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SYNTHESIS OF HOECHST 33258 ANALOGUES DESIGNED TO TARGET HUMAN TUMOR HELICASES

The syntheses of certain analogues of the DNA minor groove binding agent Hoechst 33258 designed to explore the potential for bioreductive activation and as selective inhibitors of human tumor helicases are described. The structural modifications include the following: substitution of pyridine for benzene ring of the piperazinvl benzimidazole moiety and replacement of one benzimidazole unit by a imidazoquinone moiety. Introduction The design of DNA sequence-specific binding agents has received considerable attention because of their potential as anticancer drugs. The synthetic bis-benzimidazole Hoechst dye 33258 is known to bind to the minor groove of double helical DNA selectively at 5' AATT sites (1). The interaction of Hoechst 33258 with DNA has been extensively studied by biophysical methods including footprinting, NMR and X-ray techniques (2).Structural data on Hoechst 33258-DNA complexes from X-ray crystallography (3,4) and NMR studies (5-7 ) provide evidence for minor groove binding. The flexible nature of the bis-benzimidazole ring system permits the drug to adopt an optimum conformation and thus bind effectively to double stranded DNA (8). In addition, the quinone class of bioreductive alkylating agents has received increasing attention because of their potential role in cancer therapy. Certain quinones are able to act as bioreductively activated alkylating agents (9). Mitomycin C, a naturally occurring antitumor antibiotic, and the corresponding mitosene analogues bearing a para-quinone moiety, are capable of bioreductive activation to generate reactive quinone methides that alkylate biomolecules (10). Recently, the benzimidazole ring system has been designed as a reductive alkylator by functionalizing the quinone derivative of the ring system with -CH2X, where X is a leaving group (11). These latter types of Vol. 5, No. 1, 1999 Synthesis of Hoechst 33258 Analogues designed to target human tumor helicases quinone derivatives result in quinone methide formation upon quinone reduction (11) and this suggests that if we incorporate a quinone methide precursor into the Hoechst 33258 structure it should be effective both as a sequence and site directed groove binder as well as selective alkylator. Several indole quinones have recently been studied as bioreductive drugs (12). These studies aroused our interest in this area and the synthetic and biological studies of prototypes of such analogues of Hoechst 3325S bearing a quinone moiety have been reported including their property of sequence selective inhibition of human tumor helicases (13-15).