Non-camptothecin topoisomerase I active compounds as potential anticancer agents

The success of two camptothecin analogues against human cancers has prompted pharmaceutical companies and academic laboratories to not only initiate camptothecin analogue programs of their own, but also to either screen for or to rationally design novel topoisomerase (topo) I active agents. The primary focus of this review is on those agents that most closely mimic the actions of camptothecin, the prototype topo I acting agent. Indolocarbazoles are the most exploited and advanced chemotype, being led by NB-506 and J-107088, both of which have entered Phase I/II clinical evaluations by Merck/Banyu. Kyowa Hakko Kogyo, while expanding the K252a/staurosporine series, identified topo I active agents bur continued to the clinic with the protein kinase inhibitor UCN-01. Approximately 100 non-proprietary indolocarbazoles have been described in the literature by a consortium of academic scientists working in conjunction with scientists at Aventis and Novartis. Their intent appears to be more academic than commercial and this association has now ended. An academic group, through an agreement with Avax Technologies is commercially exploring benzimidazoles, terbenzimidazoles, coralyne and protoberberines. Indenoisoquinoline NSC 314622 and anthracenyl-amino acid conjugate NU/ICRF 505 are interesting and novel structures that have not yet progressed to the clinic. The naphthacenedione family includes saintopin, which was discovered by Kyowa Hakko Kogyo. This company appears to be focusing on UCE6 Other agents include nogalamycin, dexniguldipine HCl (B859-35), ecteinascidin 743 (Et 743) and phthalascidin (Pt 650). 2280-DTI and 2890-DTI may be true catalytic inhibitors of topo I. Only NB-506, J-107088, dexniguldipine and Et 743 have undergone or are presently undergoing Phase I/II clinical evaluation with little information coming forth, except for Et 743, which is yielding responses against sarcomas.