Medicinal chenistry

1. 1
A. Cytotoxic drugs
 1. Alkylating agents
 2. Platinum coordination complexes
 3.Antimetabolites
 4.Antibiotics
 5. Plants
B. Targeted drugs
1. Tyrosine protein kinase inhibitors
2. EGF receptor inhibitors
3. Angiogenesis inhibitors
4. Biological response modifiers
 C. Hormonal drugs
CLASSIFICATION OF ANTICANCER DRUGS

2. Drugs from Natural source
A variety of the anticancer agents available
today are derived from natural sources
 Microbial sources (antibiotics) and
 Plants
Both the antibiotic and natural product from
plants classes have multiple inhibitory effects
on cell growth; however,
They primarily act to disrupt DNA function
and cell division.

3. Mechanisms by which these agents target DNA is
 Intercalation,
 Alkylation, and
 Strand breakage either directly or as a result of enzyme
inhibition.
Steps in Intercalation
 Intercalating drugs contain a planar aromatic or
heteroaromatic ring system which can slip into the double helix
of DNA and distort its structure.
 Drug should induce a cavity between base pairs so that
insertion may occur b/n drug and DNA.
 The interaction of the intercalator (drug) and the adjacent base
pairs of DNA occurs by the overlap of p-orbitals of the
intercalator and the base pairs.
 The p-orbitals of the intercalator/intercalation species are
provided by a combination of aromatic and conjugated systems
that impart the planarity required for intercalation.

4. The side chains of intercalator has a cationic
moiety, which may form ionic bonds with the anionic
phosphate backbone in DNA.
The overall result of these interactions is to cause
a local bend or kink or cut in DNA resulting in a local
shape distortion.
Inhibition of topoisomerase /DNA gyrase
(Topoisomerase enzymes are responsible for the
unwinding and relaxation of DNA so that transcription
may occur)

5. Classification of Antitumor Antibiotics drugs
Many of the antineoplastic antibiotics are produced by
the soil fungus Streptomyces.
Anthracyclines: Doxorubicin, Daunorubicin,
Epirubicin, Mitoxantrone, and Idarubicin.
Actinomycins/Chromomycins: Dactinomycin
and Plicamycin.
Miscellaneous: Mitomycin and Bleomycin.

6. Antracyclines
Doxorubicin (previously called adriamycin)
belongs to a group of naturally occurring antibiotics called
the anthracyclines, and was isolated from Streptomyces
peucetius in 1967.
It is very similar in structure to Daunorubicin—differing
only in one hydroxyl group at C9 acetyl group in
daunorubicin & hydroxy acetyl group in doxorubicin.
O
O
OH
OH
OH
C CH2
O
OH
OO
H
H
OH
H
NH2H
H
CH3
OCH3
ABCD
Doxorubicin
1
2
3
4 5 6 7
8
9
1011
12
O
O
OH
OH
OH
C CH3
O
OO
H
H
OH
H
NH2H
H
CH3
OCH3
ABCD
Daunorubicin
1
2
3
4 5 6 7
8
9
1011
12

7. The second generation anthracyclines
Epirubicin and Idarubicin lacks the methoxy
group at C4 , so it is more polar and has an
altered metabolism which prolongs its half-
life.
O
O
OH
OH
OH
C CH2
O
OH
OO
H
OH
H
H
NH2H
H
CH3
OCH3
ABCD
Epirubicin
O
OH
OH
OH
OH
C CH3
O
OO
H
H
OH
H
NH2H
H
CH3
ABCD
Idarubicin
1
2
3
4 5 6 7
8
9
101112

8. SAR
• The anthraquinone chromophore is an important structural feature of the
anthracyclines.
• the anthraquinone chromophore, consisting quinone and a hydroquinone
moiety on adjacent rings.
• The phenolic hydroxy groups present in this core were found to undergo
ready acylation and alkylation under standard reaction conditions.
• It has been shown that, O-methylation of the C-6 or C-11 phenolic groups
results in analogs with markedly reduced activity,
• whereas C-4 modifications such as demethylation and deoxygenation do
not affect bioactivity.
• The transformation of the C-5 carbonyl to the corresponding imino
functionality resulted in an analog that retained activity and was found to
be significantly less cardiotoxic than the parent compound.
• Ring-A, alicyclic moiety bearing the two-carbon side chain group and
the tertiary hydroxyl group at C-9 and also having a chiral hydroxy group
at C-7, which in turn connected to the aminosugar unit;
• the amino sugar residue, attached to the C-7 hydroxy group through an a-
glycosidic linkage;

9. Iron-mediated generation of free oxygen
radicals that damage the DNA, proteins and cell
membranes

10. Drug-DNA Complex

11. Mitoxantrone
It is a simplified, synthetic analogue of the
anthracyclines where the tetracyclic ring system has
been ‘pruned’ back to the planar tricyclic system
required for intercalation.
• There is no sugar ring which is responsible for cardio
toxic side effects.
• The pharmacophore
groups are highlighted in
box and which are responsible
For binding with DNA base
Pairs.
Anthrace ring interculate b/n DNA
base pairs.

12. Uses of Anthracyclines
Doxorubicin is used to treat a broad spectrum of solid
tumours, as well as acute leukaemias, lymphomas, and
childhood tumours.
Daunorubicin is indicated for acute leukaemias.
 Epirubicin is considered effective against breast cancer.
 Idarubicin is used in the treatment of haematological
malignancies and can be given orally.
Both epirubicin and idarubicin are second-generation
anthracyclines with less cardiac toxicity than doxorubicin
or daunorubicin.
Mitoxantrone is used for the treatment of certain
leukaemias and lymphomas, and for advanced breast
cancer.

13. Side effects of Anthracyclines
Causes cardiotoxicity
Interference with ryanodine receptors of the
sarcoplasmic reticulum in the heart muscle cells
Sugar residue is one of the cause for cvs toxicity
Free-radical formation in the heart
Leads to forms of congestive heart failure, often years
after treatment
Counteract with dexrazoxane
Liposomes can be useful as carriers to deliver
doxorubicin to target tumours and this approach
is associated with less cardiac toxicity.
Extravasation injury produce extensive local
necrosis.

14. Extravasation Injury by Doxorubicin
Redness , swelling blisters Tissue necrosis
surgery to remove tissue permanent damage

15. Actinomycins
The Actinomycins are a group of compounds
that are isolated from various species of
Streptomyces,
Phenoxazone chromophore
And has di pentapeptide portion
The 1St drug from this group is Actinomycin D
which is known as Dactinomycin
Other Pilcamycin

16. Actinomycin-D/ Dactinomycin
Phenoxazone chromophore
And has di pentapeptide
portion
The pentapeptides namely L-
threonine, D-valine, L-proline,
sarcosine, and L-methylvaline
form a lactone via the side
chain hydroxyl of L-threonine
and the carboxyl group of L-
methylvaline
An amide linkage is present b/n
the amino group of L-threonine
and carbonyls of 1 and 9 of
Phenoxazone chromophore

17. • The structural feature of dactinomycin important for
its mechanism of cytotoxicity is
• the planar phenoxazone ring, which facilitates
intercalation between DNA base pairs.
• The peptide loops are located within the minor groove
and provide for additional interactions.
• Dactinomycin binds noncovalently to double-stranded
DNA by partial intercalation between adjacent guanine
cytosine bases resulting in inhibition of DNA function.
• Additional hydrophobic interactions and hydrogen
bonds are formed between the peptide loops and the
sugars and base pairs within the minor groove.

18. Mechanism of action of Dactinomycin
Minor GrooveD
D
 By an effect on topoisomerase II
that unwinds the DNA helix for
replication
 It intercalates, in the minor groove
of DNA, between adjacent guanine-
cytosine pairs thus preventing
transcription.
DNA synthesis may also be inhibited,
and the agent is considered as cell
cycle specific for the G1 and S
phases.
Block DNA Gyrase/ topoisomerase
Uses
is given mainly intravenously to treat
paediatric solid tumours, including
Wilm's tumour and Ewing's tumour

19. Mitomycin C
N NH
O
O
O
ONH2
O
NH2
CH3
CH3
H
H
H
urethan
aziridine
take part in alkylation of DNA
quinone
(participate in free radical
reactions generating superoxide)
It is a natural product isolated from Streptomyces
verticillataus as well as from other sources.

21. Mitomycin
Reductive activation and bisalkylation of
DNA by Mitomycin C
Streptomyces caespitosus

22. Interstrand and intrastrand alkylation of DNA by bioreductively activated
mitomycin C.

23. Uses of Mitomycin C
Adenocarcinoma of the stomach, colon, or pancreas.
 Its use and application in ophthalmology has been increasing
in recent years because of its modulatory effects on wound
healing.
 Current applications include
 Pterygium surgery,
 Glaucoma surgery,
 Corneal refractive surgery,
 Cicatricial eye disease,
 Conjunctival neoplasia and allergic eye disease.