mediiciinal chemistry m,pharmacy

1. Presented to:
Dr. Vikram Deep Monga
Presented by:
Ghanshyam Teli
Rohit Pal

2. CANCER
Cancer is a disease characterized by uncontrollable,
irreversible, independent, autonomous, uncoordinated and
relatively unlimited and abnormal over growth of tissues.
• Currently 1 in 4 deaths in USA are due to cancer.
• 1 in 17 deaths are due to lung cancer.
• An estimated 2,22,520 people diagnosed lung cancer in the
United States in 2010.
• Lung cancer is the most common cancer in men.
• Breast cancer is the most common cancer in women.
• Around 15 lakh new cases are diagnosed every year in
india.

4. Examples of Benign Tumors
• Papilloma - A projecting mass on the skin (for example, a
wart)
• Adenoma - A tumor that grows in and around the glands
• Lipoma - A tumor in fatty tissue
• Osteoma - A tumor originating in the bones
• Myoma - A tumor of muscle tissue
• Angioma - A tumor usually composed of small blood or
lymph vessels
• Nevus - A small skin tumor of one variety of tissues (for
example, a mole).

5. How is cancer classified?
There are five broad groups that are used to classify cancer.
 Carcinomas are characterized by cells that cover internal and
external parts of the body such as lung, breast, and colon
cancer.
 Sarcomas are characterized by cells that are located in bone,
cartilage, fat, connective tissue, muscle, and other supportive
tissues.
 Lymphomas are cancers that begin in the lymph nodes and
immune system tissues.
 Leukemias are cancers that begin in the bone marrow and often
accumulate in the blood stream.
 Adenomas are cancers that arise in the thyroid, the pituitary
gland, the adrenal gland, and other glandular tissues.

8. CAUSES OF CANCER
There are several agents responsible for cancer. The agents (physical,
chemical and biological) which causes cancer are called carcinogens.
1. Physical agents: Uv and ionizing radiations (x-ray, gamma and
alpha and beta rays cause cancer, uv rays of sunlight, nuclear
fission. These radiations have mutagenic effect. Eg: Leukaemias,
skin, lung, breast, osteosarcoma, thyroid cancer.
2. Biological agents:
a) Bacterial agents: peptic ulcers and chronic gastritis and if these
are left untreated for along time leads to gastric cancer.
b) Fungal agents: The fungus Aspergillus flavus releases aflatoxins
in stored food and grains .If this contaminated food is consumed
(especially by Hepatitis B virus infected patients) it leads to
hepato cellular carcinoma.
c) Viral agents: Cervical cancer, Burkitt’s lymphoma, hairy cell
leukaemia, Hepatic carcinoma.

9. 3. Chemical agents: Alkylating agents, The acylating agents,
Polyaromatic hydrocarbons, Aniline, arsenic, Anthracenes,
dimethylsulphate, diepoxybutane, acetyl imidazole, dimethyl
carbamyl chloride. carcinogens like nicotine, asbestos,
coaltar, benzene, aniline dyes.
4. Genetic factors: Genetic inheritance plays a key role in
causing some of the cancers (breast carcinoma, retino
blastinoma.
5. Diet and habits: People taking rich in fats, low fibre content
and stored grains. Alcoholism, smoking, chewing tobacco and
betel nut.(pan-masala, Gutka)
6. Hormones and Drugs: Taking excessive oestrogens during
the times of pregnancy (Vaginal endometrial cancer is
prevalent in the girls born to the mothers)

10. 7. Epidemiological factors:
a) Geographical and Racial factors : Climate, soil, diet habit
and customs etc. Genetic composition also influence the
variations in cancer. Eg: Breast cancer in prevalent in
American women. Gastric carcinoma is in Japanese.
b) Environmental and cultural factors: Exposure to
industrial contaminants, smoke and radioactive metals.
Cancer of penis is very rare in Muslims and jews due to the
custom of circumcision and their female partners are less
likely to suffer(prone) to cancer of cervix.
c) Age and sex: High risk of cancer is incident at an older age
due to reduction in immunity. It is usually seen in 5th decade
of life. Men are more prone to lung cancer while women are
susceptible to breast cancer.

11. • These are those drugs which are used in the
treatment of cancer, malignancy, tumour,
carcinoma, leukemia or neoplasm.
• Neoplasm refers to a group of disease caused
by several agents via chemical compound,
radiant energy.

12. How is cancer diagnosed and staged?
Common tests include the following:
• Biopsy of the tumor
• Blood tests (which look for chemicals such as tumor markers)
• Bone marrow biopsy (for lymphoma or leukemia)
• Chest x-ray
• Complete blood count (CBC)
• CT scan
• MRI scan (magnetic resonance imaging)
• Extracting cancer cells and looking at them under a
microscope is the only absolute way to diagnose cancer. This
procedure is called a biopsy.
• Physicians will analyze your bodys sugars, fats, proteins, and
DNA at the molecular level.
• For example, cancerous prostate cells release a higher level of
a chemical called PSA (prostate-specific antigen) into the
blood stream that can be detected by a blood test.

13. TREATMENT OF CANCER
Cancer can be treated by the following means:
Surgery Robotic radical prostatectomy for prostate cancer. (3-
D) view of the surgical field, at a greatly increased
magnification, up to 15 times greater than the human eye.
Radiation therapy.
Immunotherapy.
Hormonal therapy.
Antibiotics.
Chemotherapy.
Chemotherapy is the term applied for a wide range of
chemical substances i.e. drugs that are employed in the
treating the cancer.
These drugs may act by various mechanisms like Interfering
with the replication of DNA. Inhibiting the formation of
important molecules which are needed for DNA formation
and inhibiting the mytotic spindle.

14. CLASSFICATION OF ANTINEOPLASTIC
AGENTS
1. Alkylating drugs
i. Nitrogen Mustards
Cyclophosphamide Chlorambucil

15. Melphalan Mechlorethamine
Estramustine Bendamustine
Treatment of chronic lymphatic
leukaemia and lymphomas.

16. ii. Nitrosoureas
Lomustine Carmustine
iii. Alkyl sulphones
Busulfan

17. iv. Aziridines
Thiotepa Benzotepa
V. Methylhydrazine
Procarbazine Decarbazine

18. vi. Platinum containing compounds
Cisplatin Carboplatin
Oxaliplatin
Oxaliplatin is used to
treat colorectal cancer.

21. MOA of Oxaliplatin
After activation, oxaliplatin binds preferentially to the guanine and
cytosine moieties of DNA, leading to cross-linking of DNA, thus
inhibiting DNA synthesis and transcription. Cytotoxicity is cell-cycle
nonspecific.

22. 2. Chain cutters
Calicheamicin γ1
MOA
Calicheamicin γ1 is an anti-tumour agent that was isolated
from a bacterium.
It binds to DNA and is responsible for generating radical
species which lead to the cutting of the DNA chain.

24. 3. Antimetabolites
i. Folic acid antagonists/ DHFR
Methotrexate Pemetrexed
Pralatrexate

25. MOA:
• The structures of folic acid antagonists and folic
acid are similar
• Folic acid antagonists is actively transported into
mammalian cells and inhibits dihydrofolate
reductase.
• The enzyme that normally converts dietary folate
to the tetrahydrofolate form required for
thymidine and purine synthesis.

27. ii. Pyrimidine antagonists/ Inhibitors of
thymidylate synthase
5-Fluorouracil Ralititrexed
Doxyfluridine
(newer drug of pyrmidine
analogue)

28. MOA:
• Fluorouracil is an analogue of thymine in which
the methyl group is replaced by a fluorine atom.
• It has two active metabolites: 5-FdUMP and 5-
FdUTP. 5-FdUMP inhibits thymidylate synthetases
and prevents the synthesis of thymidine, a major
building block of DNA.
• 5-FdUTP is incorporated into RNA by RNA
polymerase and interferes with RNA function.

30. iii. Purine antagonists
6-Mercaptopurine 6-Thioguanine
MOA:
• 6-Mercaptopurine is an analogue of naturally occurring purine,
which is essential component of DNA called adenine.
• 6-MP inhibit the hypoxanthine-guanine phosphoribosyl
transferase (HGPRT) which converts thioinosine
monophosphate to adenine. Adenine and guanine nucleotides
that are building blocks for RNA and DNA, thus inhibits the
DNA synthesis.

31. iv. Inhibitors of DNA polymereases
Cytarabine Gemcitabine Fludarabine
• DNA polymerases catalyse the synthesis of DNA using the
four deoxyribonucleotide building blocks dATP, dGTP,
dCTP, and dTTP

32. MOA:
• The anticancer drug cytarabine is an analogue of 2′
deoxycytidine and acts as a prodrug.
• It is phosphorylated in cells to the corresponding
triphosphate (ara-CTP) which acts as a competitive
inhibitor. In addition, ara-CTP can act as a substrate
for DNA polymerases and become incorporated into
the growing DNA chain.
• This can lead to chain termination or prevent
replication of the modified DNA.

34. 4. Microtubule Inhibitors
i. Agents which inhibit tubulin polymerization
Vincristine , Vinblastine , Vindesine and Vinorelbine
Vincristine Vinblastine

35. Phyllanthoside Spongistatin 1
Cryptophycins
Cryptophycin 52 (under clinical trails)
Maytansine 1 (New drugs)

36. Combretastatins
Combretastatin A-4
(Under clinical trails)

37. MOA: Microtubule Inhibitors binds to the microtubular
proteins of the mitotic spindle, leading to crystallization of
the microtubule and mitotic arrest or cell death.
eg: Vinnca alkaloids

38. ii. Agents which inhibit tubulin depolymerization
Paclitaxel Docetaxel

40. Recently discovered natural products which
inhibit microtubule depolymerization.
Epothilones
Eleutherobin
BMS 247550 (Under clinical trails)
Sarcodictyins

41. 5. Inhibitors of signalling pathways
i. Inhibition of farnesyl transferase and Ras protein
Lonafarnib Tipifarnib
MOA: Ras proteins are an inherent component of the
cellular signalling pathways which control cell growth and
multiplication. They are small G-proteins which bind GDP in
resting state and bind GTP in active state.

42. • Binding to GTP is temporary. Because the protein can auto-
catalyse its hydrolysis back to GDP and return to the resting
state.
• Abnormal Ras derives from a mutation of the ras gene to form
a ras oncogene.
• So Mutant Ras proteins persistently bind GTP, however, and
fail to hydrolyse it, such that they are constantly active. Due to
this uncontrolled cell growth and cell division.
• farnesyl transferase is responsible for attaching farnesyl
group to the Ras protein when it is in the cytoplasm of the cell.
• The farnesyl group is hydrophobic and acts as a hook to hold
the Ras protein to the inner surface of the cell membrane. This
is necessary if the Ras protein is to interact with other
elements of the signal transduction process.

43. ii. Protein kinase inhibitors
a) Kinase inhibitors of the epidermal growth factor
receptor (EGF-R)
Gefitinib Erlotinib

44. Lapatinib
MOA of Gefitinib
EGF-R is a membrane-bound tyrosine kinase
receptor.
Gefitinib was found to mimic ATP and bind to the
ATP-binding region of the kinase active site and
inhibit the EGFR signalling pathways

46. MAPK : Mitogen-activated protien kinase
Erk : Extracellular signal regulated kinase
Akt :
mTOR : Mammalian target of rapamycin
PIK3 :

47. b) Kinase inhibitors of the vascular endothelial growth
factor receptor (VEGF-R) or Angiogenesis Inhibitors
Vandetanib Pazopanib
MOA:
• Angiogenesis is the formation of new blood vessels. This
process involves the migration, growth, and differentiation
of endothelial cells
• Angiogenesis plays a critical role in the growth of cancer
because solid tumors need a blood supply.

49. c) Kinase inhibitors of Abelson tyrosine kinase
(BCR-ABL inhibitor)
Imatinib Nilotinib
Dasatinib

50. The Philadelphia chromosome results from a reciprocal translocation
between chromosomes 9 and 22 and generates the Bcr–Abl chimera
protein.

51. MOA :
Imatinib was found to mimic ATP and bind to the
ATP-binding region of the kinase active site and
inhibit the BCR-ABL signalling pathways

52. d) Platelet-derived growth factor receptors (PDGF-R)
Inhibitors
Sunitinib Sorafenib
MOA:
Sorafenib is a protein kinase inhibitor with activity against
many protein kinases, including VEGFR, PDGFR and RAF
kinases.
PDGF plays a role in embryonic development, cell
proliferation, cell migration, and angiogenesis.

53. e) Hedgehog pathway inhibitors
Vismodegib
MOA:
Hedgehog signaling pathway include genes involved
in cell proliferation, apoptosis, angiogenesis, cancer
stem cell maintenance. So Vismodegib inhibits
Hedgehog Signaling pathway.

54. Uses : used in treatment of basal cell carcinoma
SMO : Smoothened receptor
GLI : glioma-associated oncogene

55. 6. Antibiotics
Doxorubicin Daunorubicin
Mitomycin
Bleomycin
Dactinomycin

56. 7. Monoclonal antibodies
Pertuzumab Brentuximab vedotin

57. Pertuzumab
• Pertuzumab is a monoclonal antibody against
her2 (Human epidermal growth factor
receptor-2) and block ligand-dependent hetero
dimerization of her2 with other her family
members.

58. 8. Hormone-based therapies
8.1. Glucocorticoids, estrogens, progestins, and androgens
a) Glucocorticoids
Prednisolone Prednisone

59. b) Estrogens
Ethinylestradiol Diethylstilbestrol
c) Progestins
Medroxyprogesterone acetate Megestrol acetate

60. d) Androgens
Fluoxymesterone Testosterone propionate
8.2. Luteinizing hormone-releasing hormone(LHRH)
agonists or Gonadotropin-releasing hormone
(GNRH) agonists
Leuprolide
Goserelin

61. 8.3. Anti-estrogens
Tamoxifen Toremifene
Fulvestrant

62. MOA OF FULVESTRANT:
When fulvestrant binds to estrogen receptor
monomers it inhibits receptor dimerization,
activating function 1 (AF1) and AF2 are rendered
inactive, translocation of receptor to the nucleus is
reduced, and degradation of the estrogen receptor is
accelerated.

63. 8.4. Anti-androgens
Flutamide Abiraterone
8.5. Aromatase inhibitors
Anastrozole Letrozole

64. SAR OF NITROSOUREAS

65. • Nitro group is essential for the activity.
• Aliphatic nitrogen is required for the activity.
• The 2-chloroethyl is the essential group for
activity in carmustine. It is noted that
carmustine is bifunctional, having two 2-
chloroethyl groups.
• Lomustine is monofunctional and has as a
second substituent a cyclohexyl that does not
contribute to its cytotoxic activity but
generates an increase in its half-time.

66. SAR OF TAXOL

68. • The importance of C-13 substituted phenyl isoserine side
chain to bioactivity of paclitaxel has been acknowledged for a
long time.
• Replacement of 3’-Ph with other alkyl or alkenyl
substitutions, especially 3'-isobutenyl and 3'- isobutyl groups,
usually improves the activity of paclitaxel analogues.
• Introduction of a fluorine atom to the para position of 3'-
phenyl decreased activity in most cases.

70. SAR of protein kinase C (PKC) inhibitors
phenylaminopyrimidine

71. • A pyridyl group was added at the 3′-position of the
pyrimidine to boost its cellular activity.
• Presence of an amide group was found to confer
inhibitory action against tyrosine kinases.
• Substitution in position 6 of the diamino phenyl ring
abolished the activity against PKC.
• The addition of a methyl group in an ortho position
to the amino group increased selectivity for Bcr-Abl.
• The resulting molecule still showed poor oral
bioavailability and solubility in water, which were
considerably improved by the introduction of an N-
methyl piperazine group.

72. • To abolish its mutagenic potential, the spacer
benzene ring were introduced.
• Nilotinib shows greater
potency and effectiveness
against almost the
totality of resistant ceconferring mutations.
• By inverting the amide linking group, by replacing the
piperazine ring with 3-methylimidazole, and by
adding trifluoro-methyl group to the anilinocarbonyl
substituent to imatinib
structure, give a
potent compound
Nilotinib.

73. SAR OF GEFITINIB (IRESSA)
• Gefitinib comes under the class of kinase
inhibitors of EGF-R. It has been approved for the
treatment of refractory lung cancer.
• It was developed from potent inhibitor.

74. • It had various important features namely a secondary amine,
electron-donating substituents at positions 6 and 7, and a small
lipophilic substituent on the aromatic ring.
• The structure had useful in vitro activity, but its in vivo activity
was hampered by the fact that it was metabolized rapidly by
cytochrome P450 enzymes to give two metabolites.
• The modification of structure was such that both metabolic route
were blocked.
• The methyl group was replaced by a chloro substituent , results in
resistant to oxidation.
• A fluoro substituent was used to block oxidation of the aromatic
para -position.
Metabolically blocked compound

75. • (IC 50 9 nM) was less active in vitro as an enzyme
inhibitor, it showed better in vivo activity.
• Modifications were then carried out to optimize the
pharmacokinetic properties of the drug. A variety of
alkoxy substituents at the 6-position were tried,
culminating in the discovery of gefitinib.
• This contains a morpholine ring, which is often Introduced
to enhance water solubility.
Gefitinib

76. SAR OF CYCLOPHOSPHAMIDE
• BIS-2 CHLOROETHYLAMINO GROUP IS ESSENTIAL
• CHLORO ATOM PROVIDES MAXIMUM ACTIVITY
• LEVO-ISOMER IS INACTIVE
• TRIETHYLENE DERIVATIVE IS INACTIVE
CYCLOPHOSPHAMIDE

77. SAR OF TIPIFARNIB
• TIPIFARNIB belong to the
non-peptide farnesyl
transferase inhibitor.
• The imidazole ring and
quinolone ring both are
important for the activity.
• The imidazole ring acts as a
ligand for the zinc cofactor in
the enzyme's active site.
• The introduction of a meta-
chloro substituent in parent
compound give the compound
which is more potent.

78. • The introduction of N-
methylation of the quinolone
give more potent compound.
• On altering the position of the
nitrogen on the imidazole ring
give highly potent compound.
• Introduction of a primary
amino group to the linker
carbon of imidazole ring and
quinolone ring gives highly
potent compound named as
tipifarnib.

79. Synthesis of Bendamustine

80. Synthesis of Imatinib

81. Synthesis of Gefitinib

82. Synthesis of Pemetrexed

83. Synthesis of Combretastatins

84. Synthesis of Vandetanib

85. Synthesis of Doxyfluridine

86. Synthesis of Oxaliplatin