Drug Discovery from Natural Sources

Drug Discovery & Development (Ch 12 and 13)
Sources of biologically active compounds as drugs/drug leads

from natural sources (~50%) and from synthesis (~50%)
Up to 70% of all drugs are natural product derived or natural
product mimics
See DJ Newman, GM Cragg, Natural Products a Continuing
Source of Novel Drug Leads, Biochimica et Biophysica Acta -
General Subjects, 2013, 1830, 3670-3695.
DJ Newman, GM Cragg, J Nat Prod, 2016.
DOI: 10.1021/acs.jnatprod.5b01055
No 1
Drug Discovery and Development
Drugs from natural sources - plants, animals, insects,

microorganisms
Plants
major natural product source of drugs
the plant kingdom consists of 250,000-500,000 different species
only a small percentage have been screened for biological
activity
potential for a large number of compounds with desirable
biological activities
bioprospecting (looking for chemicals from nature) of plants now
big business
No 2
Drug Discovery and Development
Plants
pharmacognosy - the study of medicines from natural
sources
plants (and other living systems) have developed defense
strategies to ward off predators and pathogens. This
includes production of secondary metabolites as chemical
warfare
alkaloids are the most common type of drugs produced by
plants
for the importance of alkaloids in drug discovery see G. Cordell, M.
Quinn-Beattie, N. Farnsworth, Phytotherapy Research, 2001, 15, 183-
205, The Potential of Alkaloids in Drug Discovery
No 3
Drugs from plants - alkaloids
The name alkaloid comes from the concept of a compound being

alkali-like, i.e. basic in character, and containing at least one
nitrogen atom
definition of an alkaloid varies but commonly referred to as basic
heterocyclic amine-containing organic compounds derived from
amino acids
generally complex in structure and biologically active and
commonly found in plants
different alkaloids may be produced in different parts of plants,
e.g. roots, leaves seeds, etc
alkaloids are typically poorly soluble in water and their water
solutions are alkaline
e.g. R3N + H2O R3NH+ + HO
No 4
Alkaloids typically react with mineral acids (HCl, H2SO4,

HNO3, etc.) to form salts that are generally very water
soluble
R3N + H2SO4 R3NH+ + HSO4
*This definition suits most but not all alkaloids (see

Cordell journal article noted on earlier slide)
No 5
Alkaloids in brief
alkaloids often discovered following Culvenor-Fitzgerald

procedure (Mayers test) on crude natural product - very
sensitive test
ground fresh plant CH2Cl2/NH3 dil. H2SO4
CH2Cl2 extract N
material ca. 5 g
H K2HgI4 H
+N precipitate ? +N
HSO4- 2 HgI42-
Mayer's reagent
aqueous extract
No 6
Drugs from plants alkaloids
HO
morphine
O
NCH3
HO
obtained from Papaver somniferum - opium

~10% of opium, codeine 1-2%
narcotic analgesics (pain relief)
codeine in cough syrups (antitussive agent) (ArOH ->
ArOMe)
heroin (diamorphine, OHs -> OAc)
No 7
reserpine
N
MeO N
H H H
O
H
MeO OMe
O
O OMe
OMe
OMe
from root of Rauwolfia serpentina (snake root)

isolated by Ciba Pharmaceutical Company following reports
of traditional use of root for calming effect
found (-)-reserpine had tranquilising properties
No 8
atropine and scopolamine

CH3 CH3
N N
H H
O
O O
O O
OH OH
H H
Atropine Scopolamine
obtained from atropa belladona and related plants

berries squeezed into eyes to dilate pupils
used to poison - poison if taken orally
involved in control of smooth muscle - atropine in cold
remedies, eye droplets; scopolamine in travel sickness pills
No 9
Other drugs from plants
many other drugs produced by plants. These include cardiac

glycosides (steroidal sugars) such as digoxin; paclitaxel
(taxol) and camptothecin (anticancer); artemisinin
(antimalarial) CH3
H
O O
H3C
O H
HO H
CH3
O
Artemisinin
No 10
Drugs from animals
Steroids - lipid soluble substances that contain a tetracyclic

ring system comprised of 1 cyclopentane and 3 cyclohexane
rings
typical steroids:
O O CH2OH O CH2OH
O OH HO OH
O O O HO
Progesterone Cortisone Hydrocortisone Cholesterol
No 11
Drugs from animals - steroids
cortisone and hydrocortisone (cortisol) known as

corticosteroids
anti-inflammatory and anti-allergenic properties and act as
immunosupressants
used to treat skin irritations (e.g. herpes), inflammatory and
rheumatoid diseases and allergies
hydrocortisone can be bought as over-the-counter (OTC)
cream and ointment
hydrocortisone was first obtained from beef adrenal glands
(atop the kidneys): 1000 pounds of glands gave 13 mg of
hydrocortisone at a cost of $200/gram. Today
hydrocortisone costs ~$2.00/gram.
No 12
Drugs from animals - steroids
Prednisolone (right) is also a corticosteroid
Similar to hydrocortisone (cortisol, right)
Used to treat a wide variety of anti-inflammatory and

autoimmune conditions
Like many steroids highly effective in small doses and
various side effects
No 13
Drugs from animals - peptide hormones and

vitamins
Peptide hormones, such as insulin and other polypeptides

may also be obtained from animals
Approximately 1 pound of insulin can be obtained from
80,000 pounds of beef (bovine) and pig (porcine) pancreas.
Fat soluble vitamins A and D can be obtained from fish liver
oil. These vitamins play a role in night vision and bone
development, respectively
No 14
Drugs from microorganisms
several pharmaceutical firms screen microorganisms

(especially soil microbes) such as fungi, moulds and bacteria
fungi, moulds and some bacteria produce antibiotics
why?
No 15
when appropriate microorganisms are identified, they are

grown on a large scale in fermentation vats
the resultant "soup" is worked up to yield the desired pure
antibiotic
penicillins, cephalosporins, monobactams, aminoglycoside
antibiotics, e.g. streptomycin and gentamycin, erythromycin,
tetracyclines, cycloserine, and chloramphenicol have been
obtained from these fermentations
No 16
microbial drugs have also been useful outside of the area of

antibacterials
e.g. the fungal metabolites known as cyclosporins are used to
suppress the immune response during transplant operations
and the fungal metabolite lovastatin is the lead compound
HO O
for cholesterol lowering drugs (statins)
O
O
Beekman AM, Barrow RA, Aust J Chem, H
H3C O
2014, 67, 827-843 CH3 H H
CH3
H3C
Lovastatin
No 17
bacteria can be used to produce polypeptide drugs by

recombinant DNA technology
circular extrachromosomal bacterial DNA called plasmids that
replicate independently, are isolated from bacteria, e.g. E. coli
restriction endonucleases are used to cut the bacterial plasmid
DNA and the DNA that codes for the desired polypeptide drug
and the two DNA's are mixed and joined using a DNA ligase
=> recombinant DNA
No 18
the recombinant DNA is inserted into a plasmid-free strain of

E. coli and the bacteria are allowed to multiply, express the
human DNA, and produce the desired polypeptide
The fermentation mixture is subsequently worked up and the
polypeptide obtained and purified
No 19
Recombinant DNA technology
No 20
Recombinant DNA technology
the first drug product of recombinant DNA technology was

human insulin (Humulin, Eli-Lilly)
previously cow and hog pancreas used for insulin
other products of this technology include growth hormone for
dwarfism, -interferon for leukemia and Kaposi's sarcoma, -
interferon for multiple sclerosis, tissue plasminogen activator
to dissolve blood clots in myocardial infarction, blood factor
VIII:C for haemophilia, and erythropoietin for anaemia
Recombinant DNA products are always polypeptides
No 21
Drug sources from insects and other creepy

crawlies
insects have greater species diversity than any other creatures

and most have chemical defense and communication
mechanisms
insects and other creepy crawlies (spiders, scorpions
millipedes, etc) have been poorly investigated as drugs
some of these organisms have been used in traditional
medicine, for example China has used extracts from insects
for 1000s of years to treat a range of ailments including
infections, inflammation and stomach aches
No 22
Drug sources from insects and other creepy
crawlies
Insects produce a wide range of proteins and peptides as a first

fast defense line against pathogen infection
These agents act in different ways including insect immune
system activation
Some of insect peptides are very promising in treating of
serious human diseases like human immunodeficiency virus
(HIV), herpes simplex virus (HSV) or leukemia
See A.T. Dossey, Insects and their chemical weaponry: New

potential for drug discovery, Natural Product Reports, 2010,
27, 17371757, http://www.allthingsbugs.com/NPR_2012.pdf
No 23
Drug sources from marine natural products
the marine environment provides a wealth of molecules with

diverse structures not seen on land
the study of marine organisms, particularly their chemical
interaction with their environment (chemical ecology) has led
to the isolation of novel compounds that have medicinal use
includes powerful antibacterial and anticancer agents
R Montaser, H Luesch, Marine natural products: a new wave of

drugs? Future Med Chem, 2011, 1475-89.
doi: 10.4155/fmc.11.118.
No 24
Venoms and toxins as drugs
much research is now focussing on venoms/toxins as drug

leads
venoms are highly potent biologically active chemicals,
consisting of proteins, peptides and small molecules that act
for example as neurotoxins, enzymes, enzyme inhibitors and
inflammatory agents
venoms block transmissions of nerve impulses to muscles and
can cause paralysis and respiratory failure. They can also
prevent blood clotting
No 25
Venoms and toxins as drugs

Ancrod (viprinex), produced by the
Malaysian pit viper (Agkistroden rhodostom)
is an inhibitor of serine protease, and
prevents blood clotting clinical trials show
highly effective as an anti-coagulant for
treatment of stroke victims
Conotoxins are neurotoxic peptides from
marine cone snails include conotoxin
MVIIA (also known as Ziconotide or Prialt)
used for the treatment of severe and chronic
pain. Many conotoxins modulate the activity
of ion channels. Several other conotoxins
have entered clinical trials
No 26
Some strategies for targeting natural products
random screening (or partly random screening) of a large

number of extracts (generally plants) for biological activity
- relatively quick due to development of high throughput
screens
- e.g. National Cancer Institute screens isolated taxol
(paclitaxel) and camptothecin (albeit from 35,000 plants)
O
O O OH
O
O NH O
N
N
O O
H
O
OH HO O
O
O
Camptothecin
Paclitaxel
No 27
Some strategies for targeting natural products
look at toxicity reports (drugs are poisons)

e.g. curare from Chondrodendron tomentosum used for
paralysing animals during hunting - led to isolation of (+)-
tubocurarine, a skeletal muscle relaxant (neuromuscular
blocking agent), used in surgery
O OMe
Me Me
OH
N
H H
O N
Me H
MeO OH
No 28
Chemotaxonomic relationships
focuses study on a particular family or genera known to have

bioactive compounds
allows the logical selection of plants that are predicted to
contain a certain class of biologically active compounds
e.g. the family Compositae has been targeted for further
research as it is known to commonly produce sesquiterpene
lactones, a class of compounds that have shown potent
anticancer activity
active alkaloids are particularly concentrated in some plant
families, eg Rubiaceae, Solanaceae, Leguminosae,
Raunuculaceae, Berberidaceae, Papaveraceae
No 29
Biorational approach
by observing the interactions between species in the

environment, it is possible to deduce that one may contain
bioactive compounds present as a method for survival or
communication
marine organisms a particular focus of this approach
No 30
Biorational approach
e.g. antibacterial cyclic peptides from skin secretions from

frogs (e.g. Australian frog Litoria splendida)
No 31
antibacterial agents from molluscan egg masses (marine)

certain egg masses (fragile) in intertidal regions did not become
diseased or fouled despite being in the presence of marine
bacteria
surmised contained chemical defence
from egg mass of Dicathais orbita isolated antibacterial agents
inc. tyriverdin - more potent than penicillins - good drug lead
O
H Br
SMe N
tyriverdin
Br N SMe
H
O
No 32
Ethnopharmacological approach
uses traditional knowledge systems of indigenous cultures
around the world
over 80% of all known plant natural product based drugs are
derived from an ethnomedical use (known use by humans)
over a period of centuries indigenous peoples have identified,
largely by a process of trial and error, plants that are effective
in the treatment of various diseases
those plants that are still in use have proven to be effective and
have been 'filtered out' from those that were considered
ineffective
No 33
Aspirin
Willow bark has been used throughout

the centuries in China and Europe as a
medicine
Hippocrates wrote in 5th century BC
about a bitter powder extracted from
willow bark that could ease aches and
pains and reduce fevers
The study of this bark led to the
development of aspirin
No 34
Antimalarial Agent Artemisinin (qinghaosu)
Artemisinin (qinghaosu) - isolated from the

herb Artemisia annua
Used for more than 2000 years as a herbal
tea against fever and chills
Me
Potent antimalarial agent - treatments
containing artemisinin derivatives O
Me
(artemisinin-combination therapies, ACTs) O
O
are now the standard treatment worldwide
O
for Plasmodium falciparum (malaria) Me
Artemisinin O
No 35
Australian Aboriginal Medicinal Plants
Australian Aboriginal people have used plants as medicines for

thousands of years
one example of the value of the Australian Aboriginal traditional
knowledge comes from the study of the freshwater mangrove
Barrintonia acutangula for its analgesic properties
Aboriginal people in the Kimberley chew the bark to form a paste that
is applied to small wounds
its study lead to the isolation of potent medicinal compounds in current
clinical trials for pain treatment, includes with potent analgesic
properties
See book chapter on ilearn
No 36
Drugs from synthesis Ch 13
new synthetic drugs are generally obtained via:

i) modification of lead compounds
ii) development of drug from first principle
they may also be from combinatorial libraries or diversity

oriented synthesis and undergo random/selected biological
screening
No 37
Drugs from synthesis

lead compound is one that shows useful pharmaceutical
activity
- level of activity may be low
- may be undesirable side effects
BUT the lead compound provides a start
No 38

search for new leads becomes much easier if have good
biological model for the disease of interest
if the biological screen is fast to carry out, relatively
inexpensive, reasonably good indication of clinical usefulness
=> testing of large compounds feasible
accurate models for the clinic are usually slow and expensive
(not primary screen)
fast cheap model -> not particularly accurate -> useful as
primary screen
No 39
ii) development of drugs from first principles

i.e., from a knowledge of the biochemistry and physiology of
the process to be affected by that drug => rational drug
design
No 40
ii) development of drugs from first principles

involves 1) identifying a need (this is always the beginning of
any project aimed at development of new drugs); 2) studying
the biochemistry and physiology of the problem and
identifying a target for the drug; 3) designing, making and
testing a prototype drug; 4) modifying the structure of the
prototype drug to obtain the optimum drug (most active, least
toxic)
Note the prototype drug becomes a lead compound
No 41
Once we have a lead structure - then what? (Ch 13)
try to determine which parts of the molecule are important for

the activity and which are not
- requires obtaining a selected number of compounds that vary
slightly from the lead compound and study what effect this has
on biological activity
=> Structure-Activity Relationship (SAR)
particularly valuable if we know nothing/little about the
structure of the active/binding site of the target receptor
can use SARs to design better drugs
No 42
Structure-Activity Relationships of Glipine
OH
OH
N
CH3
variety of groups potentially involved in binding to target

receptor
No 43
Structure-Activity Relationships
unlikely that all interactions that are possible actually take

place - must identify those that do by altering/removing one
particular group of the molecule
binding role of OH (alcohols and phenols)
OH group may be involved in H-bonding via H/O
receptor
O
receptor
H H H O
O O
Drug Drug
No 44
H-bonding importance
converting the OH to a methyl ether/ester (relatively

straightforward) will destroy/weaken H-bonding
Conditions for forming ether/ester?
H H3C
O O
Drug Drug
O
H
O H3C O
Drug Drug
No 45
Ethers:
receptor
O
receptor
H3C
O
CH3 H O
O
Drug
Drug
No 46
An ester (acetylated derivative) also disrupts H-bonding, but if

O of OH is involved in bonding it is even more disruptive than
the methyl ether case
Why?
receptor
O
H O
O CH3
Drug
No 47
Why is ester formation so disruptive?
No 48
thus if see a decrease in activity due to conversion of OH to

OCH3 or OCOCH3 suggests OH involved in H-bonding
if still in doubt can replace OH with CH3
CH3 is isosteric with OH (same valence electrons) => similar
size but large difference in polarity (problem not always easy
to synthesise)
No 49
OR can convert OH to H
O
H3C S Cl
O
O LiAlH4
R OH R O S CH3 R H
O
tedious as this affects many functional groups and these

groups may need to be protected
No 50
Binding role of amino group
amino groups (1o, 2o or 3o) can be involved in H-bonding or

ionic bonding (via protonated form)
in neutral form can act as H-bond donor and H-bond acceptor
BUT in protonated form can not act as H-bond acceptor
ionic bonding more common
similarly to OH, commonly convert to amide effectively
prevents (or diminishes) N lone pair taking part in H-bonding
and can not form protonated species for ionic bonding
No 51

Why convert to amide?
receptor
O
H O
N CH3
Drug
No 52
Why convert to amide?
No 53
for 3o amines must dealkylate first then form amide

e.g.
R R R
CNBr CH3COCl
N CH3 N H N COCH3
R R R
Can also use VOC-Cl (vinyloxycarbonyl chloride)
No 54
Binding role of aromatic rings
aromatic rings are commonly involved in van der Waals

interactions with flat hydrophobic regions of the binding site
of target receptor
e.g.
No 55
if the ring is hydrogenated to (or replaced with) a

cylclohexane ring, the structure is no longer flat and will
interact far less efficiently with the binding site
a decrease in activity upon hydrogenation suggests aromatic

group involved in binding
No 56
problem - aromatic groups are difficult to reduce as need

severe conditions and may affect other groups
alternative - can replace ring altogether with bulky alkyl
group, but this may be a major synthetic challenge
No 57
Binding role of double bonds
double bonds (like aromatic rings) due to being planar, bind to

flat hydrophobic regions of the binding site
No 58
Binding role of double bonds
double bonds can be readily reduced to

alkyl group, which are more bulky
if original double bond involved in van der
Waals interactions with flat surface, upon
reduction, the bulkier alkyl will have much
less interaction
therefore a decrease in activity upon
reduction would suggest double bond
involved in hydrophobic interactions
No 59
Binding role of ketones
ketones are commonly found in

drugs
can interact with protein target
through H-bonding or dipole-
dipole interactions
reduction to the alcohol allows
determination of binding role
No 60
Binding role of amides
amides can interact with protein targets via H-bonding

hydrolysis or reduction of the amide allows binding
importance to be examined
See textbook for further discussion of binding roles

No 61
Lead modifications (Ch 13)
once the importance of structural groups for activity are

established, look at synthesis of analogues (structural
modifications) to typically
increase biological activity
reduce side effects
provide easy and efficient administration to patients
No 62
Lead modifications
synthesis of analogues used to be purely random, now various

strategies for structural modifications
include:
variation of substituents
extension of structure
chain extension/contractions
ring expansions/contractions
ring variations
isosteres
simplification of structure
rigidification of structure (conformation restriction)
No 63
Variation of substituents
once the essential groups for activity are determined the

substituents can be varied at that site
common variations used are generally those that are easy to
synthesise
aim of variations is to fine tune molecule to optimise activity
one substituent should be varied at a time
even such minimal variation may change more than one
physical factor
No 64
Variation of substituents - alkyl substituents
if molecule contains OH (phenol/alcohol) or NH or ester or

amide can add alkyl groups of varying length and steric bulk
(can do this without OH, etc, but may be synthetically more
challenging)
e.g. methyl, ethyl, iso-propyl, tert-butyl
allows examination of steric effect
No 65
Variation of substituents
No 66
CBMS306/842
When would such a change be unwise to OH/NH group?
No 67
note for amines varying alkyl groups on N atom may alter

basicity and/lipophilicity
this can affect how strongly a drug binds to the binding site
and how easily it crosses membrane barriers
No 68
variation of alkyl substituents may allow probing of the size of

a hydrophobic pocket
e.g.
No 69
May also allow greater selectivity

e.g.
+
H too
+ N big
H
N
hydrophobic +H
binding site ionic binding site +
N H
hydrophobic N
binding site ionic binding site
receptor 1 receptor 2
+
H selectivity for receptor 1
N less side effects than smaller molecule
No 70
Aromatic substituents
can vary substitution pattern on the ring

this may increase activity if the relevant binding groups are
not already in the ideal positions for binding
e.g.
No 71
electronic effects may also be important

e.g. basicity of amines depends on location of electron
withdrawing and electron donating groups
electron withdrawing/donating groups if para will affect
basicity of aromatic amines more than if meta
due to para position having contribution of resonance and
inductive effects and meta only inductive effects
No 72
e.g.
No 73
once the best site for aromatic substitution is determined can

then vary substituents themselves to alter steric and electronic
effects
e.g.
COOH COOH
H3C Cl
H H
NH2 NH2
N N
H H
Poor inhibitor of IDO Good inhibitor of IDO
No 74
Extension of Structure
often a biologically active molecule binds to some of the

binding sites but does not bind to all potential binding sites
extension of structure may optimise all binding sites to give a
better drug (e.g. enzyme inhibitor or receptor agonist/antagonist)
e.g.
No 75
Extension of Structure - simplified

representation
No 76
Extension of Structure
e.g. ACE inhibitors
No 77
Chain Extensions/Contractions
some drugs have two important binding groups linked together

by a chain
e.g. many of the natural neurotransmitters
if the chain length is not ideal for best interactions
shortening/lengthening of chain may increase interactions
No 78
CBMS306/842
Ring Expansions/Contractions
if a drug has a ring it is often worthwhile to synthesise

analogues with ring expanded/contracted
may enhance binding by putting binding groups of molecules
closer to binding sites
e.g.
No 79
CBMS306/842
Ring Expansions/Contractions
e.g. cilazaprilat
No 80
Ring Variations
can replace aromatic ring (benzene) with heteroaromatic ring

(or vice-versa)
e.g. Nevirapine
No 81
Ring Variations
can replace aromatic ring (benzene) with heteroaromatic ring

(or vice-versa)
e.g. pronethalol
H OH H OH
H
HO N N
HO
adrenaline pronethalol
No 82
Use of Isosteres
Strictly isosteres are atoms/groups of a similar size containing the

same number of atoms and valence electrons (outer shell electrons).
IUPAC definition.
e.g. O2-, F-, Ne (all have 8 valence electrons)
G. Patrick refers to isosteres as atoms/groups of atoms that have the
same number of outer shell electrons
e.g. S, NH, CH2 all have 6 valence electrons and are therefore isosteres
of O (6 valence electrons)
Likewise SH, NH2, CH3 have the same number of valence electrons (7)
as OH and they are all isosteres
AND CH=CH, SCH2, CH2CH2, OCH2 are isosteres AND F, Cl, Br, I
are isosteres.
No 83
Use of Isosteres
Note for the G. Patrick definition isosteres are not all the same
size. Therefore they can be used to determine size effects
when interchange isosteres from the same column of the
periodic table and can determine electronic effects when
interchange isosteres along the same row.
No 84
Use of Isosteres
Friedman's isosteres definition extends to groups with the

same valency (not necessarily same number of valence
electrons, e.g. H and F) and to ring equivalents. See next
slide.
No 85
Use of Isosteres
The following table is attributed to Friedman and it shows the common isosteric atoms
and groups arranged into classes by valency.
Class I (monovalent): H,F,Cl,Br,I,OH,SH,NH2,CH3

Class II (divalent): O,S,NH,CH2
Class III (trivalent): N,P,As,CH, S+
Class IV (tetravalent): C,N+,P+, S++
Class V Ring equivalents:
-CH=CH-,-S- (benzene, thiophene)
-CH=, -N= (benzene, pyridine)
-O-, -S-, -NH- (tetrahydrofuran,
tetrahydrothiophene, cyclopentane, pyrrolidine)
Interchanging isosteric atoms or groups of atoms within a class is allowable. These

interchanges preserve valency (lead to real molecules) and generate isosteres. (Note for
examples that H = -H, OH = -OH, etc and that R-H and R-OH are isosteres as are R-O-R
and R-S-R.)
No 86
Use of Isosteres
isosteres are often used in the design of enzyme inhibitors

may aid metabolic stability
replacing groups with isosteres from the same row makes
generally a small difference to the size of analogues but can
markedly effect polarity, electronic distribution and bonding
No 87
Use of Isosteres
e.g. -blocker propranolol

O N
H
OH
replacement of OCH2 with isosteres CH=CH, SCH2/CH2CH2

eliminates activity
replacement with NHCH2 retains activity (although reduced)
what does this show?
No 88
Use of Isosteres
replacing methyl of methyl ester groups with isostere NH2

group can stabilise esters susceptible to enzymatic hydrolysis -
aid metabolic stability
No 89
Use of Isosteres
fluorine is considered as an isostere of H as it is virtually the

same size
therefore replacement of H with F has very little steric effect
BUT electronic effect is very different as F is highly
electronegative
if we wish to examine electronic effects on activities without
any steric effects we can use F
F is particularly useful in enzyme inhibition
No 90
Use of isosteres for enzyme inhibition:
5-fluoruracil
5-fluoruracil inhibits the enzyme thymidilate synthetase

(enzyme) normal metabolic pathway for uracil
the normal metabolic pathway produces thymidine, which is
necessary for DNA synthesis and subsequent production of
protein
No 91

5-fluoruracil
THF tetrahydrofolate
O N
O H
H HN
HN
O N Enzyme
O N
H DRP DRP deoxyribose phosphate
uracil
O
CH3
-H + HN
+ Enzyme + THF
O N
DRP
No 92
5-fluoruracil
THF tetrahydrofolate
O N
O F
F HN
HN
O N Enzyme
O N
H DRP DRP deoxyribose phosphate
5-fluorouracil
O
CH3
-F + HN
+ Enzyme + THF
O N
DRP
No 93

5-fluoruracil
strictly speaking 5-fluoro deoxyuridine monophosphate

(FdUMP) is the enzyme inhibitor O
F
HN
O N
DRP
often referred to as a suicide substrate inhibitor

the enzyme is committing suicide by reacting with the pseudo-
substrate (inhibitor)
No 94
Non-classical isosteres
the carboxyl (CO2H) and sulfonamido (SO2NH) groups are

not strictly isosteric due to the extra O atom on S, but they are
similar in size and the CO and SO are isosteric and OH and
NH2 are isosteric based on Friedmans rule so e.g.
sulfanilamide and p-aminobenzoic acid are virtually isosteric
H2N SO2NH2 H2N CO2H
No 95
non-classical isosteres, e.g. pyrrole rings have been used as

replacements for amides (same shape and some similarity with
electronic effects - pyrrole more rigid and more stable)
e.g.
NEt
NEt
O N
H N H
OMe OMe
SO2Et SO2Et
sultopride DU 122290
No 96
Transition-state isosteres are compounds that mimic the

crucial features of the transition state and are relatively
stable
e.g. O HO O
H2O OH
N N OH H2N
H H
HO H
transition state isostere
No 97
Simplifying structures
discard non-essential groups without losing activity

advantage - simpler compounds easier and cheaper to
synthesise (however sometimes increase side-effects and
reduce selectivity)
simplification used to develop local anaesthetic procaine
CO2 Me
Me
Et2 NCH2CH2 O
N H O
O
O
H
NH2
cocaine procaine
No 98
Rigidification of structures
generally one conformation of a molecule binds best to target

site
if a molecule is flexible it has the opportunity to bind to other
receptors, which leads to side effects (also takes time to get in
the right conformation)
rigidification of molecules can maximise and speed up binding
and decrease side effects
No 99
e.g. hypothetical neurotransmitter
No 100
CBMS306/842
How could you enhance binding to receptor 1 and prevent

binding to receptor 2?
No 101

Drug Discovery from Natural Sources

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Drug Discovery from Natural Sources

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Drug Discovery & Development (Ch 12 and 13)

Sources of biologically active compounds as drugs/drug leads

Drug Discovery and Development

Drugs from natural sources - plants, animals, insects,

Drugs from plants - alkaloids

The name alkaloid comes from the concept of a compound being

Alkaloids typically react with mineral acids (HCl, H2SO4,

*This definition suits most but not all alkaloids (see

alkaloids often discovered following Culvenor-Fitzgerald

obtained from Papaver somniferum - opium

Drugs from plants - alkaloids

from root of Rauwolfia serpentina (snake root)

atropine and scopolamine

obtained from atropa belladona and related plants

Other drugs from plants

many other drugs produced by plants. These include cardiac

Steroids - lipid soluble substances that contain a tetracyclic

Drugs from animals - steroids

cortisone and hydrocortisone (cortisol) known as

Prednisolone (right) is also a corticosteroid

Similar to hydrocortisone (cortisol, right)

Used to treat a wide variety of anti-inflammatory and

Drugs from animals - peptide hormones and

Peptide hormones, such as insulin and other polypeptides

several pharmaceutical firms screen microorganisms

Drugs from microorganisms

when appropriate microorganisms are identified, they are

microbial drugs have also been useful outside of the area of

Drugs from microorganisms

bacteria can be used to produce polypeptide drugs by

the recombinant DNA is inserted into a plasmid-free strain of

Recombinant DNA technology

the first drug product of recombinant DNA technology was

Drug sources from insects and other creepy

insects have greater species diversity than any other creatures

Insects produce a wide range of proteins and peptides as a first

See A.T. Dossey, Insects and their chemical weaponry: New

Drug sources from marine natural products

the marine environment provides a wealth of molecules with

R Montaser, H Luesch, Marine natural products: a new wave of

much research is now focussing on venoms/toxins as drug

Venoms and toxins as drugs

random screening (or partly random screening) of a large

Some strategies for targeting natural products

look at toxicity reports (drugs are poisons)

focuses study on a particular family or genera known to have

by observing the interactions between species in the

e.g. antibacterial cyclic peptides from skin secretions from

antibacterial agents from molluscan egg masses (marine)

Willow bark has been used throughout

Artemisinin (qinghaosu) - isolated from the

Australian Aboriginal Medicinal Plants

Australian Aboriginal people have used plants as medicines for

new synthetic drugs are generally obtained via:

they may also be from combinatorial libraries or diversity

Drugs from synthesis

i) modification of lead compounds

i) modification of lead compounds

Drugs from synthesis

ii) development of drugs from first principles

ii) development of drugs from first principles

Once we have a lead structure - then what? (Ch 13)