Nagamura S, Asai A, Amishiro N, Kobayashi E, Gomi K, Saito H
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
J Med Chem. 1997 Mar 14;40(6):972-9. doi: 10.1021/jm9606094.
A series of N-cinnamates of the A-ring pyrrole compound of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. The 4'-methoxy- and 4'-BocNH-cinnamates exhibited strong in vitro anticellular activity among the synthesized compounds. The ortho substitution of the 4'-methoxycinnamate did not affect the anticellular activity and contributed to an enhancement of water solubility. Most of the 8-O-(N,N-dialkylcarbamoyl) derivatives of the 4'-methoxycinnamate displayed remarkably superior in vivo antitumor activity to duocarmycin A or B2. Moreover, it is noteworthy that these 8-O-(N,N-dialkylcarbamoyl) derivatives exhibited significant antitumor activity at wider range of doses as compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment B.
合成了一系列多卡霉素A环吡咯化合物的N-肉桂酸酯，并评估了它们对HeLa S3细胞的体外抗细胞活性以及对小鼠肉瘤180的体内抗肿瘤活性。在合成的化合物中，4'-甲氧基肉桂酸酯和4'-BocNH-肉桂酸酯表现出较强的体外抗细胞活性。4'-甲氧基肉桂酸酯的邻位取代不影响抗细胞活性，且有助于提高水溶性。4'-甲氧基肉桂酸酯的大多数8-O-(N,N-二烷基氨基甲酰基)衍生物在体内抗肿瘤活性方面明显优于多卡霉素A或B2。此外，值得注意的是，与B段具有三甲氧基吲哚骨架的A环吡咯衍生物相比，这些8-O-(N,N-二烷基氨基甲酰基)衍生物在更宽的剂量范围内表现出显著的抗肿瘤活性。
