Cytotoxic alpha-bromoacrylic derivatives of distamycin analogues modified at the amidino moiety.
The design, synthesis, in vitro and in vivo activities of novel alpha-bromoacrylic derivatives of distamycin A, modified at the amidino moiety by the replacement with basic or non-basic groups are reported. In spite of the relevance of these modifications of distamycin frame, the new derivatives are potent cytotoxics. The presence of the amidino moiety, is, therefore; not an absolute requirement for the activity. In particular due to a favorable myelotoxicity/cytotoxicity ratio, guanidino derivative PNU 166196 was selected for clinical development.
Cozzi
P
P
Department of Chemistry, Pharmacia & Upjohn, Discovery Research Oncology, Milan, Italy. paolo.cozzi@eu.pnu.com
Beria
I
I
Caldarelli
M
M
Geroni
C
C
Mongelli
N
N
Pennella
G
G
D000578:Amidines / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D004214:Distamycins / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D014407:Tumor Cells, Cultured
D000578:Amidines; D000970:Antineoplastic Agents; D004214:Distamycins