Structure-activity relationships, cisplatin compounds

The earliest structure-activity relationships indicated that the transplatinum geometry is inactive— significantly higher doses must be given before any therapeutic effect is seen. In 1991, it was reported that alteration of amine structure and the introduction of sterically hindered amines produced cytotoxicity similar to that of cisplatin.162 The first examples used planar amines and a variety of tra s-[PtCl2(L)(L )] compounds have been synthesized and evaluated ((21)-(26), Figure 12).163... 

Both pyridine (pyr) and quinoline (quin) compounds are efficient cross-linking agents but not potent cytotoxic agents. Interstrand cross-linking is thus not by itself a sufficient requirement for cytotoxicity. These results were also of considerable interest because the mononuclear precursors were found to be similar in cytotoxicity to cisplatin itself, violating the classical structure-activity relationship of platinum compounds. Yet incorporation into the dinuclear structure did not produce active compounds ... 

From the animal screens emerged the set of structure-activity relationships enumerated earlier (Section IV.E.l). Both cisplatin and carboplatin conform to these rules, and to date no compounds with demonstrably better antitumor activity have been tested in humans. The decision to move an experimental drug into the clinic is a difficult one, however, and it may be that molecules such as cis-[Pt(NH3)2(4-Br-py)Cl]Cl (see Section V.D.V.c) would be effective for tumors that are refractive to cisplatin chemotherapy. In any case, the foregoing chain of events, from studying the effects of a compound on cells in culture through animal screens and eventually to humans, constitutes the principal route for introducing a new anticancer drug. The process can take more than a decade. 

Concurrent with the clinical development of cisplatin, an intense synthetic program to develop structure-activity relationships was initiated. Apart from the importance of this work in the understanding of the mechanism of action of cisplatin, the systematic search for analogues derived from a clinically-used compound provides an important source of new compounds [45]. For instance, of 22 new drugs introduced into clinical trials by the National Cancer Institute in the four-year period from 1975, eight were analogues of previously tested anti-cancer agents. 

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