Synthesis and antitumor activity of duocarmycin derivatives: modification of segment-A of A-ring pyrrole compounds.
A series of 3-substituted A-ring pyrrole compounds of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S(3) cells and in vivo antitumor activity against murine sarcoma 180 in mice. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among 3-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.
Amishiro
N
N
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd., 1188 Shimotogari, Nagaizumi, Sunto, Shizuoka 411-8731, Japan.
Okamoto
A
A
Murakata
C
C
Tamaoki
T
T
Okabe
M
M
Saito
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001854:Bone Marrow Cells / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D020128:Inhibitory Concentration 50; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010976:Platelet Count / Q000187:drug effects; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D012510:Sarcoma 180 / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C120794:4'-methoxycinnamoyl 2-methyl-3-bromo-A-ring-pyrroleduocarmycin; D000970:Antineoplastic Agents; D007211:Indoles; D011760:Pyrrolidinones