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Chapter: Medicinal Chemistry : Antineoplastic Agents

Anthracyclines: Daunorubicin, Doxorubicin, Idarubicin, Valrubicin, Bleomycin Sulphate, Mitomycin-C : Dactinomycin or Actinomycin D, Plicamycin (Mithramycin)

Antineoplastic Agents - SYNTHESIS AND DRUG PROFILE



Anthracyclines occur as glycosides of the anthracyclinone. The glycosidic linkage usually involves the-7hydroxyl group of anthracyclinone and the β enentiomer of sugar with L-configuration. Anthracyclinone refers to an aglycone containing the anthraquinone chromophore within a linear hydrocarbon skeleton related to that of tetraycline.



Properties and uses: Daunorubicin is obtained from the fermentation of Streptomyces peuletieues. This drug bind to the DNA and inhibit nucleic acid synthesis, mitosis, and promote chromosomal aberration. These drugs are used for the treatment of acute myclocytic leukaemia, primary hepatocellular carcinomal, and ovarian endometrial carcinoma.



Properties and uses: Doxorubicin hydrochloride is an orange-red crystalline hygroscopic powder, soluble in water, and slightly soluble in methanol. Doxorubicin is 14-hydroxy daunoruibicin obtained from the cultures of Streptomyces peuletiues. It is one of the most effective antitumour agent. It is used in the treatment of acute lymphocytic leukaemia, breast, lung, ovarian, thyroid, gastric carcinoma, and Hodgkin’s disease.

Assay: It is assayed by adopting liquid chromatography technique.

Dosage forms: Doxorubicin HCl injection I.P., Doxorubicin HCl tablets I.P., Doxorubicin injection B.P.



Properties and uses: Idarubicin is demethoxy daunorubicin. It is a synthetic analogue of naturally occurring anthracyclines. It is used in acute myelogeneous leukaemia and acute lymphocytic leukaemia.



Properties and uses: Valrubicin is a derivative of doxorubicin in which the amino group has a trifluoroacetyl substituent and 14-hydroxy group is converted to valerate ester.


Bleomycin Sulphate

Properties and uses: Bleomycin sulphate is a mixture of cytotoxic glycopeptidase isolated from the strain of Streptomyces verticillers. It is mixture of closely related compounds with bleomycin A2 and B2, Bleomycins occurs naturally as blue copper chelates. Inside, the cell, bleomycin forms a complex with Fe (II), gives rise to hydroxyl radical and superoxide radicals. These radicals cleave the phosphodiesterase bond of DNA. This degradation of DNA strands is thought to be a lethal event in cells. It is effective in the treatment of testicular carcinomas. It is also useful in the treatment of squamous cell carcinomas of the head, neck, oesophagus, skin, and the genito-urinary tract, including the cervix, vulva, scrotum, and penis.



Properties and uses: Mitomycin exists as blue-violet crystals or crystalline powder, slightly soluble in water, freely soluble in dimethylacetamide, sparingly soluble in methanol, and slightly soluble in acetone. It is obtained from Streptomyces eqespitosus; it contains three different carcinostatic functions, quinone, carbamate, and aziridine. The molecule is unreactive in its natural state. After intracellular enzymatic or spontaneous chemical reduction of the quinone and loss of the methoxy group, mitomycin becomes a bifunctional or trifunctional alkylating agent. The drug inhibits DNA synthesis at the O6 and N7 positions of guanine. In addition, single-strand breakage of DNA are caused by mitomycin. It is used in gastric and pancreatic carcinoma.

Assay: It is assayed by adopting liquid chromatography technique.


Dactinomycin or Actinomycin D

Properties and uses: It is obtained form the cultures of Streptomyces antibioticus. It consists of tricyclic phenoxazone ring in the quinone oxidation state and two identical polypeptide and intercalates into the double helical DNA. The main biochemical consequence of the intercalation of actinomycin into DNA is the inhibition of DNA and RNA synthesis, which in turn leads to depletion of protein and cell death.


Plicamycin (Mithramycin)

Properties and uses: It is an aureolic acid derivative obtained from Stremyles plicatus or Streptomyces argillaceus. It forms a complex with divalent metals, such as magnesium and calcium and such complex formation is required before binding with DNA. It inhibits DNA dependent RNA polymerase, which leads to cell death. It is used in the treatment of embryonal tumours of the testes and metastic cancers.

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