Figure 25.5 Tetravalent complexes

Mechanistic studies with JM335 in carcinoma cell lines49 have revealed DNA-binding properties different from those of cisplatin. JM335 induces DNA single-strand breaks (formation of this DNA lesion is cell-line dependent) and interstrand cross-links. Interestingly, DNA extracted from cells treated with JM335 is not recognized by an antibody elicited against DNA modified by cisplatin. In addition, the kinetics of apoptosis is more rapid for JM335 than for its cis-isomer. However, JM335 is generally less cytotoxic than cisplatin probably because of its inactivation by thiols; so, it has not been selected for clinical trials. Nevertheless, it remains one of the more interesting and active trans-platinum complexes.

Another attractive design strategy might involve a relatively non-toxic precursor, a pro drug, which could be selectively photoactivated at the site of the tumor thereby minimizing side effects. Photoactive Pt(IV) azide complexes were recently synthesized51 which are stable in human blood plasma and which, on irradiation with visible light, can undergo reductive elimination reactions in aqueous solution and liberate dinitrogen. Whereas no binding to DNA occurred in the dark, upon irradiation with blue light (457.9 nm) DNA was platinated at the same sites as by treatment with cisplatin.52 Hence, the complexes can be viewed as 'pro-drugs' for cisplatin-type complexes although photoactivation may lead to novel reactive intermediates. Work is now needed to investigate potential photoinduced cytotoxicity toward cancer cells, and optimization of the wavelength of photoactivation via changes in the ligands in these octahedral cis-diazido Pt(IV) complexes.

One way to affect the biological activity of cisplatin is also to target this drug to DNA differently by the attachment of the platinum moiety to a suitable carrier.53,54 Compared with untargeted analogues, such compounds may exhibit a different DNA-binding mode, including sequence selectivity. Importantly, this change of the DNA-binding selectivity has been shown already to result in good in vitro and in vivo activity in tumors resistant to conventional agents. One class of platinum complexes targeted to DNA involves cisplatin linked to an

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