Cisplatin analogues

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. 

An examination of the structures shows that they include complexes with NH3 and substituted chloride groups, i.e. cyclobutanedicarboxylato, and complexes substituted on the amine, i.e. 1,2-diaminocyclohexane, as well as a Pt(IV) complex. The systematic lUPAC names, along with abbreviations and trivial names, have been summarized [54]. This neces- 

The aqueous solubility and acute toxicity data are summarized in Table 

Aqueous solubility and acute toxicity for cisplatin and analogues. 

V along with a comparison of their activity versus LI 210, cisplatin-resistant LI 210, and B16 melanoma. The data show that while some complexes may be better than cisplatin in the primary LI 210 screen none are more active in the next screen, B16. Indeed, only one complex (the sodium salt of cw-[Pt(NH3)2(hydroxymalonato)]) has consistently been more active in this screen [48]. An interesting point is that the two screens rank the platinum complexes somewhat differently [7, 48], and no complexes are superior in both screens. Most compounds have better aqueous solubility than the original compound and have lower toxicity, as measured by acute toxicity values. Only one complex (Complex 26) has an LD50 equivalent to cisplatin and, in one survey, actually slightly less [55]. 

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Murray V, Whittaker J, McFadyen WD (1998) DNA sequence selectivity of cisplatin analogues in intact human cells. Chem Biol Interact 110(l-2) 27-37... 

Weiss RB, Christian MC. New cisplatin analogues in development. Drugs 1993 46 360-377. 

Woloschuk DM, Pruemer JM, Cluxton RJ Jr. Carboplatin a new cisplatin analogue. Drug Intell Clin Pharm 1988 22(ll) 843-9. 

Alonso A, Almendral MJ, Curto Y, Criado JJ, Rodriguez E, Manzano JL. New fluorescent antitumour cisplatin analogue complexes, study of the characteristics of their binding to DNA by flow injection analysis. J Fluoresc 2007 17 390-400. 

Despite the synthesis of many hundreds of cisplatin analogues over the past 20 years, there have been relatively few leads to the discovery of novel platinum drugs capable of circumventing tumour resistance to cisplatin/carboplatin. 

Although thousands of cisplatin analogues have been synthesized and screened only about 28 platinum compounds have entered clinical trials as anticancer agents [6,9]. Of these only four are currently approved. Those approved are cisplatin (Scheme 8.22), carboplatin (Scheme 8.23), oxaliplatin (Scheme 8.24), andnedapla-tin (Scheme 8.25). Only the first two are commercially available for general use in the treatment of cancer. 

J. C. Dabrowiak, M. S. Balakrishnan, J. Clardy, G. D. van Duyne, and L. Silviera NMR and Crystallographic Studies on a Second Generation Cisplatin Analogue (Platinum Coordination Complexes in Cancer Chemotherapy, Eds. M. P. Hacker, E. B. Douple, and I. H. Krakoff), p. 63. Martinus-Nijhoff (1984). 

Cisplatin (cis-Diamminedichloroplatinum(ll)), has been used as a versatile and highly effective treatment for various cancers. Unfortunately, the amounts that can be prescribed are limited by its nephrotoxicity. Of the multiple cisplatin analogues that have been synthesized and tested,... 

The cisplatin analogues 73 were synthesized from L-arabinose in a multi-step procedure via epoxide and epimine intermediates. The potent serine protease inhibitors, 2-amino-2,6-dideoxy-6-guanidino-D-glucose and its 2-iV-acetyl derivative 74, were synthesized by reaction of benzyl 2-N-protected-2,6-diamino-2,6-dideoxy-a-D-glucopyranosidewith3,5-dimethylpyrazolylfoniiamidinium nitrate followed by hydrogenolysis. ... 

The platinum complexes 26 and 27 of sucrose derivatives have been diesized as cisplatin analogues. The diamines 28 and 29 were prepared from D-mannitol and convorted into the Pt complexes 30 and 31. The conqtlexes 32 and 33 were also prepared - again as cisplatin analogues. Similarly, the complexes 34-36 were prepared from L-atabinose. ... 

Figure 10.3.1. Second generation of cisplatin analogues (a) carboplatin (CBDCA, JM 8) (b) spiroplatin (TNO 6) (c) oxoplatin (d) iproplatin (CHIP, JM 9).

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