CC-1065 and the duocarmycins: recent developments

Abstract

It is accepted that neoplastic diseases are related to gene alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA based moieties. In this field, analogues of naturally occurring antitumour agents, such as CC-1065 and/or the duocarmycins, represent a new class of highly potent antineoplastic compounds, currently under investigation. CC-1065 and duocarmycins represent a class of exceptionally potent antitumour antibiotics that derive their biological effects from the reversible, stereo-electronically-controlled sequence selective alkylation of DNA. All natural compounds showed a cytotoxicity against leukaemia L1210 cell lines in the range 10 - 220pM but while CC-1065 showed a good antitumour activity in an in vivo model (optimal dose from 10 - 100 μg/g), duocarmycins showed weak antitumour activity. Despite its potency, CC-1065 cannot be used in humans due to eventual fatality. For this reason many scientists have focused their attention on this class of compounds, in order to obtain new derivatives with equal in vitro potency but a better profile in in vivo models. This effect is accompanied by dramatic changes in the morphology of hepatic mitochondria. On this basis, the recent developments on SARs for this class of compounds and their possible use as therapeutic agents are reviewed, with particular emphasis on recent patent literature and, finally, a conclusive opinion will be given on this topic.

• alkylating agents
• antitumour agents
• CC-1065
• DNA minor groove
• duocarmycins