Synthesis and antitumor activity of new benzoheterocyclic derivatives of distamycin A

The design, synthesis, and in vivo and in vitro antileukemic activity of a novel series of compounds (13-22 and 34), in which different benzoheterocyc lic rings, bearing a nitrogen mustard or a benzoyl nitrogen mustard or an a lpha-bromoacryloyl group as alkylating moieties, are tethered to a distamyc in frame, are reported, and structure-activity relationships are discussed. The new derivatives were prepared by coupling nitrogen mustard-substituted , benzoyl nitrogen mustard-substituted, or alpha-bromoacryloyl-substituted benzoheterocyclic carboxylic acids 23-32 with desformyldistamycin (33) or i n one case with its two-pyrrole analogue 35. With very few exceptions, the activities of compounds bearing the same alkylating moiety are slightly aff ected by the kind of the heteroatom present on the benzoheterocyclic ring. All novel compounds, with one exception, showed in vitro activity against L 1210 murine leukemia cell line comparable to or better than that of tallimu stine. The compounds in which the nitrogen mustard and the alpha-bromoacryl oyl moieties are directly linked to benzoheterocyclic ring showed potent cy totoxic activities (IC50 ranging from 2 to 14 nM), while benzoyl nitrogen m ustard derivatives of benzoheterocycles showed reduced cytotoxic activities , and one compound (16) of this cluster was the sole derivative devoid of s ignificant activity. Compound 18, a 5-nitrogen mustard N-methylindole deriv ative of distamycin, showed the best antileukemic activity in vivo, with a very long survival time (%T/C = 457), significantly increased in comparison to tallimustine (%T/C = 133), and was selected for further extensive evalu ation. Arrested polymerase chain reaction and direct DNA fragmentation assa ys were performed for compound 18 and the structurally related compounds 13 -17 and 19. The results obtained have shown that both alkylating groups and oligopeptide frames play a crucial role in the sequence selectivity of the se compounds.