Formation of platinated GG cross-links on DNA by photoactivation of a platinum(IV) azide complex.
Platinum(II) diam(m)ine complexes such as cisplatin are effective anticancer drugs but have accompanying side effects. We are exploring the design of platinum complexes with low toxicity that could be photoactivated selectively at the target site. We show here that the Pt(IV) azide complex cis, trans-[Pt(en)(N(3))(2)(OH)(2)] is unreactive towards DNA until irradiated with visible light. Transcription mapping studies of a 212-bp fragment of pSP73KB plasmid DNA treated with cis, trans-[Pt(en)(N(3))(2)(OH)(2)] and irradiated with visible light showed that the platination sites were similar to those observed for cisplatin, and were mainly in GG sequences. HPLC analysis of enzymatic digests of an irradiated sample of a 40-bp DNA duplex treated with the same complex also revealed preferential formation of GG cross-links. Since such DNA lesions are thought to be responsible for the induction of apoptosis in cancer cells by platinum drugs, the use of unreactive photoactivatable platinum pro-drugs may become an effective strategy for the design of a new generation of platinum anticancer complexes.
D000970:Antineoplastic Agents / Q000737:chemistry*; D001386:Azides / Q000737:chemistry; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000138:chemical synthesis* / Q000302:isolation & purification; D006147:Guanine / Q000737:chemistry*; D010777:Photochemistry; D010778:Photochemotherapy; D017671:Platinum Compounds / Q000737:chemistry*; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D001386:Azides; D018736:DNA Adducts; D017671:Platinum Compounds; D006147:Guanine; D004247:DNA; D002945:Cisplatin