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
• The causation of neoplasms: Genetic factors, Chemical carcinogens
(arsenic, soot, coal tar, etc.), polycyclic hydrocarbon carcinogens etc.
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.
Not used further due to high toxicity, low
solubility in water, oily nature & blister
producing property (mustard gas)
Given by intravenous administration of freshly
prepared solution because gradual degradation of
the aziridium ion by interaction with water.
• Hodgkin’s disease
•Important candidate for well-
known MOPP regimen
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
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
Important methanesulfonate is Busalfan
•Bone marrow transplant
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
2, 4, 6-Tris (ethyleneimino)-S-triazine N, N′, N′′-Triethylenethio-phosphoramide
17. Interaction of the drug with DNA
18. 4. Nitrosoureas
•First synthesized at Southern Research Institute, Birmingham.
•Important Nitrosoureas are: Carmustine and Lomustine
•Decomposition of Nitrosoureas-
for DNA alkylation
•Brain tumours e.g., leukemias (metastasized to
•Along with Prednisone for Multiple mycloma
•As secondary therapy, along with others for
Lymphomas & Hodgkin’s disease
•Compounds that prevent the biosynthesis of normal cellular metabolite.
•Possess close structural resemblance to the metabolite to be antagonized.
Antifolic acid compounds
Analogues of Purines
Analogues of Pyrimidines
Amino acid antagonists
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
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
• Purine analogues are designed by replacing the 6-hydroxyl group
of Hypoxanthine & Guanine by isosteric thiol/sulfhydryl groups.
• Important purine analogues are- Mercaptopurine Azathiopurine
29. Analogues of Pyrimidines
• Two most important Pyrimidine analogues are-
30. •This analogue is a Thymidylate Synthase (TS) inhibitor.
•TS works by methylating deoxyuridine
monophosphate(dUMP) to form deoxythymidine
•Fluorouracil causes scarcity of dTMP (thymidine component)
resulting in cell death of the rapidly dividing cancer cells via
•A stable covalent 5-FU-TS ternary complex is formed that
blocks the synthesis of thymidine.
Mechanism of action of
31. Structure Synthesis
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.
•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
•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’
•Known as Anthracyclines due to the presence of a
tetracyclic ring bearing an anthraquinone
•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.
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
37. Imides & Amides
•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
•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.
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
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)
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.
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
•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
Name Chemical nature Uses Adverse effects
Along with Vinblastine &
Bleomycin for metastatic testicular
& ovarian tumours, cervical, neck
In high doses, continuous
L-asparaginase E coli L-aspargine
Acute lymphoblastic leukemia(ALL) Side effects like allergies,
development of immune
response & anaphylactic
Megestrol acetate 17-Hydroxy-6-
Advanced breast cancer, advanced
High B.P., Amenorrhea,
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
According to clinical utility, anti-TB drugs are divided into two
(a) First-line drugs : high antitubercular efficacy & low toxicity-
routinely used. Types:
Isoniazid (H), Rifampin (R), Ethambutol (E),
(b) Second-line drugs : low antitubercular efficacy or high
toxicity; used in patients unable to tolerate/ resistant to first-line
Fluoroquinolones, Cycloserine, Ethionamide, Aminosalicylic acid,
47. •Synthetic, water-soluble, heat-stable compound
dispensed as the dihydrochloride salt
• Given in the combination with RHZ
•a semi synthetic derivative of naphthalene was produced by
•Binds to the bacterial DNA-dependent RNA polymerase - inhibits RNA
• Bactericidal for mycobacteria
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.
•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
49. Second-line drugs
•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.
•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
•structural analogue of p-aminobenzoic acid (PABA)
•highly specific for M. tuberculosis - not effective against other mycobacterium
•Combined with isoniazid
•limited to the treatment of MDR tuberculosis
•Discouraged its use : primary resistance, poor compliance due to GI intolerance,
p-amino salicylic acid
51. Aminoglycosides (Amikacin, Kanamycin)
•Treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multi-drug
•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.
• 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
• 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
• 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.
1. A. Kar, Medicinal Chemistry, Fourth edition, 794-827, 784-789.
2. Iqbal J, et al., Plant-derived anticancer agents: A green anticancer approach, Asian Pac J Trop Biomed
3. First.R, Narciclasine-An Amaryllidaceae alkaloid with potent antitumour and anti inflamatory
properties, Planta med, (2016)
4. H. Khan, M. Saeedi, S. M. Nabavi, M. S. Mubarak, A. Bishayee, Glycosides from Medicinal Plants as
Potential Anticancer Agents: Emerging Trends Towards Future Drugs, Current Medicinal Chemistry,
(2019), 26, 2389-2406.
5. S. Saeidnia, New Approaches to Natural Anticancer Drugs, SpringerBriefs in Pharmaceutical Science
& Drug Development, (2015), 52-58
6. Shrivastava A, Khan AA, Khurshid M, Kalam MdA, Jain SK, Singhal PK, Recent Developments in
L-asparaginase Discovery and Its Potential as Anticancer Agent, Critical Reviews in Oncology and
8. Bhattacharya, B. and Mukherjee, S. Cancer Therapy Using Antibiotics. J. of Cancer Therapy, (2015) ,
9. Jnawali and Ryoo, First– and Second–Line Drugs and Drug Resistance, Tuberculosis - Current Issues
in Diagnosis and Management, (2013), 163-170.
10. Shehzad A., Rehman G., Ul-Islam M., Khattak W. A., & Lee, Y. S., Challenges in the development of
drugs for the treatment of tuberculosis ,The Brazilian J. of Infect. Dis, (2013), 17(1), 74–81.
11. Mary J. Meegan, Niamh M. O’Boyle, Special Issue “Anticancer Drugs”, Pharma., (2019), 12, 134
12. Sarkar S, Ganguly A, Sunwoo HH, Current Overview of Anti-Tuberculosis Drugs: Metabolism and
Toxicities, Mycobact Dis, (2016), 6(2), 209.