Cytotoxic agents derivatives

Cyclophosphamide (Cytoxan) is the most versatile and useful of the nitrogen mustards. Preclinical testing showed it to have a favorable therapeutic index and to possess the broadest spectrum of antitumor activity of all alkylating agents. As with the other nitrogen mustards, cyclophosphamide administration results in the formation of cross-links within DNA due to a reaction of the two chloroethyl moieties of cyclophosphamide with adjacent nucleotide bases. Cyclophosphamide must be activated metabofically by microsomal enzymes of the cytochrome P450 system before ionization of the chloride atoms and formation of the cyclic ethylenimmonium ion can occur. The metabolites phosphoramide mustard and acrolein are thought to be the ultimate active cytotoxic moiety derived from cyclophosphamide. 

Camptothecin, an alkaloid isolated from a Chinese tree Camptotheca acuminate), is a potent cytotoxic agent, acting by the inhibition of DNA topoisomerase I. Derivatives that are fluorinated on the aromatic ring A have been studied, leading to two drug candidates for cancer therapies (Figure 8.7) ° exatecan is in Phase IB development,and diflomotecan is an E-homocamptothecin currently in Phase II trials for several solid cancers. 

A series of thieno[2,3- ]pyridine derivatives has been studied as cytotoxic agents against a tumorigenic cell line. Compound 156 is found to be the most potent derivative in the series <2004BML3411>. 

Unlike these nonspecific agents, mycophenolate mofetil (6.4) tends to be a lymphocyte-specific cytotoxic agent. Mycophenolate mofetil is a semisynthetic derivative of mycophe-nolic acid, isolated from the mold Penicillium glaucum. It inhibits both T and B lymphocyte action. Since it inhibits the enzyme inosine monophosphate dehydrogenase, which catalyses purine synthesis in lymphocytes, this agent has a more specific effect on lymphocytes than on other cell types. Mizoribine (6.5) is a closely related drug which inhibits nucleotide synthesis, preferentially in lymphocytes. 

Podophyllotoxin and its derivatives are active cytotoxic agents with specific affinity for the microtubule protein of the mitotic spindle. Normal assembly of the spindle is prevented, and epidermal mitoses are arrested in metaphase. A 25% concentration of podophyllum resin in compound tincture of benzoin is recommended for the treatment of condyloma acuminatum. Application should be restricted to wart tissue only, to limit the total amount of medication used and to prevent severe erosive changes in adjacent tissue. In treating cases of large condylomas, it is advisable to limit application to sections of the affected area to minimize systemic absorption. The patient is instructed to wash off the preparation 2-3 hours after the initial application, since the irritant reaction is variable. Depending on the individual patient s reaction, this period can be extended to 6-8 hours on subsequent applications. If three to five applications have not resulted in significant resolution, other methods of treatment should be considered. 

Pyrrolo[2,l-c][l,4]benzodiazepin-5-one dimer derivatives, (IV), prepared by Thurston (4) were effective as cytotoxic agents against human lung, colon, CNS, melanoma, renal, and breast cancer cell lines. 

In a subsequent investigation by the author (7), cdk2/cyclin kinase inhibitors were prepared consisting of (5-bromo-l,3-thiazol-2-yl)amino derivatives, (VII), and were effective as cytotoxic agents without producing indiscriminate damage to both normal and tumor cells. 

Diphenyl-4-hydroxy-4,5-dihydro-l/7-pyrazoles and 3,5-diphenyl-l//-pyrazoles were synthesized and evaluated for in vitro cytotoxic activity against a panel of human cancer cell lines <2005BML3177>. A series of pyrazole oxime ether derivatives 884 were prepared and examined as cytotoxic agents <2005BML3307>. 

Irinotecan-based combination Irinotecan is a campto-thecin-derivative, which as a prodrug is converted into a cytotoxic agent by means of carboxylesterase. It is considered to be one of the most active cytostatics in... 

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