A new class of cytotoxic DNA minor groove binders: alpha-halogenoacrylic derivatives of pyrrolecarbamoyl oligomers.
DNA minor groove binders represent a class of cytotoxic antitumor agents whose DNA sequence specificity may lead to a high selectivity of action. Tallimustine, benzoyl nitrogen mustard derivative of distamycin A, showed excellent antitumor activity in preclinical tests but also a severe myelotoxicity. Novel nitrogen mustard derivatives of distamycin showing improved activity profile were recently identified. In particular, cinnamic nitrogen mustard and cinnamic ethyl half-mustard analogs of tallimustine showed increased potency and more favorable cytotoxicity/myelotoxicity ratio. However a series of alpha-halogenoacrylamido derivatives of distamycin-like frames showed an activity profile substantially improved in comparison to tallimustine. In particular PNU-166196, alpha-bromo-acrylamido derivative of four pyrrole distamycin-like frame ending with a guanidino moiety, showed high cytotoxic potency even on tumor cell lines resistant to alkylating agents and camptothecin, broad antitumor activity and myelotoxicity dramatically reduced in comparison to tallimustine. This compound was found to bind to minor groove TA-rich sequences but appeared unreactive in classical in vitro DNA alkylation assays. With respect to the apparent lack of DNA alkylation we speculated that an intracellular reactive nucleophilic species, e.g. glutathione (GSH), could activate the reactivity of the compound leading to alkylation of DNA in vivo. Recent evidence of both covalent interaction of PNU-166196 with plasmidic DNA in the presence of GSH and of enhanced cytotoxicity in tumor cells characterized by high levels of GSH were obtained. PNU-166196, in view of its excellent activity profile and its outstanding favorable cytotoxicity/myelotoxicity ratio, was selected for clinical development and is undergoing phase I studies.
Cozzi
P
P
Pharmacia, Department of Chemistry, Discovery Research Oncology, Nerviano, Milan, Italy. paolo.cozzi@eu.pnu.com
D000178:Acrylamides / Q000494:pharmacology*; D000478:Alkylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004214:Distamycins / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000178:Acrylamides; D000970:Antineoplastic Agents; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C066900:tallimustine; C030000:stallimycin; D004247:DNA; D005982:Glutathione Transferase; D005978:Glutathione