CC-1065 and the duocarmycins: recent developments

It is accepted that neoplastic diseases are related to gene alteration or o ncogene 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 moieti es. 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 duoca rmycins represent a class of exceptionally potent antitumour antibiotics th at derive their biological effects from the reversible, stereo-electronical ly-controlled sequence selective alkylation of DNA. All natural compounds s howed a cytotoxicity against leukaemia L1210 cell lines in the range 10-220 pM but while CC-1065 showed a good antitumour activity in an in vivo model( optimal dose from 10-100 mug/g), duocarmycins showed weak antitumour activi ty. Despite its potency, CC-1065 cannot be used in humans due to eventual f atality. For this reason many scientists have focused their attention on th is class of compounds, in order to obtain new derivatives with equal in vit ro potency but a better profile in in vivo models. This effect is accompani ed by dramatic changes in the morphology of hepatic mitochondria. On this b asis, 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 give n on this topic.