1. Anticancerous &
Antitubercular drugs
Presented by:
Sanskrita Madhukailya
M.Sc.
Dept. of Chemistry, Dibrugarh University

2. CANCER OR MALIGNANT NEOPLASM
• The term ‘Cancer’ is used to describe a large group of diseases that are
characterized by cellular malfunction.
• Cancerous cells have lost their regulatory mechanism that control cell
growth & multiplication.
• The unregulated cell growth forms a ‘Tumor’. Two types of tumors:
Benign & Malignant.
• Benign tumor stays at the same place, Malignant tumors grows rapidly &
continuously, invades new tissues to set up secondary tumors
(Metastasis).
• The causation of neoplasms: Genetic factors, Chemical carcinogens
(arsenic, soot, coal tar, etc.), polycyclic hydrocarbon carcinogens etc.

3. CLASSIFICATION
Antineoplastic drugs are classified under the
following five categories, namely:
 Alkylating Agents
 Antimetabolites
 Antibiotics
 Plant products
 Miscellaneous compounds

4. Alkylating agents
• a fully saturated Carbon atom of the alkylating group attaches to nucleophile, or
• alkylate the substance with which they react, through Covalent bonds.
Alkylating agents
Mustard
Methanesulphonate
Ethylenimines
Nitrosoureas
Not used further due to high toxicity, low
solubility in water, oily nature & blister
producing property (mustard gas)
instead
Nitrogen Mustard
(4 categories)

5. 1. Nitrogen Mustard
• Stable solids
• Low vapour pressure
• High solubility in water.
• 4 categories Mechlorethamine Hydrochloride
Melphalan
Cyclophosphamide
Chlorambucil

6. Mechlorethamine
Hydrochloride
Structure Synthesis
Given by intravenous administration of freshly
prepared solution because gradual degradation of
the aziridium ion by interaction with water.
Uses
• Hodgkin’s disease
•Lymphomas
•Thrombocytopenia
•Leucopenia
•Important candidate for well-
known MOPP regimen
MOPP:
M-Mechlorethamine, O-Oncovin, P-Procarbazine, P-Prednisone

7. 1. β-chloroethyl moieties lose Cl- ions, generate
carbonium and azardium (ethylerimonium ions)
- extremely reactive.
2. In DNA they alkylate guanine moieties; one arm
alkylates one guanine group and the second
arm another guanine on the opposing strand
of prevailing double-stranded DNA,
3. the DNA becomes irreversibly cross-linked,
4. inhibition of mitosis, besides causing
chromosomal breakage
Mechlorethamine
Hydrochloride (cont.)

8. Melphalan
Structure Synthesis
Uses
•Multiple myeloma
•Breast cancer
•Ovarian cancer
•premenopausal women who have
undergone radical mastectomy.
Melphalan inhibits DNA & RNA synthesis via formation of
interstrand cross-links with DNA, binding to N7 position of
guanine

9. Mechanism of action of Melphalan

10. Cyclophophamide
Structure Synthesis
Uses
•Multiple myeloma
•Chronic lymphatic leukemia
•Acute leukemia
•Acute lymphoblastic leukemia
Substitution at C-4 position
(a) : R1 = R2 = —CH2-CH2-Cl ; R3 = H ; R4 = C6H5, 4-phenyl cyclophosphamide
(b) : R1 = R2 = —CH2-CH2-Cl ; R3 = H ; R4 = CH3, 4-methyl cyclophosphamide
(c) : R1 = R3 = —CH2-CH2-Cl ; R2 = R4 = H, Ifosfamide
(d) : R1 = R2 = R3 = —CH2-CH2-Cl ; R4 = H, Trofosfamide

11. Mechanism of action of Cyclophosphamide
•Drug is activated by
Cytochrome P450 (CYP)
isozymes CYP2B6 &
CYP3A4/5
•Phosphoramide mustard
is the ultimate alkylating
agent.

12. Chlorambucil
Structure Synthesis
Uses
•Hodgkin’s disease
•Lymphosarcoma
•Primary microglobulinemia
•Chronic lymphocytic leukemia Chlorambucil is the least toxic & slowest acting;
commonly used nitrogen mustard.

13. 2. Methanesulfonates
•Long alkylene chains separates the reductive sulfonate
ester groups; excluding the possibility of formation of
reactive ring structures
•The ester groups have direct alkylating ability
•Methanesulfonate ion (weak nucleophilic group) is
displaced from carbon by strong nucleophilic group in the
biological system
Important methanesulfonate is Busalfan

14. Busalfan
Structure Synthesis
•Granulocytic leukemia
•Bone marrow transplant
Uses
1. It is a cell cycle non-specific alkylating neoplastic agent.
2. It is used in combination with Cyclophosphamide or
fludarabine/clofarabine as a conditioning agent.
3. It was recently used in a study to examine the role of
platelet-transported serotonin in liver regeneration.

15. 3. Ethylenimines
•There are two important ethylenimine drugs, they are:
Triethylenemelamine (TEM) Triethylenethio phosphoramide
and
2, 4, 6-Tris (ethyleneimino)-S-triazine N, N′, N′′-Triethylenethio-phosphoramide

16. Triethylenethio phosphoramide
(Thio-tepa)
Synthesis
(Recrystalized from water)
Uses
•Breast cancer
•Ovarian cancer
•Colon-rectum cancer
•Bronchogenic carcinomas
•Malignant lymphomas

17. Interaction of the drug with DNA
N7-gua-DNA monoadduct
N7-diguanyl-DNA
Interstrand crosslink
N7-gua-DNA monoadduct

18. 4. Nitrosoureas
•First synthesized at Southern Research Institute, Birmingham.
•Important Nitrosoureas are: Carmustine and Lomustine
•Decomposition of Nitrosoureas-
Agent responsible
for DNA alkylation

19. Mechanism of DNA alkylation
by Nitrosoureas

20. Carmustine
•Brain tumours e.g., leukemias (metastasized to
the brain)
•Along with Prednisone for Multiple mycloma
•As secondary therapy, along with others for
Lymphomas & Hodgkin’s disease
Structure Synthesis
Uses

21. Lomustine
•Primary & metastatic brain
tumours.
•Secondary therapy in Hodgkin’s
disease
Uses
Structure Synthesis

22. Antimetabolites
•Compounds that prevent the biosynthesis of normal cellular metabolite.
•Possess close structural resemblance to the metabolite to be antagonized.
Antimetabolites
Antifolic acid compounds
Analogues of Purines
Analogues of Pyrimidines
Amino acid antagonists
(4 categories)

23. Antifolic acid compounds
• prevents the synthesis of folic acid, required by the tissues.
• Also known as “Antifolics” or “Folate antagonists”.
• Antifolics kill cells by inhibiting DNA synthesis in the S phase
of the cell cycle
• Bind strongly to dihydrofolate reductase (DHFR), inhibiting
the conversion of dihydrofolic acid to tetrahydrofolic acid,
inhibiting the synthesis of purines and thymidines.
• Most important among Antifolics is Methotrexate

24. Methotrexate
Structure
Synthesis
•Acute lymphoblastic leukemia,
•Prophylaxis of meningeal leukemia,
•Choriocarcinoma,
•Trophoblastic tumours in women, etc.
Uses

25. 3 cytotoxic actions of methotrexate-
Mechanism of action of
methotrexate

26. Analogues of Purines
• Purines are integral components of RNA, DNA and coenzyme
that are synthesized in proliferation of cancer cells.
• Analogues antagonizes the purine leading to formation of false
DNA.
• Purine analogues are designed by replacing the 6-hydroxyl group
of Hypoxanthine & Guanine by isosteric thiol/sulfhydryl groups.
• Important purine analogues are- Mercaptopurine Azathiopurine
and

27. Mercaptopurine
Structure Synthesis
Orthoimmune encephalomyletis, thyroiditis, childhood leukemia (in combination with
Vincristine, Methotrexate, Prednisone)
Uses

28. Azathioprine
Structure Synthesis
Immunosuppressant, rheumatoid arthritis, prevent transplant rejection, ulcerative colitis etc.
Uses

29. Analogues of Pyrimidines
• Two most important Pyrimidine analogues are-
Fluorouracil Cytarabine
and
Fluorouracil :
Synthesis
Structure

30. •This analogue is a Thymidylate Synthase (TS) inhibitor.
•TS works by methylating deoxyuridine
monophosphate(dUMP) to form deoxythymidine
monophosphate(dTMP)
•Fluorouracil causes scarcity of dTMP (thymidine component)
resulting in cell death of the rapidly dividing cancer cells via
thymineless death.
•A stable covalent 5-FU-TS ternary complex is formed that
blocks the synthesis of thymidine.
•Colon cancer
•Esophageal cancer
•Stomach cancer
•Breast cancer
•Cervical cancer
Uses
Mechanism of action of
Fluorouracil

31. Structure Synthesis
Cytarabine
It is converted to cytosine arabinose triphosphate which competes with cytidine for
incorporation into DNA, preventing its replication in the S phase of cell cycle.
Uses: acute myelogenous leukemia, meningeal leukemia etc.

32. Amino acid antagonists
• The amino acid antagonists broadly act as a glutamine
antagonists in the synthesis of formylglycinamidine ribotide
from glutamine and formylglycinamide ribotide.
• Important example is Azaserine, that inhibits purine biosynthesis
Leukemia, Hodgkin’s disease etc.
Uses
Structure

33. Antibiotics
•The word “antibiotic” refer to compounds of natural origin; while synthetic antibiotics have
the support of natural background.
•Cancer chemotherapeutic agents are introduced by microorganisms
•Important Anticancerous antibiotics are Daunorubicin
Dactinomycin
1)
2)

34. Dactinomycin
•Obtained from species of Streptomyces.
•Also known as Actinomycin D.
•Inhibits the DNA-dependent RNA-polymerase.
•It binds to DNA, intercalates between the base
pairs, and finally hinders RNA synthesis.
•Used in the treatment of sarcomas, germ cell &
trophoblastic tumours, melanoma & Wilms’
tumour etc.
Structure

35. Daunorubicin
•Known as Anthracyclines due to the presence of a
tetracyclic ring bearing an anthraquinone
chromophore.
•Inhibitors of topoisomerase II (a key enzyme
involved in DNA synthesis), yielding oxygen
radical, ultimately inhibiting DNA synthesis.
•Used for treatment of breast cancer, acute non-
lymphocytic leukemia, Hodgkin & non-Hodgkin
lymphoma & sarcoma etc.
Structure

36. Plant products
• Several medicinal plant species & their phytochemicals
inhibit the progression & development of cancer.
• Studies of Dustin in 1938 on the cytotoxicity of colchicine
announced the search for plant-based antineoplastic agents.
• Plant products based on their chemical nucleus are divided
into 5 categories.
Imides & Amides Tertiary amines Heterocyclic amines
Lactones Glycosides
They are:

37. Imides & Amides
1) Colchicine
•An alkaloid extracted from the plants of Colchicum autumnale.
•It binds permanently to tubulin, stabilizes microtubule
formation, arrest cell cycle at different phases and induces
apoptosis.
•Action is not specific and targets rapidly dividing normal cells
and arrest their cell cycle.
•Quite toxic; so less toxic semisynthetic derivatives are
developed for treatment of cancer.
Colchicum autumnale

38. 2) Narciclasine
•Narciclasine is named after the plant genus Narcissus
(daffodil), isolated from the bulbs of the plant (1967).
•Inhibits cell growth by blocking protein biosynthesis.
•RNA synthesis was not affected, DNA synthesis slightly
diminished at high concentrations.
•Its binding site is located on the 60S subunit of ribosome,
overlap with peptidyl transferase inhibitors
Narcissus

39. Tertiary amines
1) Vinca alkaloids
•Includes Vinblastine & Vincristine.
•Isolated from Catharanthus roseus (Family: Apocynaceae)
•Binds to micro tubular protein tubulin in dimeric form,
arresting the cell cycle at metaphase.
•Used for treatment of Hodgkin’s disease, Lymphomas, acute
leukemia (with Prednisone)
Catharanthus roseus

40. Heterocyclic amines
•Isolated from Camptotheca acuminata (Nyssaceae).
•Used for treatment of solid tumours, small cell lung cancer,
colorectal cancer, ovarian cancer etc.
•Important ones are: camptothecin, hydroxycamptothecin
and methoxy camptothecin.
Camptotheca acuminata

41. Lactones and Glycosides
•Podophyllotoxin and deoxypodophyllotoxin ,two alkaloids
obtained from Podophyllum emodi and the May Apple
Podophyllum peltatum (Berberidaceae).
•Podophyllotoxin is an aromatic lactone that arrests the metaphase
activity in the DNA synthesis
•Solamargine, a steroidal glycoside isolated from Solanum
incanum.
•Some other kinds of antineoplastic glycosides isolated from
Antiaris toxicaria are Antiarioside J, Antiarioside N,
Toxicarioside B, Convallatoxin etc. Solanum incanum.

42. Miscellaneous drugs having
Anti-cancerous properties
Name Chemical nature Uses Adverse effects
Cisplatin cis-
dichloroplatinum
Along with Vinblastine &
Bleomycin for metastatic testicular
& ovarian tumours, cervical, neck
cancer etc.
In high doses, continuous
myelosuppression
L-asparaginase E coli L-aspargine
amidohydrolase
Acute lymphoblastic leukemia(ALL) Side effects like allergies,
development of immune
response & anaphylactic
shock.
Megestrol acetate 17-Hydroxy-6-
methylpregna-3,6-
diene-3,20-dione
Advanced breast cancer, advanced
endometrial cancer
High B.P., Amenorrhea,
Anaemia etc.

43. ANTI-TUBERCULAR
DRUGS

44. TUBERCULOSIS (TB)
• Contagious disease, caused by Mycobacterium tuberculosis bacteria.
• Transmitted through inhalation of (as few as 10 Mycobacetrium tuberculosis
bacteria) aerosolized droplets when the patient coughs, sings or speaks.
• Mainly affects the lungs but can affect other parts of the body.
• Dr. Robert Koch discovered Mycobacterium tuberculosis bacteria on 24th
March, 1882 (24th March: World TB Day).
• TB skin test & TB blood tests are performed to diagnose the infection.
• Persons with weakened immune systems are more prone to TB, for eg., people
with HIV.

45. CLASSIFICATION
According to clinical utility, anti-TB drugs are divided into two
categories-
(a) First-line drugs : high antitubercular efficacy & low toxicity-
routinely used. Types:
Isoniazid (H), Rifampin (R), Ethambutol (E),
Pyrazinamide (Z)
Streptomycin (S),
(b) Second-line drugs : low antitubercular efficacy or high
toxicity; used in patients unable to tolerate/ resistant to first-line
drugs. Types:
Fluoroquinolones, Cycloserine, Ethionamide, Aminosalicylic acid,
Aminoglycosides, Capreomycin.

46. Synthesis
•Bactericidal activity against susceptible strains of M. tuberculosis.
•Treatment of latent infection,
•Administration : Oral, IV
•Toxicity : Hepatotoxic
Isoniazid
First-line drugs

47. •Synthetic, water-soluble, heat-stable compound
dispensed as the dihydrochloride salt
• Bacteriostatic
• Given in the combination with RHZ
Ethambutol
•a semi synthetic derivative of naphthalene was produced by
Streptomyces mediterranei.
•Binds to the bacterial DNA-dependent RNA polymerase - inhibits RNA
synthesis
• Bactericidal for mycobacteria
Rifampin

48. •Relative of nicotinamide
• Stable and slightly soluble in water but weak drug
•Pyrazinamide is converted to pyrazinoic acid (active form) – by
mycobacterial pyrazinamidase, disrupts mycobacterial cell membrane
metabolism and transport functions.
Pyrazinamide
•Part of aminoglycosides antibiotic
• First clinically useful antitubercular drug, but less effective than
Isoniazid or rifampin.
• Acts only on extracellular bacilli – poor
penetration into cells.
•Vertigo and hearing loss - common adverse effects and may be
permanent
Streptomycin

49. Second-line drugs
Fluoroquinolones
•They have broad-spectrum antimicrobial activity
•They have excellent in vitro and in vivo activity against M. tuberculosis
•The cellular target of FQs in M. tuberculosis is DNA gyrase, a type II topoisomerase.
•Typical examples of the fluoroquinolones are:
Ofloxacin, ciprofloxacin, levofloxacin, and moxifloxacin.
Cycloserine
•Obtained from S. orchidaceus.
•acts as an inhibitor of cell-wall synthesis.
•readily absorbed via the oral administration.
•for the adequate treatment of multidrug-resistant tuberculosis along with certain
other primary drugs.

50. •A derivative of isonicotinic acid and has been used as an antituberculosis
agent since 1956.
•Blocks the synthesis of mycolic acids.
•Poorly water soluble and available only in oral form.
•Gastrointestinal side effects, such as abdominal pain, nausea, vomiting and
anorexia.
Ethionamide
•structural analogue of p-aminobenzoic acid (PABA)
•highly specific for M. tuberculosis - not effective against other mycobacterium
species
•Combined with isoniazid
•limited to the treatment of MDR tuberculosis
•Discouraged its use : primary resistance, poor compliance due to GI intolerance,
etc.
p-amino salicylic acid

51. Aminoglycosides (Amikacin, Kanamycin)
•Treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multi-drug
resistant strains.
•Primarily affect protein synthesis in M. tuberculosis and resistance to these drugs is associated with
changes in the 16S rRNA .
•Used in combination with at least one and preferably two or three other drugs.

52. CONCLUSION
• Cancer is one of the leading causes of morbidity & mortality worldwide, 14M
new cases, 8.2M deaths in 2012 compared to 18.2M new cases, 9.6M deaths in
2018.
• FDA(U.S. Food & Drug administration), recently approved Selinexor, a first-in-
class selective inhibitor of nuclear export to treat RRMM.
• Oncology drug development is challenging- emergence of multidrug resistance
(MDR) & relapse.
• Success rate for clinical development of anti-cancerous drugs is ~10%, cost
greater than 1billion US$.
• Hepatotoxicity is the major side-effect of first-line antiTB drugs (expect
ethambutol).
• Majority TB deaths occur in persons being HIV-positive. Diabetes is also known
to increase the risk of developing TB by three-folds.
• Success rate of Anti-TB drugs are less due to bacterial resistance.
• The priority now should be to maintain the basic principles of treatment using
chemotherapy but implement these efforts with greater vigor.

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