Health science

1. CHEMISTRY OF ANTI CANCER
AGENTS
1
Asrat E. (BPharm., MSc.)

2. ANTI CANCER AGENTS
Introduction
• Cancer is a disorder of cells in the body
• It begins with a group of cells that fail to respond to the normal control mechanism
and continue to divide without control
2

3. • Cancer is caused by abnormalities in cells
• Inherited genes from parents
• Outside exposures to the body such as chemicals, radiation or even infectious
agents
• The defective genes are called oncogenes
• Substances which cause changes that can lead to cancer are called carcinogens
3
Cont’

4. • A benign tumor is the one that remains localized
• A malignant tumor invades neighboring tissues, enters blood vessels, lymphatic
vessels and other spaces, and can be carried to other areas of the body to form new
tumors
• Metastasis
4
Cont’

5. Terminology
• Nomenclature of types of cancer is sometimes ambiguous
• Cancer may be named after the discoverer as Wilm’s tumor, Hodgkin’s disease,
Kaposi sarcoma
• Sometimes named after the tissue from which the neoplasm is derived
5
Cont’

6. • Cancer: Un wanted growth
• Tumor: A swelling or mass of cells which does not have any physiological function
• Neoplasm: A medical term for cancer
• Malignant: Tending to become worse and cause death
• Metastasis: Process by which malignant cells spread to other parts of the body
6
Cont’

7. During embryonic developments tissues derive from three layers:
• Ectodermal (form skin and nerve)
• Mesodermal (form bone, muscle, and cartilage)
• Endodermal (form intestinal system)
• Sarcoma: derived from mesodermal tissues
• Carcinoma: derived from ecto- or endodermal tissues
• Carcinosarcoma: derived from two tissue types ecto- or intradermal and mesodermal
• Teratoma: derived from all three tissue types
• Leukemia: derived from blood leukocytes
7
Cont’

8. External Causes of Cancer
Viruses
Chemicals
Cigarette Smoking
Radiation
8
Cont’

9. Major cancer risk factors
Smoking (lung, oral, larynx, esophagus)
Diet (A high-fat diet has been associated with an increased risk for cancer of
the prostate, endometrium, and colon and rectum)
Genetics (Alteration in gene- Mutation)
Occupation and Environment (UV, asbestose)
Infectious Agents (Bacteria, virus)
9
Cont’

10. Properties of cancer/ Hallmarks of cancer
Self-sufficiency in growth signal
Insensitivity to anti-growth signals
Evading programmed cell death (Apoptosis)
Limitless replicative potential
Developing blood vessels (Angiogenesis)
Tissue invasion and metastasis
They escape from the immune system
Tumour promoting inflammation
Gene instability and mutation
No contact inhibition
De-regulating cellular energetics
10

11. 11
Cell division cycle

12. 12
Cont’

13. 13
Cont’

14. Treatment of Cancer
• The specific approach used to treat cancer depends upon the specific type of
cancer, location, and its stage
• However, in most therapeutic approaches there will be a contribution of a chemical
anticancer compound
14

15. 1) Surgery
• Applied when cancer is still in the primary stages
• When be sure that the entire tumor can be excised without causing significant
damage of the vital organs
• Surgery can also be used for diagnostic purposes
15
Cont’

16. 2) Photo radiation therapy
• Is achieved when a photosensitizing drug is activated by light to form products that are
lethal to tumor cells
• Tumors are localized selectively by injection of HPD (Haematoporphyrin derivatives)
• After a 24-72 hours interval, fluorescence can be observed in tumor tissues by the use
of probes of fiber optics
• To destroy tumors, light from a tunable dye laser of (620-640 nm or red light) is
directed onto the tumors
• Normal tissues which have minimal absorbency (620-640 nm) are minimally damaged
16
Cont’

17. 3) Radiation therapy
• Gamma rays from radio isotopes as 60Co or X-ray are used
• May be better than surgeries in case of some cases as well as it destroys microscopic
cancer cells after surgery
• Before surgery it reduces tumor and decreases metastasis
• It is subjected to limitations because of its carcinogenic effects
• Radiation sensitizers are of
Help to increase damaging effect of radiation without increase in radiation dose
5-fluorouracil, dactinomycin, misonidazole and razoxane (+1,2-bis(3,5-
dioxopiperazin- 1-yl) propane)
17
Cont’

18. H
H
CH3
N N
O
O
CH CH2 N N
O
O
18
Razoxane
5-fluorouracil
Misonidazole
Cont’

19. 4) Immunotherapy
• Mostly used in follow up treatment
• Involves stimulating the body’s own defenses by immunotherapy to destroy the last few
cancer cells remaining after surgery, radiotherapy or chemotherapy
• The methodology attempts to boost the levels of lymphocytes, specifically T-cells and B-
cells lymphocytes
• The major role of T- cells is to destroy foreign cells, including malignant and
premalignant cells
• B-cells produced in the bone marrow and lymph nodes make antibodies in response to
a foreign protein which may be expressed by cancer cells
• Therapy of this type consists of the administration of interferon
19
Cont’

20. 5) Chemotherapy
Used to
• Cure a specific cancer
• Reduce the size of a tumor prior to surgery
• Sensitize tumors to radiation therapy
• Destroy microscopic metastases after tumors are surgically removed
• Used as complementary to either surgery or radiation therapy
20
Cont’

21. • Assumed that malignant cells take-up extra cellular materials at a great rate than the
normal cells
• However there are few normal cell types that are rapidly proliferating including hair
cells, bone marrow cells and cells lining the gastrointestinal tract
However, chemotherapeutic agents have some drawbacks:
1. They are less useful for large tumors since such tumors are not well perfused with
blood
2. They are basically cytotoxic and can kill normal cells too
21
Cont’

22. 6) Combined Chemotherapy
• It is highly effective in treating a wide range of cancer conditions
• Each drug in the combination should have a unique mechanism of action
providing that the drugs did not have overlapping toxicity
22
Cont’

23. 7) Adjuvant therapy
• A chemotherapy with surgery and radiation
• Used in infancy stage and highly susceptible cells to drugs
23
Cont’

24. 8) Gene Therapy
• The treatment of any condition through the transfer of genetic material
• Gene delivery systems are based on viral and non-viral approaches
• They can enter tumor tissue due to the increased permeability of tumor vessel walls
• Used as tumor target transport vehicles for DNA or drugs
24
Cont’

25. CHEMOTHERAPEUTIC AGENTS
Classification
1. Alkylating agents
2. Antimetabolites
3. Hormones and Antihormones
4. Antibiotics
5. Plant products
6. Miscellaneous
25

26. 1. ALKYLATING AGENTS
• Alkylating agents contain chemical groups which have the ability of forming covalent
bonds with nucleophilic substances in the cell (DNA, RNA and certain enzymes)
• Most of the anticancer alkylating agents are bifunctional
• Possess two alkylating groups
• They are thus able to react with two groups and can cause intra- or inter-chain cross-
linking, that can interfere with transcription and replication of DNA
26

27. Classification of alkylating agents
A. Nitrogen mustards
B. Nitrosoureas
C. Aziridines
D. Sulfonic acid esters
E. Triazines
F. Platinum complexes
27

28. A.Nitrogen Mustards
• Their original use stems from the observation during world war I
• Individuals heavily exposed to mustard gas suffered damage to bone marrow and
lymphoid tissues
• Mustard gas: highly toxic, insoluble in water
• Nitrogen mustard derivatives: less toxic, salts are solids and water soluble
28
Cl
N
Cl
R

29. Mechanism of Action of Nitrogen Mustards
Aliphatic Substituted Nitrogen Mustards
• The molecules undergo neighboring group reactions
• The nitrogen atom displaces a chlorine atom to give strained three-membered
aziridinium intermediates
• The highly strained three-membered ring rearranges by scission to the carbonium ion,
which in turns reacts with the nucleophilic groups
• The attack leads to irreversible covalent bond formation with the substrate
29

30. CH2
CH2
N
CH2
CH2
H3C
Cl
Cl
:
N
CH2 CH2
Cl
+ Cl
-
Aziridinium ion
H3C
CH2
CH2
N
CH2
CH2
H3C
Nu
Cl
CH2
CH2
N
CH2
CH2
H3C
Nu
Nu
Nu H3C
-
Cl
+
CH2 CH2
N
Nu
Nu = nucleophilic center rich in electrons (OH, NH2, SH, COOH, SO3H ) present in
enzymes, proteins RNA and DNA
Nu
30
Cont’

31. Aromatic Substituted Nitrogen Mustards
• The aromatic ring decreases the nucleophilicity of the Nitrogen atom
• Are relatively stable toward aziridinium ion formation
• The highly reactive carbonium ion species react with nucleophilic (electron-rich)
sites on nucleic acids and proteins (alkylation occurs via SN1 mechanism)
31
Cont’

32. + -
Cl
CH2
CH2
N
CH2
CH2
H3C
Nu
Nu
Nu
CH2
CH2
N
CH2
CH2
H3C
Nu
CH2
CH2
N
CH2
CH2
H3C
Nu
Cl
Nu
Cl
+
CH2
CH2
N
CH2
CH2
Ar
Cl
CH2
CH2
N
CH2
CH2
Ar
Cl
Cl
-
32
Cont’

33. CH2
CH2
N
CH2
CH2
Cl
R
Cl
CH2
CH2
N
CH2
CH2
OH
R
OH
H2O
33
• Stabile in water
• So, drugs are marketed as dried powders to be put in solution before use as IV
infusion fluid
Cont’

34. HN
N
N
N
O
H2N
R
N
NH
N
N
R
O
NH2
N
R
2 Steps
HN
N
N
N
O
H2N
R
N
NH
N
N
R
O
NH2
Cl
N
Cl
R
+ +
Cl
- Cl
-
34
• The strongly nucleophilic N7 of guanine, is
probably the main molecular target for
alkylation in DNA
• However N1 and N3 of adenine and N3 of
cytosine may also be affected
Alkylation of DNA by Nitrogen Mustards

35. Structure-Activity Relationship
• Aliphatic nitrogen mustards are more lipid soluble therefore more bioactive
• The more localized the unshared pair of electrons on N the higher is the reactivity
• Aromatic nitrogen mustards are of low basicity with a slow rate of C+ formation
therefore the molecules can reach distant sites
• The presence of an amino acid moiety with nitrogen mustard may direct the drug to
a metabolic site affecting cancer
• Mono-functional alkylating agents are less bioactive
• Iodine or fluorine atoms instead of chlorine decrease the activity (slow formation of
C+ ion)
• Bromine atoms lead to very reactive molecules but with high toxicity
35

36. 36
N
H3C
Cl
Cl
+
H
Cl
-
2,2’- Dichloro-N-methyldiethylamine hydrochloride
i. Mechlorethamine HCl (Mustine HCl)
• Is used in the treatment of Hodgkin’s diseases and other malignant neoplasm including
lung carcinoma, chronic myelocytic leukemia and brain tumors
• Adverse effects include bone-marrow depression, nausea and vomiting, neurological
disorders, and liver disorders
• It is administered intravenously and intracavitary
Cont’

37. ii. Mustrone (Mechlorethamine-N-oxide)
• 2,2’-Dichloro-N-methyldiethylamine-N-oxide
• The toxicity of the parent compound is greatly reduced with only slight reduction
inactivity
• It is active after metabolic reduction to mechlorethamine
37
O
N
H3C
Cl
Cl
Cont’

38. iii. Chlorambucil (Leukeran)
• 4-[4’-Bis-(2-chloroethyl)aminophenyl]butyric acid
• It is used in the treatment of leukemias and lymphomas and various other malignant
neoplasms
• It is the slowest acting and least toxic nitrogen mustard
• Adverse effects include bone-marrow depression, GIT disturbances, neurotoxicity,
lung disorders and sterility
• It is administered orally
38
O
HO
N
Cl
Cl
Cont’

39. 4-[ Di-(2-Chloroethyl)amino]-L-phenylalanine
iv. Melphalan (Alkeran)
• Phenylalanine-N-mustard 4-[ Di-(2-Chloroethyl)amino]-L-phenylalanine
• Melphalan is used for its antineoplastic action in the treatment of multiple myeloma
and in other malignant neoplasm including tumors of the breast and ovary
• Adverse effects include bone marrow depression, rashes, and GIT disturbances
• It is active orally
39
N
O
Cl
Cl
NH2
HO
Cont’

40. v. Cyclophosphamide (Endoxan)
2-[Di-(2-Chloroethylamino]-1-oxa-3-aza-2-phosphacyclohexane-2-oxide
40
P
N
O
O
N
Cl
Cl
• Is an alkylating antineoplastic agent, which can be given orally or by intravenous
injection
• Although it is chemically related to the nitrogen mustards, the nucleophilicity of the
mustard nitrogen is less likely to form an aziridinium ion than are the alkyl-substituted
nitrogen mustards
• It requires activation in the body to take effect
Cont’

41. Bioactivation of Cyclophosphamide
• It is converted to the active compound mainly in the liver
• Converted to 4-hydroxycyclophosphamide and aldophosphamide by enzymatic
oxidation
• Aldophosphamide is chemically unstable, undergoing conversion to acrolein and
phosphamide mustard
• Acrolein causes urotoxicity, therefore Mesna which is acrolein antidote should be
given HSCH2CH2SO3Na (Sodium mercaptoethanesulfonic acid)
• Mesna is water soluble and forms a non-toxic product with acrolein
41
Cont’

42. HCOCH2CH-S-CH2CH2SO3 Na
42
CYP450
Unstable carbinolamine
(Active)
Phosphoramide mustard
H
P
N
O
O
N
Cl
Cl
HO
H
H2
P
N O
N
Cl
Cl
O
CHO
P
N O
N
Cl
Cl
HO
H2
CH2 CH CHO
+
(O)
Aldophosphamide (unstable)
Acrolein
P
N
O
O
N
Cl
Cl
• Used in the treatment of various
malignant diseases including
lymphoma, myeloma, and a variety of
solid tumors
• Adverse effects include
myelosuppresion and hemorrhagic
cystitis (which may be prevented with
mesna) as well as GIT, pulmonary, and
cardiac toxicity, alopecia and sterility.
• It is administered as tablets.
Mesna
Cont’

43. Structure-Activity Relationship
1. The Bis(2-chloroethyl) is essential for activity
2. Other halogen atoms decrease the activity
3. The trimethylene chain between N and O shows no activity because of the
aziridinium cation formation is not possible
4. The S(-) isomer is more active than the R(+) isomer asymmetric Phosphate atom
43
P
N
O
O
N
Cl
Cl
Cont’

44. vi. Mafosamide
44
P
N
O
O
N
Cl
Cl
S
NaO3S
H
• It is a combination between cyclophosphamide and mesna
Cont’

45. Vii. Uracil
• 5-[Bis(2-Chloroethyl) amino] uracil
• It is a combination of the structural features of N-mustard and a nucleotide which
acts as a carrier for the active species
• It is administered orally
45
N
N
O
O
N
Cl
Cl
H
H
Cont’

46. i. Carmustine (BCNU)
• 1,3-Bis(Chloroethyl)-1-nitrosourea
• Carmustine is a neutral molecule that is highly lipophilic and poorly soluble in water
• Have efficient access to the blood-brain barrier
• It is rapidly metabolized after intravenous administration to its active forms
• The vinyl cation is the ultimate alkylating agent
• 2-Chloroethylisocyanate which gives 2-chloroethylamine, an additional alkylating
agent
46
C
N
O
NO
N
Cl
Cl
B.Nitrosoureas

47. H
Cl
N N
NO
O
Cl
N
O
H
N
O
Cl
+
+
C
O N
Cl
N N
OH
Carmustine
_
H2O
Cyclic oxazolidine
Vinyl diazotic acid 2-Chloroethylisocyanate
H
2
C=CH +
2-Chloroethylamine
H2N Cl
Vinyl cation
N N
O
NO
Cl
Cl
47
Carmustine metabolism
Cont’

48. 48
• Alkylation of DNA and RNA is the proposed mechanism of action of carmustine
• However, its lack of cross resistant with nitrogen mustards suggests alternate
mechanisms of action
• It may involve enzyme inhibition by carbamoylation of proteins
• Carmustine is used in the treatment of leukemia, lymphomas, malignant
melanoma and brain tumors
• Adverse effects include bone-marrow depression, pulmonary fibrosis, and effects
on liver, kidneys, and eyes
Cont’

49. ii. Lomustine (CCNU)
1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea
• It is a nitrosourea antineoplastic agent similar to carmustine
• It is formulated as capsules
49
H
C
N
N
O
NO
Cl
Cont’

50. C.Aziridines (Ethyleneimines)
• Aziridine is a 3 membered nitrogen heterocycle that reacts with nucleophiles in order to
relief ring strain
• At acidic pH, the aziridine group is protonated to provide a reactive aziridinium ion that
is known to alkylate DNA
50
Cont’

51. i. Triethylenemelamine (TEM, Tetramine)
• 2,4,6-Tris(1-aziridinyl)-s-triazine
• It is an aziridine containing compound
• It is used as an adjuvant to radiation therapy of retinoblastoma and injected in to carotid
artery
51
N
N
N
N N
N
Cont’

52. ii. Thiotepa
• Tris(1-aziridinyl)phosphine sulfide
• An aziridine containing drug, used in carcinoma of breast, bladder, Hodgkin’s and
nonHodgkin’s lymphoma
• It is administered intravenously, intracavitary and intravesical
• Metabolic desulfuration leads to a toxic metabolite
52
N
N
N P
S
N
N
N P
O
Toxic metabolite
Cont’

53. D.Sulphonic Acid Esters
Busulphan (Myleran)
• 1,4-Butanediol dimethylsulfonate
• Busulphan is an alkylating agent with a methanesulfonic acid acting as a leaving group
• It is used to treat chronic myelocytic leukemia
• It is formulated as tablets
• Adverse effects include prolonged and sometimes irreversible bone-marrow
depression, and pulmonary fibrosis
53
S
O
O
S
CH3
H3C
O
O
O
O
Cont’

54. E.Triazines
Dacarbazine (DTIC)
• 5-(3,3-Dimethyl-1-triazenyl)imidazol-4-carboxamide
• Dacarbazine is a cell-cycle nonspecific antineoplastic agent which may function as an
alkylating agent after its activation in the liver
54
N
N
N
CONH2
N
H
N
CH3
CH3
Cont’

55. Mechanism of action
• It is used mainly in the treatment of metastatic malignant melanoma and Hodgkin’s
lymphoma
• It is administered intravenously and intramuscularly
55
H
H
N
N
CONH2
N N N CH3
N NH CH3
N
N
CONH2
N
H
Demethylation
In liver +
N N CH3
+
Diazomethane
:
+
+
N
N
CONH2
NH2
CH2O
Cont’

56. Diazomethane is capable of methylating the N7 of guanine
2-Azahypoxanthine (Antimetabolite for purine)
56
N
N
N
N
DNA
O
H2N
H
CH3 N N
+
:
In acid medium +
N
N
N
CONH2
N
H H
N
N
CONH2
N N Nu
+
Nu
N
N N
N
N
O

57. Cis-Dichlorodiaminoplatinum (II)
F.Platinum compounds
i) Cisplatin (Platinol)
• It is a platin complex
• Contains two ammonia molecules and two chlorine atoms in a cis configuration
• It reacts with nitrogen atoms of DNA preferentially with N7 of deoxyguanylic acid
forming intrastrand and interstrand cross-links
• Transplatin is inactive as it lacks the stereochemistry required for cross linking
57
Cl
Cl
Pt
H3N
H3N
Cont’

58. Mechanism of Action
58
Pt
H3N Cl
Cl
H3N
H2O
Pt
H3N Cl
H3N N
N
N
N NH2
O
H
Sugar
7
N
N
N
N NH2
O
Pt
H3N
Cl
NH3
Sugar
Sugar
N
N
N
N NH2
O
Pt
H3N
NH3
H2O
H2O
N
N
N
N
O
H2N
Sugar
7
OH2
7 +
+
7 7
Sugar
N
N
N
N
O
H2N
N
N
N
N NH2
O
Pt
H3N
NH3
Sugar
DNA adduct
Cross link

59. ii. Carboplatin (Paraplatin)
O
Pt
O
O
O
59
It is less toxic than cisplatin and used in ovarian cancer.
Cont’

60. 2.ANTIMETABOLITES
• Antimetabolites are compounds that prevent the biosynthesis or utilization of
normal cellular metabolites
• They are closely related in structure to the metabolite being antagonized
• Many antimetabolites are enzyme inhibitors
• They may combine with the active site as if they are the substrate or cofactor
60

61. A. Folic acid Antagonists
• Folic acid is essential for the synthesis of nucleic acids
• It is reduced to dihydrofolic acid (DHFA) then to tetrahydrofolic acid (THFA) by
folate reductase
• Tetrahydrofolic acid picks up a methyl group from serine or methionine and is
converted into N5,N10-methylene tetrahydrofolic acid
• Tetrahydrofolic acid is also involved in biologically important reactions not directly
involved in cell proliferation
61
Cont’

62. R1 R2
Folic acid OH H Metabolite
Aminopterin NH2 H Antimetabolite
Methotrexate NH2 CH3 Antimetabolite
N
N
N
N
H2N
CH2
R1
R2
N C N
O
CH
CH2
COOH
CH2 COOH
H
10
1
4
5
62
Cont’

63. Mechanism of action
• Methotrexate is 4-amino-N10-methyl petroylglutamic acid
• It acts as an antifolate
• Binds irreversibly to the enzyme dihydroflate reductase
• Prevents the formation of the co-enzyme tetrahydrofolic acid
• It also inhibits thymidylate synthetase
63
Cont’

64. • Like tetrahydrofolate, methotrexate becomes polyglutamated within the cell
• This process favors intra cellular retention of the compound
• The production of compounds that depend on tetrahydrofolate (adenine, guanine,
thymidine and the amino acids methionine and serine) will be decreased
• Methotrexate binds much more strongly to the enzyme than does folic acid
64
Cont’

65. • Folic acid therefore cannot reverse the long lasting toxic effects of methotrexate
• But, Folinic acid can compete with methotrxate
• Since it can still carry out one-carbon in spite of the fact that folate reductase is
inhibited
• This is the rationale for using folinic acid (leucovorin) as an antidote for methotrexate
• Methotrexate is administered in tablet form and used to treat acute leukemia, meningeal
leukemia, carcinoma of breast, head, neck, lung, ovarian and bladder carcinoma
65
N
N
N
N
H2N
O
N
N COOH
O COOH
CHO
H H
H
H
Leucovorin Rescue
Cont’

66. • Continuous infusion of methotrexate is more toxic than one push injection of the
same dose
• So giving the patient about 200 times the therapeutic dose will allow cancer cells to
be exposed rapidly to very high doses in short time
• Injection of leucovorin after few hours will supply normal cells with THFA
Reading assignment- Other folate derivative anticancer agents
66
Cont’

67. 67
B.Purine Antagonists
6-Mercaptopurine (6MP) and 6-thioguanine (6TG)
• Are not active until they are converted to their respective nucleotides by a
pyrophosphorylase enzyme (lethal synthesis)
• Tumor cells or normal cells that have very low levels of the enzyme are resistant to
these agents
• They interfere with the de novo synthesis of purines
N
N
NH2
N
N
N
N
N
N
H2N
O
H
Adenine Guanine
H
Natural bases
H
Cont’

68. X.O.
X.O.
X.O.
Inactivation
6-Thiouric acid
6-Thioxanthine
6-Mercaptopurine
Gout
H H
H
N
N
N
N
O
O
SH
H H
N
N
N
N
OH
HO
OH
H
H
Uric acid
Xanthine
Hypoxanthine
N
N
N
N
SH
O
N
N
N
N
SH
N
N
N
N
OH
HO
H
N
N
N
N
OH
X.O.
68
• Co-Administration of Allopurinol with 6-Mercapotopurine
• Allopurinol used as an adjuvant to chemotherapy is that it prevents uric acid toxicity
caused by the release of purines from destroyed cancer cells
Cont’

69. C. Pyrimidine Antagonists
N
N
O
O N
N
O
NH2
N
N
O
O
CH3
Uracil Cytosine Thymine
H H
H H
H
H
In RNA In DNA
69
Natural pyrimidines
Cont’

70. N
N
O
O
F
H
H
70
i. 5-Fluorouracil (5FU)
• A uracil analogue
• The 5th position of uracil is substituted by a Florine atom
• It inhibits thymidylate synthetase enzyme
• Since position 5 is occupied, the methylation is impossible

71. ii. Floxuridine (5-Fluorodeoxyuridine)
• 5- Fluorouracil-2’-deoxyribose
• It needs only the phosphate group addition for activation
• Cancerous cells may undergo mutation and develop
resistance upon prolonged treatment with purine and
pyrimidine antimetabolites
• The formation of alkaline phosphatase enzyme would break
6-mercaptopurine
71
H
N
N
O
O
F
O
OH
HO-H2C
(5-Fluorodeoxyuridine)
Cont’

72. 3.HORMONES AND ANTIHORMONES
• Tumors derived from hormone-sensitive tissues may be hormone dependent
• Their growth can be inhibited by hormones of opposing actions (hormone antagonists)
• Hormones essential for reproduction are also responsible for development and growth
of breast, prostate and uterine cancer
72

73. A. Hormone-Dependent Breast Cancer
• Estrogens bind to an estrogen receptor in estrogen target site (uterus, vagina, pituitary
gland) to give Estrogen-Receptor complex with subsequent response
• The tumor cells that contain estrogen and estrogen receptors are referred as estrogen
receptor rich (estrogen receptor positive)
• This tumor type responds well to endocrine therapy (antiestrogen)
• The tumor with low estrogen receptors is said to be estrogen poor (estrogen receptor
negative) responds poorly to endocrine treatment
• The presence of progesterone receptors indicates active estrogen system
73
Cont’

74. • Ethinylestradiol is used in the treatment of breast cancer in postmenopausal women
• Androgens are active against metastatic breast cancer in about 20% of postmenopausal
women
• Progesterone and its analogs are active against certain neoplasms that are stimulated by
estrogens
• High doses of progestines or androgens antagonize the proliferative action of estrogen
• Endometrial carcinoma is treated with estrogens
74
Cont’

75. Tamoxifen-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
• It is a Nonsteroidal antiestrogen used in the treatment of the advanced breast cancer
• Competatively inhibits the estrogen receptor and the transcription of estrogen-
responsive genes
• It is bioactivated first to produce the active hydroxylated derivative
75
Bioactivation
O CH3
N
CH3
HO
O CH3
N
CH3
Cont’

76. B.Hormone-Dependent Prostatic Cancer
• Most of prostatic tumors are androgen-dependent
• In prostate circulatory androgens undergo metabolic activation to a derivative with
high binding affinity for androgen receptors
76
OH
O
Testosterone
OH
O
H
Bioactivation
5a-Reductase
found in neoplasm
Cont’

77. • Androgen antagonists are used for the treatment of metastatic prostate cancer
• They block the action of testosterone and dihydrotestosterone
Antiandrogens may be classified into :
a) Steroidal compounds (cyprotone, chlormadinone and megesterol)
b) Nonsteroidal compounds (flutamide (eulexin)) which has to be bioactivated first
77
HN
CF3
NO2
O
CH
CH3
CH3
HN
CF3
NO2
O
C OH
CH3
CH3
Bioactivation
Flutamide
Cont’

78. 4.ANTIBIOTICS
• Several compounds that were originally evaluated for their antibiotic activity have
been clinically useful anticancer agents
• They were rejected as antibiotics because of their toxicity
• This property was subsequently helped for their application as anticancer agents
• The source of most antitumor antibiotics is from microbial fermentation
78

79. i.Anthracyclines
• They represent a major class of antineoplastic agents
• Have tetracyclic quinone containing ring nucleus attached to a unique
daunosamine sugar
• Isolated from the fermentation broths of Streptomyces peucetius
• Several semisynthetic derivatives have been prepared in an attempt to reduce
the cardiotoxicity common to this class of compounds
• These include daunorubicin, doxorubicin, idaurubicin and epirubicin
79
Cont’

80. OH
R4
=
,
OH
R1
R2
= CH3O, =
= OH , R3
Epirubicin:
, R4
= OH
H
=
R3
=
R2
=
R1
Idarubicin:
OH
=
R4
,
H
=
R3
,
H
=
R2
= CH3O,
R1
Daunorubicin:
OH
=
R4
,
H
R3
,
OH
= =
= CH3O, R2
R1
Doxorubicin:
8
R2
CH2
12
1
5
R4
R3
O
NH2
CH3
R1
O
O
OH
OH
OH
O
CO
80
Cont’

81. 81
O
O
OH
OH
OH
C CH2
O
OH
O
O
H
H
OH
H
NH2
H
H
CH3
OCH3
A
B
C
D
Doxorubicin
1
2
3
4 5 6 7
8
9
10
11
12
Structure Activity Relationship
• The anthraquinone chromophore (ring D, C and B) is an important structural feature
• The phenolic hydroxyl groups undergo ready acylation and alkylation under standard
reaction conditions
• O-methylation of the C-6 or C-11 phenolic groups results in markedly reduced activity
• Modifications at C-4 such as demethylation and deoxygenation prolong the half life
with no effect on bioactivity (Idarubicin)
Cont’

82. • An imino functionality at C-5 resulted less cardiotoxic analog with retained activity
Ring-A,
• Alicyclic ring bearing carbon side chain group
• A chiral hydroxy group at C-9
• Connected to the amino sugar unit at C-7 attached with a α-glycosidic linkage
82
Cont’

83. Mechanism of action
• The flat structure of anthraquinone nucleus results in the ability of anthracyclines to
interact with DNA perpendicularly to its long axis
• The amino sugar confers added stability to this binding through its interaction with
the sugar phosphate backbone of DNA
• The interaction leads to break-up of single- and double-stranded DNA
83
Cont’

84. • The anthraquinone ring system of anthracyclines are capable of generating reactive
oxygen species such as .OH radical and super oxide radical anions (.O-O- )
• These free radicals produce destructive effects upon the cell
• The generation of free radicals may also account for the cardiotoxicity of the
anthracyclines
• Due to lack of oral activity, they are administered intravenously
84
Cont’

85. 85
• Iron-mediated
generation of free
oxygen radicals
Cont’

86. Mitoxantrone
• It is a simplified, synthetic analogue of the anthracyclines
• 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 intercalate between DNA base pairs
86
Cont’

87. ii. Bleomycins
• Bleomycins are a group of metal-chelating glycopeptide antibiotics that degrade DNA
• Their molecule feature two pivotal domains
1. DNA domain which allows interaction with DNA and RNA
2. Binding site which undergoes metal binding
• Which is involved in chelation of ferrous iron and interaction with the oxygen,
resulting in the oxidation of the iron and generation of superoxide
• Used for the treatment of squamous cell carcinomas of the head and neck
87
Cont’

88. 88
Cont’

89. iii.Mitomycin C
• Isolated from Streptomycin caespitosus
• It possesses several functional groups capable of antitumor activity
• The quinone moiety
• The aziridine ring system
• The carbamate functionality
• Are involved in the action of the drug and the drug is classified as a bio-reductive
alkylating agent
89
Cont’

90. • Undergo bio-reductive activation and elimination of methanol
• Results in nucleophiles in DNA leading to either mono- or dialkylation products
• The drug is poorly absorbed via orally and is administered IV
90
Cont’

91. Mechanism of action
91
• Interstrand and intrastrand alkylation
of DNA by bioreductively activated
mitomycin C
Cont’

92. iv.Dactinomycin (Actinomycin D)
• Isolated from Streptomyces parvullus
• Consists of tricyclic phenoxazone ring and two identical
pentapeptide lactones
• The pentapeptides are made up of L-proline and L-
threonine plus the essential amino acids D-valine,
sarcosine and N-methylvaline
• An amide linkage is present between the amino group of
L-threonine and carbonyls of 1 and 9 of Phenoxazone
chromophore
92
Cont’

93. • The planar phenoxazone ring facilitates intercalation between DNA base pairs
• Important for its mechanism of cytotoxicity
• The peptide loops provide for additional interactions in the minor groove
• Undergo non-covalent interaction with double-stranded DNA by partial intercalation
between adjacent guanine cytosine bases
• Results inhibition of DNA function
• Additional hydrophobic interactions and hydrogen bonds are formed between the
sugars and base pairs within the minor groove
93
Mechanism of action
Cont’

94. • The ring system is planar and can intercalate or insert into
DNA between base pairs
• The distortion caused by the presence of the intercalating
agent affects the action of topoisomerase II
• Which normally regulates unwinding of coiled double-
stranded DNA
• This in turn, interferes with DNA replication and
transcription
94
Cont’

95. • Mitotis inhibitors
• They particularly inhibit the formation of the mitotic spindle
• Mitosis involves the polymerization of protein tubulin to form mitotic spindle
• Antimitotic agents interfere with
• Polymerization of the microtubules
• Cause the formation of abnormal mitotic spindle structures
• In the absence of a properly formed mitotic spindle, the chromosomes cannot
correctly segregate and this ultimately leads to cellular death
95
5-PLANT PRODUCTS (ANTIMITOTIC AGENTS)

96. 1. Vinca Alkaloids
96
Vincristine,Vinblastin and Vinorelbine
• These alkaloids are composed of two multi ringed units
• They contain tertiary amino groups that form salts which are freely soluble in water
N
N
OH
CH2
-CH3
COOCH3
OCOCH3
CH2
-CH3
N
CH3O
CO2CH3
OH
H
N
H
R
H
Vincristine: R = CHO
Vinblastin: R = CH3
H2SO4
.
Cont’

97. 97
• Vinorelbine is a second generation semisynthetic derivative, modified in the
catharanthin or 'upper' portion of the vinblastine structure
• Morerecently, a bis-fluorinated vinorelbine derivative, vinflumine, has been
synthesized by the application of superacid chemistry
• They have a weak binding property to the tubulins, unlike the vincristine
Cont’

98. 98
Cont’

99. 99
Cont’

100. ii.Taxans
100
• Dried inner bark of Western/ Pacific yew (Taxusbrevifolia)
• 0.01 -0.04% of taxol; 1 kg Taxol-900 kg bark (2000 -3000 trees)
It consist of
• Taxol/Paclitaxel
• Docetaxel (more potent analogue)
It is a diterpenoid compound that contains a
complex taxane ring as its nucleus has
• A=6M
• B=8M
• C=6M
• D=4M (Oxetane)
The side chain linked to C13 the taxane ring
is essential for antitumor activity

101. • Paclitaxel and docetaxel are taxan derivatives
• Docetaxal is a taxoid differing in structure from
paclitaxel in having one less acetate group and a
tertiary butyl carbamate group in place of the
benzamido group
101
O
HO O
NH
O
R
1
H3C
HO
O
O
CH3
CH3
R
2-O O
CH3
OH
O
H
OCOCH3
1'
2'
3'
1
2
3
4
5
6
Paclitaxel: R1 = C
6
H
5
; R2 = Acetyl
Docetaxal: R
1
= (CH3)3C-O; R2 = H
Cont’

102. Structure activity relationship
102

103. • The drugs promote an assembly of tubulin to stable
microtubules
• Inhibit disassembly of the microtubulins to their
monomer form
• Interfere with a mitotic spindle
103
Mechanism of action
Cont’

104. Podophyllotoxines
• From Podophyllum peltarum (May apple),
Podophyllam emodi (Family: Berberidaceae)
• Affects DNA topoisomerase II (not intercalating) DNA
strand breakage
• They cause DNA linkages or DNA strand breaks by
inhibiting topoisomerase II
104

105. Camptothecins
• Camptothecin is a naturally occurring cytotoxic alkaloid
• Extracted from a Chinese bush (Camptothecaacuminata) in 1966
• It targets the complex between DNA and topoisomerase-I
• This leads to DNA cleavage and cell death, so no synthesizing new DNA
• Induction of destructive enzymes such as serine proteases and endonucleases
• The camptothecin show selectivity for cancer cells over normal cells (higher levels
of topoisomerase I in cancer cells than normal cells)
105

106. • In Camptothecin the lactone group is important for activity, but at blood pH it is in
equilibrium with the less activering-opened carboxylate structure
• Introducing substituents on A and B rings can increase the activity and produced
clinically useful semi-synthetic analogues of camptothecin called Irinotecan
andtopotecan
• They retain the important lactone group and were designed to have aqueous solubility
by adding suitable polar functional groups such as alcohols and amines
• Irinotecan is aurethane prodrug that is converted to the active phenol (SN-38) by
carboxylesterases, predominantly in the liver
106
Cont’

107. 107
Cont’

108. End of the lecture
Thank You!!!
108