In this presentation , you can see the classification of Anti-obesity drugs and mechanism of action of ecah class

1. S.J.M COLLEGE OF PHARMACY,
SJM CAMPUS, NH-4 BYEPASS
CHITRADURGA- 577502, KARNATAKA
M.PHARM SEMINAR
SUBJECT:-ADVANCED PHARMACOLOGY II
TOPIC: ANTICANCER DRUGS
SUBMITTED BY,
AKSHAY KUMAR C P
1ST
M PHARM
DEPT.OF PHARMACOLOGY
SUBMITTED TO,
MRS. HEENA KOUSER
ASST. PROFESSOR
DEPT.OF PHARMACOLOGY
SJM COLLEGE OF PHARMACY CHITRADURGA,
KARNATAKA

2. ANTICANCER DRUGS

3. ALKYLATING AGENTS:
1. The alkylating agents impair cell function by forming covalent bonds with the amino, carboxyl,
sulfhydryl and phosphate groups in biologically important molecules.
2. The most important sites of alkylation are DNA, RNA, and proteins. The electron-rich nitrogen at the 7
position of guanine in DNA is par-ticularly susceptible to alkylation. Alkylating agents depend on cell
proliferation for activity but are not cell-cycle- phase–specific.
3. A fixed percentage of cells are killed at a given dose. Tumor resistance probably occurs through efficient
glutathione conjugation or by enhanced DNA repair mechanisms. Alkylating agents are classified
according to their chemical structures and mechanisms of covalent bonding; this drug class includes the
nitrogen mustards, nitrosoureas, and platinum complexes, among other agents
NITROGEN MUSTARDS:
MECHLORETHAMINE
Alkylating agents work by three different mechanisms:
1. Attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in
their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the
affected DNA.
2. DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA
from being separated for synthesis or transcription, and
3. The induction of mispairing of the nucleotides leading to mutations. Mechlorethamine is cell cycle phase-
nonspecific.

4. CYCLOPHOSPHAMIDE
1. The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard.
2. This metabolite is only formed in cells that have low levels of ALDH(aldehyde dehydrogenase).
3. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7
positions (known as interstrand and intrastrand crosslinkages, respectively).
4. This is irreversible and leads to cell apoptosis. Cyclophosphamide has relatively little typical
chemotherapy toxicity as ALDHs (Aldehyde dehydrogenases) are present in relatively large
concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively
proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting
aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites
phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-
elimination (the carboxylate acts as an electron-donating group, forbidding the transformation),
preventing nitrogen mustard activation and subsequent alkylation. Cyclophosphamide induces beneficial
immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:
1. Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumour-bearing hosts
2. Induction of T cell growth factors, such as type I IFNs, and/or
3. Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an
immunologic space niche.
Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to
enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as
active vaccination strategies, inducing objective antitumor immunity.

5. ANTIMETABOLITES
1. Antimetabolites are structural analogs of the naturally occurring metabolites involved in DNA and RNA
synthesis.
2. As the constituents of these metabolic pathways have been elucidated, a large number of structurally
similar drugs that alter the critical pathways of nucleotide synthesis have been developed.
3. Antimetabolites exert their cytotoxic activity either by competing with normal metabolites for the
catalytic or regulatory site of a key enzyme or by substituting for a metabolite that is normally
incorporated into DNA and RNA.
4. Be- cause of this mechanism of action, antimetabolites are most active when cells are in the S phase and
have little effect on cells in the G0phase. Consequently, these drugs are most effective against tumors that
have a high growth fraction.
5. Antimetabolites have a nonlinear dose-response curve, such that after a certain dose, no more cells are
killed despite increasing doses (fluorouracil [5-FU] is an exception). The antimetabolites can be divided
into folate analogs, purine ana-logs, adenosine analogs, pyrimidine analogs, and substituted ureas

6. FOLATE ANTAGONIST
METHOTREXATE
1. It is a folic acid antagonist . It binds to dihydrofolate reductase (DHFR) and prevents the formation of
tetrahydrofolate (THF). This is a coenzyme essential in several reactions in protein synthesis. The
deficiency results in inhibition of protein synthesis. Thus rapidly affected multiplying cells are the most
affected.
2. Folic acid is required in the synthesis of thymidylate (a pyrimidine) and of purine nucleotides an thus for
DNA synthesis. Methotrexate is a very slowly reversible competitive inhibitor of dihydrofolate reductase
(DHFR).
3. The affinity of DHFR for methotrexate is 100000 times greater than that for dihydrofolate. Thus,
methotrexate prevents nucleic acid synthesis and causes cell death. Folinic acid circum vents this
biodynthetic block and thus non-competitively antagonizes the effect of methotrexate.

7. ANTIBIOTICS
PYRIMIDINE ANTAGONISTS
5-FLUOROURACIL
It is a pyrimidine analog. It inhibits the enzyme thymidylate synthetasee due to which it inhibits the
synthesis of thymine and thereby inhibits DNA synthesis.
5-Fluorouracil is a prodrug that is activated by anabolic phosphorylation to form
1. 5-fluorouridine monophosphate, which is incorporated into RNA, inhibiting its function and its
polyadenylation
2. 5-fluorodeoxyuridylate, which binds strongly to thymidylate synthetase and inhibits DNA synthesis.
3. Incorporation of 5-fluorouracil itself into DNA causes mismatching and faulty mRNA transcripts.

8. ANTIBIOTICS
DOXORUBICIN
It forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II
activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-
religation reaction that topoisomerase II catalyzes.
cytotoxic actions of anthracyclines lead to apoptosis, and include
1. Intercalation between adjacent base pairs in DNA, leading to fragmentation of DNA and inhibition of
DNA repair, enhanced by DNA topoisomerase II inhibition
2. membrane binding alters membrane function and contributes to cardiotoxicity
3. free-radical formation also causes cardiotoxicity.

9. EPIPODOPHYLLOTOXINS
ETOPOSIDE
1. DNA topoisomerase II is a nuclear enzyme that binds to and cleaves both strands of DNA. It is necessary
for DNA replication and RNA transcription.
2. Etoposide stabilizes the topoisomerase II–DNA complex, leading to apoptosis, as for camptothecins.
VINCA ALKALOIDS
1. Vinca alkaloids bind to β-tubulin, a protein that forms the microtubules which are essential for the
formation of the mitotic spindle.
2. They prevent β-tubulin polymerizing with α-tubulin and thus inhibit mitosis.
3. Blockade of microtubular function involved in neuronal growth and axonal transport probably accounts
for their neurotoxicity.
TAXANES:
PACLITAXEL
1. Paclitaxel binds to the β-subunit of tubulin and antagonizes the depolymerization of microtubules, halting
mitosis.
2. Cells are blocked in the G2/M phase of the cell cycle and undergo apoptosis.
MISCELLANEOUS
IMATINIB
1. Imatinib is an ATP mimetic. It competitively inhibits several tyrosine kinases, most potently BCR-ABL
and platelet-derived growth factor receptor tyrosine kinases (IC50s, 100–300 nM) and amutated c-KIT. In
CML, the BCR-ABL fusion protein is pivotal in driving cellular replication and proliferation pathways.
2. In GIST it is c-KIT that is overactive and drives proliferation. Inhibition of these tyrosine kinases causes
the cell to undergo apoptosis.