Transcript Antineoplastic drugs
Moustafa K. Soltan
Cancer=neoplasm=tumor=high rate of cell proliferation or cell division in an
uncontrolled, uncoordinated, and unorganized manner by malignant cells invade
adjacent cells forming daughter colonies.
**Metastasis: secondary growth originating from the primary tumor growimg
elsewhere in the body.
Antineoplastic drug: cytotoxic chemical substance that suppress the proliferation
of neoplasm via
1) Mitotic arrest.
2) Interference of transcription of nucleic acid.
**All antineoplastis are cytotoxic except hormones, so they have no specificity
for cancer cells, so the major problem of their use is that they affect non
carcinogenic cells such as:
Bone marrow, lymph tissue, GIT mucosa and hair cells which become highly
affected by their use.
Classification of antineoplastic drugs:
1) Alkylating agents: 1.A-nitrogen mustards:
Mechlorethamine HCl, chlorambucil, melphalan, uracil mustard,
1. B-aziridine derivatives : trimethylene melamine, thiotepa
1. C-nitrosourea derivatives: carmustine, lomustine.
1. D-alkyl sulfones: busulfan.
1. E- miscellaneous alkylating agents: pipobroman.
2) Antimetabolites: antagonists of metabolites involved in nucleic acid synthesis.
2.A-folic acid antagonists: methotrexate.
2. B-pyrimidine antagonists: 5-fluorouracil.
2. C-Purine antagonists: 6-mercaptopurine.
3) Anticancer antibiotics: dactinomycin, bleomycin, doxorubicin, mitomycin.
4) Plant products: vinblastine, vincristine, colchicines and podophyllotoxin.
5) Hormones: androgens like testosterone and estrogen, antiestrogenics like
6) Immunotherapy: levimasol and tilorone.
7) Miscellaneous agents: hydroxyl urea, cisplatin, hexamethylmelamine.
1) Alkylating agents:
General mechanism of action of alkylating agents:
they form reactive intermediates in vivo which act as alkylating agents for
nucleophilic groups of active centers in the body like DNA and enzymes, such
nucleophilic groups are :
amino groups, ring nitrogen atoms, phosphate anions, and thiolate anions
Mechaniom of action of nitrogen mustards:
ethylene immonium ion
at physiological PH
N + Cl
active intermediate that alkylate
nucleophilic attack bimolecular
nucleophilic centers in the cancer
Nuand non-cancer cell!!
Nu Again +Nu- / -ClNu
Uses: 1) certain leukemia
2) Breast, lung cancer
Conversion of the nitrogen to its oxide reduces its toxicity with small reduction in
its antitumor activity, Its reactivity is due to formation of highly reactive cyclic
oxonium ion, which has the ability of alkylation as nitrogen mustard.
Uses: 1)orally active, agent of choice of Chronic lymphocytic
2) Agent of second choice in the treatment of
choriocarcinoma, testicular carcinoma with methotrexate
Uses : in wide variety of tumors.
** L form is the active one.
Synthesis of chlorambucil
1)HNO3 / H2SO4
2) 2-propanol / HCl
1) H2 / Pd reduction
2) ethylene oxide
COOCH(CH 3) 2
specific synthesis for melphalan: like chlorambucil as above, but start from
phenylalanine, but we protect amnio group
before nitration by acetylation and COOH
gropup by esterification
Mode of action
Cl H C
open chain O
The phosphamide bridge connecting the mustard nitrogen and the
phosphorous atom is cleaved by phosphatase (phosphamidase) enzyme which
is present in larger amounts in cancer cells than non-cancer cells what
increase alkylating activity in cancer cells and enhance the selectivity to
specific synthesis of cyclophosphamide:
Assay: )due to halide content :as above
)due to phosphorous content:
H SO / HNO
phosphomolypdate complex which is ppted by quinoline, filtered, washed,
then dissolved in kn xss of N/ NaOH, residual NaOH is back titrated by
N/ HCl using (phph and thymol blue) as indicator.
5-[bis(2-chloroethyl)amino]uracil, uracil= pyrimidine-2,4-dione
combines the feature of nitrogen mustard and nucleotide antimetabolite…
** Uracil ring act as carrier for the alkylating group.
Aziridine derivatives.( ethyleneimines)
These compounds are activated in slightly acidic media to an active alkylating
They can be orally used with precautions:
1) taken in an empty stomach.
2) coadministered with NaHCO3 to neutralize stomach acidity
TEM= trimethylene melamine
Uses :mainly in metastatic carcinoma of breast and ovary.
N P N
N P N
Titrate liberated NaOH by st HCl and
Methyl orange as indicator.
MOA: sulfur stripping, in which the compound react with thiol group of
glutathione and cysteine, So as to form cyclic sulfonium intermediate
which is converted into metabolite -hydroxythiolane- , -dioxide.
Such metabolite inhibit DNA synthesis and so prevent cell proliferation, growth.
+ CH SO + H
ASSAY: Hydrolysis by reflux with water, leading to hydrolysis into
, -butanediol and methanesulfonic acid CH SO H is produced
which can be titrated with st NaOH and phph as indicator.
Uses: 1) due to its ability to pass BBB, it can be used in brain tumors
And other tumors like leukemia that metastasized to the brain ( metastatic
2) secondary agent in combinations for Hodgkins disease and other
+ N2 + OH
act as alkylator
centers in cell
synthesis of lomustine: