Non-camptothecin topoisomerase I active compounds as potential anticancer agents

The success of two camptothecin analogues against human cancers has prompte d pharmaceutical companies and academic laboratories to not only initiate c amptothecin analogue programs of their own, but also to either screen for o r to rationally design novel topoisomerase (topo) I active agents. The prim ary focus of this review is on those agents that most closely mimic the act ions of camptothecin, the prototype topo I acting agent. Indolocarbazoles a re the most exploited and advanced chemotype, being led by NB-506 and J-107 088, both of which have entered Phase I/II clinical evaluations by Merck/Ba nyu. Kyowa Hakko Kogyo, while expanding the K252a/staurosporine series, ide ntified topo I active agents bur continued to the clinic with the protein k inase inhibitor UCN-01. Approximately 100 non-proprietary indolocarbazoles have been described in the literature by a consortium of academic scientist s working in conjunction with scientists at Aventis and Novartis. Their int ent appears to be more academic than commercial and this association has no w ended. An academic group, through an agreement with Avax Technologies is commercially exploring benzimidazoles, terbenzimidazoles, coralyne and prot oberberines. Indenoisoquinoline NSC 314622 and anthracenyl-amino acid conju gate NU/ICRF 505 are interesting and novel structures that have not yet pro gressed to the clinic. The naphthacenedione family includes saintopin, whic h was discovered by Kyowa Hakko Kogyo. This company appears to be focusing on UCE6 Other agents include nogalamycin, dexniguldipine HCl (B859-35), ect einascidin 743 (Et 743) and phthalascidin (Pt 650). 2280-DTI and 2890-DTI m ay be true catalytic inhibitors of topo I. Only NB-506, J-107088, dexniguld ipine and Et 743 have undergone or are presently undergoing Phase I/II clin ical evaluation with little information coming forth, except for Et 743, wh ich is yielding responses against sarcomas.