New Water-Soluble Duocarmycin Derivatives: Synthesis and Antitumor Activity of A-Ring Pyrrole Compounds Bearing β-Heteroarylacryloyl Groups

Abstract

A series of A-ring pyrrole compounds of duocarmycin bearing 4'-methoxy-beta-heteroarylacryloyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the 4'-methoxy-beta-heteroarylacrylates displayed in vitro anticellular activity equivalent to that of 4'-methoxycinnamates. Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates, compound 15b having a (4-methoxy-3,5-pyrimidinyl)acryloyl as segment-B (Seg-B) showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B, which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates. Moreover, these 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates had high aqueous solubility.

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

“…Compound 75b proved to have antitumour activity approaching that of KW2189 in vivo. All compounds showed comparably low peripheral blood toxicity and increased water solubility (>20 mM) compared to that compound bearing the trimethoxyindolyl or 4-methoxycinnamate side chains as the DNA binding subunit [123].…”

DNA minor groove binders as potential antitumor and antimicrobial agents

“…A series of KW-2189 derivatives modified at the C-8 phenolic hydroxyl group as thiocarbonate, ester, and hydrazinocarboxylate, and bearing a cynnamoyl or heteroarylacryloyl moiety instead of the original tri-methoxyindole skeleton were synthesized by Kyowa and some of these showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared to their clinical candidate KW-2189. [111][112][113] Taking into account structural characteristics of the CPI system in the KW-2189, Fukuda and coworkers designed a novel CPI system, the 3-methoxycarbonyl-2-trifluoromethylCPI (MCTFCPI, 59) system, which linked to the 5-(7-methoxybenzofuran-2-ylcarbonyl) aminoindole-2-carbonyl group at the 6-position, furnished the derivative AT-3510 (81) which was found to exhibit more excellent antitumor activity against tumor xenografts than the clinical trial candidates carzelesin, KW-2189 and the clinically widely used anticancer agent cisplatin. 114 In analogy with bizelesin, the compound 82 in which two MCTFCPI moieties were connected with a 5,5 0 -bis-(2-carbonyl-1 H-indole) group, was found to exhibit more prominent cytotoxicity against HeLaS3 human uterine cervix carcinoma and in vivo antitumor activity against Colon 26 murine adenocarcinoma than bizelesin.…”

Synthesis of bis‐heteroaryl piperazine derivatives as potential reverse transcriptase inhibitors

“…Such a pharmacomodulation has previously been successfully applied in medicinal chemistry as recently illustrated in the field of antitumor agents [13].…”