
OH
O
NH
H
NH
NH
OH
143
Cylindrospermopsis
raciborskii
H
O3SO
H3C
OH
NH
H
NH
O
N
NH
OH
Aphanizomenon ovalisporum
144
by inhibiting biosynthesis of cell-reduced glutathione [156] and also by inhibition of

protein synthesis.
The stereoselective total syntheses and reassignments of the configurations were
described in 2002 by Weinreb and co-workers [157].
Closely related to epicylindrospermopsins are ptilocaulin (145) and isoptilocaulin
(146), antimicrobial and cytotoxic cyclic 2-iminopyrimidine derivatives, derived from
the Caribbean sponge Ptilocaulis aff. Ptilocaulis spiculifer [158].
NH
HN
NH
H
H
145
NH
HN
NH
H
H
H
146
Ptilocaulis aff. P. spiculifer
They were highly active against Gram-positive and Gram-negative bacteria, yeasts,
and filamentous fungi. Structure and absolute configuration of ptilocaulin (145) have
been confirmed by total synthesis of the racemate [159] and the ( )-enantiomer [160].
5.5.2. Non-Protein Neurotoxins. Tetrodotoxin (tarichatoxin; 147) [161] is one of the
most-powerful non-protein neurotoxins known. It occurs in the liver and the ovaries of
the Japanese puffer fish (Spoerides rubripes and S. phyreus) and in the Californian newt
28
or salamander (Taricha torosa). The structure is based on a 2-iminooctahydro-1Hquinazoline skeleton. The total synthesis of 147 has been described in 1972 by Kishi
et al. [162].
O
H
H2N
Fugo, Japanese puffer fish,

Sphoerides rubripes, S. phyreus
O
H
HO
H
O
OH
N
H
N
H HO
CH2OH
H
H
OH
147
Taricha torosa
6. Glycosylated Pyrimidines
6.1. Pyrimidine Nucleic Acid Building Blocks
In 1962, James Watson (b. 1928), Francis Crick (1916 2004), and Maurice Wilkins
(1916 2004) jointly received the Nobel Prize in medicine/physiology for their
determination, in 1953, of the structure of deoxyribonucleic acid (DNA) [163].
Because the Nobel Prize can be awarded only to the living, Wilkinss colleague
Rosalind Franklin (1920 1958) could not be honored (Figs. 5 and 6). A new
understanding of heredity and hereditary disease was possible once it was determined
that DNA consists of two chains twisted around each other, or double helixes, of
alternating phosphate and sugar groups, and that the two chains are held together by
H-bonds between pairs of organic bases adenine (A) with thymine (T), and guanine
(G) with cytosine (C).
Fig. 5. From left to right: Rosalind Franklin, James Watson, Francis Crick, and Maurice Wilkins
29
Fig. 6. Sodium deoxyribose nucleate from calf thymus, Structure B, Photo 51, taken by R. E. Franklin and R. G.
Gosling. L. Paulings holographic annotations are to the right of the photo. May 2, 1952.
The background was formed by several scientific breakthroughs: the progress

achieved by X-ray crystallographers in studying organic macromolecules; the growing
evidence supplied by geneticists that it was DNA, not protein, in chromosomes that was
responsible for heredity; Erwin Chargaffs experimental finding that there are equal
numbers of A and T bases, and of G and C bases in DNA [164]; and Linus Paulings
discovery that the molecules of some proteins have helical shapes [165], arrived at
through the use of atomic models and a keen knowledge of the possible disposition of
various atoms. In unmodified RNA, uridine (148) and cytidine (149) are found as
pyrimidine-containing building blocks, whereas, in DNA, 2'-deoxythymidine (150) and
2'-deoxycytidine (151) undergo the H-binding with the purines.
NH2
NH
HO
HO
H
N H O
H(CH3)
O
OH
N
OH
OH
A N H N U(T)
N
OH
N
O
149
148
Unmodified RNA building blocks
H
O H N
N
O
NH2
N
NH
HO
N
O
OH
N
HO
N
O
OH
150
151
Unmodified DNA building blocks
G N H N C
N
N
N H O
O
H
Watson-Crick Base Pairs
30
6.2. Pyrimidine Nucleoside Modifications Found in DNA and RNA

6.2.1. Pyrimidine Modifications Found in DNA. From sponges of the genus
Carteriospongia sp., 2'-deoxyuridine (152) could be isolated in 1999 [166]. 5Methylcytosine deoxyriboside (m5C; 153) [167] has been found in wheat germ,
whereas, from T-even bacteriophages, 5-(hydroxymethyl)cytosine deoxyriboside
(hm5C; 154) [168] could be isolated.
NH2
H3C
O
HO
N
N
O
NH
HO
OH
153
OH
NH2
152
HO
HO
Carteriospongia sp.
OH
154
Improved chemistry for the synthesis of oligonucleotides with modified base

residues at defined positions has allowed detailed studies of repair, replication,
transcription, and mutagenesis at specific lesions in vitro and in vivo.
Most of the oxidized base modifications show mutagenic and toxic effects. Recently,
a review summarizing the mutagenicity, toxicity, and repair of DNA base damage
induced by oxidation [169] was published.
5-Methylcytosine deoxyriboside (m5C; 153) is a minor (e.g., 5% of the cytosines in
human DNA are methylated [170]) but significant component in eukaryotic DNA residing
in CpG sequences throughout the genome [171]. Because enzymatic DNA methylation
is considered to play an important role in gene regulation including silencing of genes,
interference with m5C integrity may result in deregulation of genes in addition to
mutagenicity and cytotoxicity. The latency of several pathogenic viruses, e.g., Epstein
Barr, Herpes simplex, and HIV, is maintained by cytosine methylation, while oxidizing
conditions and UV light have been shown to induce viral reactivation [172].
Although m5C (153) is a cytosine analogue and deaminates like cytosine, it is similar
to thymine by exhibiting two targets of oxidative attack: the 5,6-double bond and the 5Me group. Two oxidative lesions specific for m5C (153) are caused by attack on the 5Me group. The 5-(hydroxymethyl)cytosine deoxyriboside (hm5C; 154) lesion has been
detected in different preparations of native DNA [173]. In addition, it has been shown
to be present in 1% yield in poly(dG-[ 3H]m5dC) [174], probably formed from 5[methyl-3H]methylcytosine by transmutation of 3H to 3He (b-decay) as previously shown
for the generation of hm5U from thymine in [methyl-3H]thymine-labeled DNA [175].
Little is known about the biological consequences of hm5C (154) in DNA, but a
mammalian DNA glycosylase activity removing this product has been reported [176].
It has been argued that conversion of the hydrophobic Me to the hydrophilic CH2OH
31
group may interfere with the binding of transcription factors to DNA thus causing
changes of gene expression. It may also interfere with the conservation of the
methylation pattern during replication. It has been estimated that ca. 20 m5C (153)
residues are oxidized to hm5C (154) per human cell per day [177]. However, the T-even
bacteriophages of E. coli have 2'-deoxycytidine (151) replaced with hm5C (154) [178],
arguing against hm5C (154) being cytotoxic or mutagenic.
6.2.2. Pyrimidine Modifications Found in RNA. Both the structural diversity and
extent of posttranscriptional modification in RNA is remarkable, with 96 different
nucleosides presently known in all types of RNA [179]. The largest number, 81, with
the greatest structural diversity, is found in tRNA, 30 in rRNA, 12 in mRNA, and 13 in
other RNA species, most notably snRNA. Based on lessons learned primarily from
tRNA, it is clear that many modification motifs and their sequence locations tend to be
conserved, although distinct differences among the three primary phylogenetic
domains are observed. The fewer number of modifications reported from the archaeal
RNAs, to a limited extent, reflects fewer investigations compared with bacteria and
eukarya. Extensive studies of tRNA [180] led to the discovery of new modified
nucleosides as well as increasing knowledge of the array of functional roles of
modification. RNA-Derived ribonucleosides of known structure, including those from
established sequence positions, as well as those detected or characterized from
hydrolysates of RNA, are collected in the RNA Modification Database [181];
therefore, this review only gives a brief overview over the naturally occurring
pyrimidine ribonucleosides.
In addition to the normal G, A, U, C residues, the high-molecular-mass rRNA
contain modified nucleosides. Generally spoken, the modifications can be distinguished
from cytidine- and uridine-derived analogues. They are mostly represented with
pseudo-uridine (y) and methylated (both at the base and the 2'-OH of ribose).
Furthermore, some oxidation and amination products thereof and sulfanylderivatives
can be found. Although some modification sites in rRNA are extremely conserved in
evolution, the number of modified residues in rRNA differs strongly in different
organisms and increases dramatically from eubacteria to multicellular eukaryotes. The
51 pyrimidine modifications, 155 205, found in all types of RNA are shown below. The
function of most of these modifications has not been investigated yet.
The earliest RNA-derived mutant which could be isolated was orotidine (206) from
a mutant of Neurospora crassa in 1905 [22]. Later, it was discovered that orotic acid
plays the key role in the de novo synthesis of pyrimidines described in Chapt. 4.
6.3. Naturally Occurring Pyrimidine O-Nucleosides
Vicine (209) appears to be the first simple pyrimidine derivative found to occur in
nature. It was discovered in 1870 in vetch seeds (Vicia sativa, Vicia faba L.) [182] by
Ritthausen [183]. He also discovered a similar substance, convicine (210) [184], in
vetch. However, it was not until 1896, after being able to separate a nitrogen-containing
base, divicine (207), which he believed to be a mixture of glucose and galactose, that
Ritthausen realized [185] that vicine (209) was a glycoside. While being unsuccessful in
elucidating the structures of vicine (209) and divicine (207), he isolated and identified
alloxantin (208) from acid hydrolysate of convicine (210), which, later, was confirmed
32

NH2
N
N
155
sC
mC
NH2
N
Rib
Rib
4
157
mC
OH
N
N
Rib
156
CH3
N
N
Rib
5
HN
Rib
2
H3C
CH3
NH
NH2
mC
158
hm5C
159
NH2
O
NH2 O
H
fC
CO2H
H
Rib
160
ac C
NH2
NH2
HN
CH3
161
N
H
HN
H
OH
Cytidine (149)
162
NH2 O
N
OH
Rib
k C (lysidine)
CH3
O
O
CH3
HO
(CH2)4
NH2
Rib
4
NH
CH3
HN
CH3
N
HO
N
R
Cm
163
R
m5Cm
164
m4Cm
165
f5Cm
N
R=
166
ac4Cm
167
OH
CH3
33
O
HN
HO
O
O
OH
OH
OH
206
Mutant of Neurospora crassa
34
NH2
H
N
NH2
HO
HN
OH
O
NH2
OH
207
NH2
OH
H
N
HO
OH O
O
H
OH
209
HO
208
Vicia faba L.
H
N
O
NH
OH
O
O
NH2
OH
OH
210
Vicia sativa
by Fischer and Johnson [186]. Only in 1953, the correct formulas of vicine (209) and its
aglucon, divicine (207), were established [187].
Isouramil (211) [188] can easily be prepared from commercially available
isobarbituric acid (212) by a nitrosation reaction to 213, followed by reduction to 211
with NaS2O4 (Scheme 28).
Scheme 28
Starting from 3,4-dihydro-2H-pyran (214), reaction with hydroxyacetonitrile gives

[(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]acetonitrile (215), which, upon condensation
with guanidine, yields the ester 216 (Scheme 29). Hydrolysis of 216 with H2SO4
provides divicine (207) [189].
Scheme 29
Vicine (209) and divicine (207) have been shown to cause favism, a metabolic
disorder due to deficiency of glucose-6-phosphate dehydrogenase (G6PD) and
glutathione (GSH). Favism seems to appear upon ingestion of fava (broad) bean,
which may lead to haemolytic crises. Recently, it was found that the content of the
35
antinutritional factors such as vicine and convicine present in vetch species influences
the fattening of rabbits (inclusion of 20% vetch seeds decreased the weight gain by
11% and increased the fat consumption by 7%) [190].
More than 120 years after the discovery of vicine (209) and convicine (210), a barabino nucleoside of divicine (207), called charine (217), could be isolated from
Momordica charantia L., a climbing vine, which is used in folk medicine for various
ailments [191]. Unripe fruits are mainly used for diabetes; the hypoglycemic properties
could be verified as well in animals as in humans [192]. In addition to this effect, it is
used for stomach aches, colds and fevers, rheumatism, gout, and the introduction of
abortion. In Ayurvedic medicine it has been described as stimulant, blood purifier,
laxative, and antihelmintic. Powdered fruit is also claimed to be useful in healing
wounds, leprous and malignant ulcers [192], whereas Turkish folk medicine uses the
fruits for the internal treatment of peptic ulcers. The anti-ulcerogenic effect could be
established scientifically [193].
HO
OHO
H
N
NH2
N
NH2
OH
217
Momordica charantia L.
6.4. Glycosylated Pyrimidine Antibiotics

6.4.1. Naturally Occurring Peptidyl Nucleoside Antibiotics. In yeast and fungi, chitin
serves as mechanical support and useful protective barrier for cell walls. Since chitin is
absent from vertebrates, inhibition of its biosynthesis has been considered as a safe and
largely selective therapeutic option. Formation of chitin and its deposition is a highly
complex and interconnected series of biochemical and biophysical events, and the last
step of this biosynthesis is governed by an enzyme called chitin synthase [194] or chitin
synthetase.
The best known and most effective inhibitors of chitin synthase, with marked
antifungal activities, are the naturally occurring polyoxins (218) and neopolyoxins
(nikkomycins; 219) [195]. As inhibitors of chitin synthetase, they exhibit antifungal
activity, but lack antibacterial activity. Since they also lack mammalian toxicity, they
represent potentially useful models for the development of effective agents for the
treatment of opportunistic fungal infections [196].
Direct clinical application of the natural peptidyl-nucleosides is compromised by
their attenuated in vivo activity, apparently due to their hydrolytic lability and
inefficient fungal-cell-wall permeability.
36

R1
R3
O
(S)
H2N
(S)
(S)
(S)
OH
CO2R2
O
N
H
NH2
(R)
(R)
N
(R)
(S)
HO
NH
O
Polyoxin H (218h) R1 = Me, R2 = X, R3 = OH

Polyoxin J (218j) R1 = Me, R2 = R3 = OH
Polyoxin K (218k) R1 = H, R2 = X, R3 = OH
Polyoxin L (218l) R1 = H, R2 = R3 = OH
O
COR2
H2N
N
(R)
(S)
(R)
(R)
HO
Polyoxin C (218c) R1 = HOCH2, R2 = OH

Polyoxin I (218i) R1 = HOCH2, R2 = X
NH
OH
CO2H
(S)
OH
NH2
N
H
U
(R)
(S)
(R)
(R)
HO
U=
N
O
=
(S)
(S)
OH
(S)
(S)
NH2
N
H
HO
HN
NH
O
O
(R)
(R)
CO2H
OH
COR2
CH3 O
NH
Nikkomycin A (219a)
R1
X=
CH3
(S)
(S)
(R)
(Z )
Polyoxin M (218m) R1 = H, R2 = OH
O
H2N
Polyoxin D (218d) R1 = CO2H, R2 = R3 = OH

Polyoxin E (218e) R1 = CO2H, R2 = OH, R 3 = H
Polyoxin F (218f) R1 = CO2H, R2 = X, R3 = OH
Polyoxin G (218g) R1 = HOCH2, R2 = OH, R3 = H
OH
(S)
Polyoxin A (218a) R1 = HOCH2, R2 = X, R3 = OH

Polyoxin B (218b) R1 = HOCH2, R2 = R3 = OH
B
(R)
(S)
HO2C
X=
(S)
CO2H
NH
OH
Streptomyces tendae
219bf
Nikkomycin B
(219b) R1 = 4-HO-C6H4, R2 = H, B = U
Nikkomycin J
(219c) R1 = 4-hydroxypyridin-2-yl, R2 = X, B = U
(219d) R1 = 4-hydroxypyridin-2-yl, R2 = X, B =
y
Nikkomycin pseudo-J (-J)
Nikkomycin Z
(219e) R1 = 4-hydroxypyridin-2-yl, R2 = H, B = U
Nikkomycin pseudo-Z (-Z)
y
(219f) R1 = 4-hydroxypyridin-2-yl, R2 = H, B =
Degradation inside the cell does not seem to be a problem, since polyoxins have
been shown to resist Candida peptidases [197]. Polyoxins (218) could be isolated from
culture broths of Streptomyces cacoi var. asoenis [198], whereas nikkomycins (219)
were found in Streptomyces tendae [199].
Opportunistic infections caused by various pathogenic fungi have progressively
increased and become a serious problem in chemotherapy. Therefore, currently a lot of
medical [200] and synthetic studies of polyoxins (218) [201] and nikkomycins (219)
[202] were initiated.
6.4.2. Naturally Occurring 4-Aminohexose Pyrimidine Nucleoside Antibiotics. The
antibiotics of this group possess a nucleoside structure and may be regarded as analogs
37
of the tRNA 3'-terminal adenosine. In addition, gougerotin and blasticidin S show the
presence of a structural motif traceable in chloramphenicol and lincomycin, namely, the
peptide group with the adjacent C(a)-atom. Antibiotics of this group affect bacterial
ribosomes, although some of them, such as gougerotin and blasticidin S, can inhibit
eukaryotic ribosomes as well. All these antibiotics bind to the 50S ribosomal subunit
and seemingly inhibit the interaction between acceptor substrates and the PTC of the
ribosome.
Gougerotin (220) [203], isolated by Kanzaki et al. [204] from Streptomyces
gougerotii, inhibits protein synthesis by preventing the transfer of amino acids from
amino acyl tRNA to polypeptide [205].
CH3
NH
O
HOCH2
O
O
H2N
N
H H
HO
NH
220
NH2
O
N
OH
O
Furthermore, this aminoacyl-nucleoside antibacterial antibiotic 220 has shown to be

an effective inhibitor of auxin-induced elongation and protein synthesis in Avena
coleoptiles [206]. It selectively inhibits the incorporation of amino acids into protein but
not the release of completed protein chains from ribosomes. In this way, inhibition by
gougerotin (220) allows a distinction to be drawn between these two stages of protein
[207]. Being an antibiotic inhibitor acting within the peptidyl transferase center, it also
was examined for its capacity to perturb the relative positioning of the 3'-terminal
adenosine of P/P'-site-bound tRNA and the peptidyl transferase loop region of 23S
rRNA in the ribosome [208]. Gougerotin (220) also inhibits the multiplication of
certain viruses [209]. The total synthesis of gougerotin ( 1-[4-deoxy-4-(sarcosyl-dseryl)amino-b-d-glucopyranosyluronamide]cytosine; 220) was described by Fox and
co-workers [210]. Starting from the nucleoside moiety [211], 1-[4-amino-4-deoxy-b-dglucopyranosyluronic acid)]cytosine (221), first the d-serine side chain was introduced
to give 222, and finally the sarcosine chain was coupled to obtain 223, which, after
deprotection, yielded 220 (Scheme 30).
Amicetin (224) and the related compounds, bamicetin (225), oxamicetin (226), and
plicacetin (227), act as inhibitors of peptidyl transferase B, the peptidyl transferase
center on the larger subunit [212]. These ribosomal peptidyl transferase inhibitors are
antagonized by EF-G (but not EF-Tu ) with GTP [213]. Furthermore, amicetin (224)
shows significant protection of HeLa cell monolayers infected with Herpes simplex
virus type 1 [214]. Amicetin (224) is produced by Streptomyces vinaceusdrappus and by
S. fascicularis [215]. Oxamicetin (226), isolated from Arthrobacter oxamicetus [216],
was shown to be somewhat more active against Gram-negative bacteria, but less active
against Gram-positive and acid-fast bacteria. With respect to the transpeptidation step,
the inhibitory patterns of these antibiotics are similar enough as to suggest competition
for the same sites within the ribosomal peptidyl transferase, conceivably associated
38

Scheme 30
O
NH
O
HOCH2
N
CH3 H
N
O
CH3
N
CH3
OH
O
R
N
CH3 H
HOCH2
N
H3C
NH
H2N
CH3
OH
NH
H2N
OH
Amicetin (224) R = Me
Bamicetin (225) R = H
N
H3C
N
O
CH3
OH
H2N
N
O
CH3
CH3
O
OH
O
CH3 OH
Oxamicetin (226)
N
O
O
O
N
H3C
CH3 OH
Plicacetin (227)
with the aminoacyl as well as the cytosine recognition regions for the CCA-amino acid
terminus of native tRNAs.
In amicetin (224) and related structures, amicetose ( 2,3,6-trideoxy-d-erythrohexose) is linked to the amosamine moiety, resulting in a disaccharide. Also these
antibiotics show cytosine as the pyrimidine base and an amino acid (2-methylserine)
side chain. After the structure had been established in the 1950s [217], a lot of effort has
been invested for the enatioselective synthesis of these antibiotics [218].
6.4.3. Antibiotics of the Blasticidin S Type. Blasticidin S (228) is an antibiotic
produced by Streptomyces griseochromogenes and has been used extensively as an
excellent fungicide against Pyricularia oryza (rice blast). Blasticidin S blocks the
protein biosynthesis in as well eukaryotic as prokaryotic cells [219].
Blasticidin S (228) was first isolated in 1958 by Takeuchi et al. [220]. Its structure
consists of two parts, cytosinine [221] and l-blastidic acid [222]. By incorporation of
isotopically labeled compounds, the primary precursors of the biosynthesis have been
identified as cytosine, d-glucose, l-arginine, and methionine [223]. One of the enzymes
39
NH 2
N
CO2H
NH
H2N
NH2 O
NH
CH3
228
Pyricularia oryzae
neutralizing the action of this antibiotic is blasticidin deaminase, isolated from Bacillus
cereus. The gene coding of blasticidin deaminase can be used to construct retroviral
vectors [224]. The total synthesis of blasticidin S (228) starts from l-a,g-diaminobutanoic acid (A2bu) (Scheme 31). First, a tert-butoxycarbonylation of Ng-[(benzyloxy)carbonyl]-A2bu, derived from a copper complex, was carried out (! 229). Chain
elongation leading to protected b-ornithine 230 could be effected by an Arndt Eistert
reaction. The ester 230 obtained was saponified to give the corresponding carboxylic
acid 231, which was then hydrogenated with a Pd/C catalyst to 232, removing the
(benzyloxy)carbonyl group. After tosylation of the w-amino group (! 233), Nmethylation to 234 was carried out. After removal of the Boc protection group, a Cu
complex of the resulting b,w-diamino acid 234, allowing the selective modification of
the w-amino group with O-methylisourea, blastidic acid (235) was obtained.
Scheme 31
a) ClCO2Et, N-methylmorpholine, AcOEt, 158. b) CH2N2 , AcOEt/Et2O, 158. c) PhCO2Ag, MeOH, 08.
d) 2m NaOH. e) H2 , 5% Pd/C, MeOH. f) TsCl, 1m NaOH. g) MeI, 2m MeOH, dioxane. h) 25% HBr, 1108.
i) CuCO3 Cu(OH)2 , H2O. j) O-Methylisourea, 1m NaOH. k) H2S, 6m HCl.
Cytosinine has the structure of a 2,3-dideoxy-4-aminohex-2-enopyranoside. A new

approach successfully employs a [3,3]-sigmatropic rearrangement of allyl cyanate 237
to isocanate 238 for the construction of the unsaturated amino sugar moiety 239 of
protected cytosinine (236) [225] (Scheme 32).
40

Scheme 32
a) 4-Methoxyphenol, BF 3 Et2O, benzene. b) LiAlH4 , THF. c) (t-Bu)Me2SiCl, 4-(dimethylamino)pyridine

(DMAP), Et3N, CH2Cl2 . d) Cl3CCONCO, CH2Cl2 . e) K2CO3 , MeOH/H2O. f) Ph3P, CBr4 , Et3N, CH2Cl2 . g)
Cl3CCH2OH. h) Bu4NF, AcOH, THF. i) Swern oxidation. j) NaClO2 , NaH2PO4 , t-BuOH/H2O. k) CH2N2 ,
MeOH. l) Silver(II) bis(hydrogen dipicolinate), MeCN, H2O. m) Ac2O, pyridine. n) Silylated N4-[4-(tertbutyl)benzoyl]cytosine, TMSOTf, CH2Cl2 (a/b 1 : 1). o) Zn, AcOH. p) Ac2O, pyridine. q) Separation.
6.4.4. C-Nucleoside Antibiotics. Ezomycins (240) are a group of antifungal

antibiotics produced by a Streptomyces sp., and they are active against certain
phytopathogenic fungi such as Sclerotinia sclerotiorum de Bery, which causes stem rot
of French bean (Phaseolus vulgaris L.) and Botritius. The compounds have been
isolated and characterized by Sakata et al. in 1974 [226].
Ezomyzins A1 , B1 , and C1 (240a, 240c, and 240e, resp.), which contain the lcystathionine component, show antifungal activities (240c is the most active), whereas
ezomycins A2 , B2 , C2 , and D2 (240b, 240d, 240f, and 240h, resp.), which lack this
pseudopeptide, are probably artifacts, derived by partial hydrolysis and rearrangement
[227]. Some members (B, C, D series) bear a C(5)-glycosylated pseudo-uracil rather
than the more usual N(1)-linked pyrimidine nucleoside base. A notable feature of these
compounds is the anhydrooctose unit in place of the usual ribose in nucleosides. A
related anhydrooctose is present in the octosyl acids, i.e., octosyl acid A (241), isolated
from Streptomyces cacaoi var. asoenis [228].
The complete synthesis of an ezomycin C-nucleoside, even lacking the cystathionine residue as in B2 (240d) poses several difficulties (for reviews, see [229]). A number
of synthetic routes to the ezoaminuronic acid moiety have appeared [230], and several
groups [231] have synthesized octosyl nucleosides that resemble the ezomycin
components 240.
H
N
O
CO2H
OH
41
OH
241
6.4.5. Spongothymine and Spongouridine. From a Caribbean sponge, Cryptotethia

crypta, and later from the acorn worm Ptychodera flava [232], two arabinonucleosides,
spongothymidine (ara-T; 242) [233] and spongouridine (ara-U; 243) [234], could be
isolated.
O
O
NH
HO
HO N
O
OH
NH
HO
HO N
O
OH
242
243
They have been shown to be the 1-b-d-arabinofuranosides of thymine (11) and

uracil (13), respectively. The first synthesis of 242 was described by Fox et al. [235].
Ara-U (243) is devoid of antiviral activity, whereas ara-T (242) inhibits the replication
of some DNA viruses (HSV-1, HSV-2, varicella-zoster, vaccinia, and pseudo arabies)
42
but not CMV or RNA viruses in cell culture [236]. Ara-T (242) is highly effective
against HSV-1 and -2 at non-cytotoxic concentrations [237], being a substrate for HSV1-induced pyrimidine kinase, but neither for the kinases of the host cell nor for HSV
mutants, which lack the ability to induce deoxypyrimidine kinase [238]. Furthermore, it
inhibits the phosphorylation of thymidine and deoxycytidine by cell-free extracts
prepared from HSV-1-infected cultures, but not by extracts prepared from non-infected
cells or cells infected with HSV TK-mutants [238]. Ara-T (242) is cytotoxic for L cells
but not TK cells [238], both viral DNA and host-cell DNA synthesis is inhibited in
HSV-1-infected cultures, but DNA synthesis is not appreaciably affected in infected
cells [238]. Ara-T (242) also inhibits equine Herpes virus type I in cell culture but not
TK-mutants of the same virus [239]. These data are consistent with the observation that
242 is inhibitory for those Herpes viruses, which induce thymidine kinase after infection,
i.e., HSV types I and II [240], varizella-zoster virus [241], equine Herpes virus type I
[239], vaccinia virus [242], but not CMV [243]. Furthermore, ara-T (242) triphosphate
inhibits the DNA polymerase-a to a greater extent than DNA polymerase-b, the
inhibition is competitive with respect to dTTP [244]. These promising results in
antiviral research led to the development of analogue compounds, i.e., zidovudine
(AZT; 2), ara-C, or d4T [3], being powerful drugs in the fight against viral infections.
6.5. Pyrimidine Diphosphate Derivatives
The information that regulates the way in which cells recognize and respond to their
neighbors resides in the area of contact between cells, in particular, in the molecular
structures present at their surface. Complex carbohydrates are the major components
of the cell-surface recognition processes [245]. Glycosyltransferases are the enzymes
essential for the biosynthesis of complex N-linked oligosaccharides [246]. Several
mammalian glycosyltransferases have been purified to apparent homogeneity [247],
largely due to the use of specific affinity absorbants mostly nucleoside diphosphates,
linked to a support matrix by a linker arm attached through the 5'-pyrophosphate group
of the ribose moiety [248]. Uridine-diphosphate-glucose (244), the coenzyme of
galactowaldenase, was isolated and studied chemically by Leloir and co-workers [249].
Its structure has been confirmed by synthesis from uridine-5'-diphosphate and a-dglucose-1-phosphate [250]. Other uridine-diphosphate sugar components also occur in
nature, for example, uridine-diphosphate-galactose (245) [251], uridine-diphosphateacetylglucosamine (246) [252], uridine-diphosphate-glucuronic acid (247) [253],
uridine-diphosphate-acetylglucosaminuronic acid (248), and more complex derivatives
of the latter containing amino acid and polypeptide residues attached presumably to
the uronic acid residues [254]. Nowadays, the pyrimidine diphosphate derivatives are
mostly prepared enzymatically [255].
Pyrimidine represents a unique basic heterocyclic system with respect to its
chemodiversity. The large biodiversity of particularly tropical marine organisms or
plants provides a huge resource to extend the chemodiversity of pyrimidine derivatives
and to find new lead structures for medicinal chemistry.
The number of publications on pyrimidines is endless. I apologize to all colleagues
who have made important contributions to the matter of this article, and whose work is
not cited here.

O
HO
O
OH
OH
O P O P O
OH
OH
HO
OH
NH
O
OH
OH
O
OH
OH
OH
OH
OH
CH3
OH
NH
OH
O
OH
O
O
NH
O P O P O
NH
OH
HOOC
O
OH
O
N
O
245
HO
O
OH
OH
244
OH
NH
O P O P O
OH
43
O P O P O
OH
OH
OH
OH
OH
O
OH
247
246
O
HOOC
O
OH
OH
NH
O P O P O
O
NH
OH
CH3
248
OH
O
OH
OH
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Received June 17, 2004

Pyrimidine As Consituent of Naturally Bioactive Compounds

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CHEMISTRY & BIODIVERSITY Vol.

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Due to long-lasting interest in pyrimidine derivatives as potential drugs, the

2. The Nucleic Bases

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

2.1. General Aspects of the Chemical Pyrimidine Syntheses

Fig. 2. Types of pyrimidine synthesis

The required aminomethylidene intermediate 17 may be obtained from the

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

3. The Prebiotic Synthesis of Pyrimidines

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Starting from diaminofumaronitrile (31), formation of 5-hydroxyuracil (32) [60]

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

4. Biosynthesis and Catabolism of Pyrimidines

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

orotidine 5'-monophosphate (OMP) decarboxylase (EC 4.1.1.23). Inhibitors of the

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Fig. 3. Albizzia julibrissin

dehydropyrimidinase (EC 3.5.2.2). b-Ureidopropionase releases NH3 and CO2 to give

5. The Unglycosylated Pyrimidine in Natural Products

5.1. Pyrimidine-Containing Amino Acids

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

The extracts of L. tingitanus appeared to contain the highest concentration of this

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

In the first pathway, 2-aminopyrimidine-4-carboxylic acid (53), which was earlier

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

5.3.3. The Bleomycin Glycopeptides. Bleomycin (75) and related glycopeptides

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Bleomycin Derivatives found in nature:

Fig. 4. Coordination of M (Cu2, Fe2 ) and O2 by bleomycin (75)

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Heteromine F (77a) R = Me2N

5.4.2. Alkaloids from Crambe crambe. From a Mediterranean sponge, some

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

bromopyrrole-containing derivatives manzacidin A C (86a 86c, resp.) were isolated

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

a) ClSO2NCO, HCO2H (3 : 1 mixture of C(6)-epimers). b) 2 mol-% Rh2(OAc)4 , PhI(OAc)2 , MgO, CH2Cl2 . c)

dropyrimidine 92 without attendant epimerization at C(4). After deprotection to 93,

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

iodocyclization with IBr in CH2Cl2 , to give the corresponding tetrahydropyrimidine

Attempts at the conversion of the iodide by displacement with benzoate as model

5.4.4. Variolin-Type Alkaloids. Certain secondary metabolites of marine organisms

Variolin B (101b) Variolin D (101c)

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

a) PhCH(Me)NCO, THF, r.t. b) Br2 , pyridine, 08. c) (2-Ethoxyvinyl)trimethyltin, DMF, PdCl2(PPh3 )2 .

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Their structures can be described as a brominated and/or hydroxylated indole

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Psammopemma sp. (sand sponge)

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Glycosmis pentaphylla Correa

Glycosmis arborea Correa

Tunicate Pyura sacciformis

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

Dichroa febrifuga is an ingredient in a traditional Chinese herbal effective against

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

5.5. Pyrimidine-Containing Toxins

CHEMISTRY & BIODIVERSITY Vol. 2 (2005)

by inhibiting biosynthesis of cell-reduced glutathione [156] and also by inhibition of

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