新型吡咯并[2,1-c][1,4]苯并二氮杂卓（PBD）-聚合物缀合物和2,2'-PBD二聚体的设计、合成及体外细胞毒性研究

Design, synthesis and in vitro cytotoxicity studies of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD)--polymade conjugates and 2,2'-PBD dimers.

作者信息

Reddy B S, Damayanthi Y, Reddy B S, Lown J W

机构信息

Department of Chemistry, University of Alberta, Edmonton, Canada.

出版信息

Anticancer Drug Des. 2000 Jun;15(3):225-38.

PMID:11049090

Abstract

A series of novel pyrrolo[2,1-c][l,4]benzodiazepine (PBD)-polyamide conjugates (1 and 2) and 2,2'-PBD dimers (3, 4 and 5) were synthesized and evaluated for cytotoxicity in >60 human tumor cell lines. In general PBD-polyamide conjugates (1 and 2) exhibit higher cytotoxic potency compared with 2,2'-PBD dimers (3, 4 and 5). Compound 2 exhibits a wide spectrum of anticancer activities against 17 cell lines in six cancer panels with LC50 values of <9 microM, and is especially effective against colon cancer, melanoma, renal cancer and breast cancer. Compound 1 selectively affects cell growth against renal cancer A 498 cell line and compound 4 affects cell growth against breast cancer MDA-MB-231/ATCC cell line with an LC50 value 0.06 microM. Increases in the chain length of the linker in 2,2'-PBD dimers significantly increase the cytotoxic potency and increases in the number of pyrrole groups in the PBD-polyamide conjugates similarly increase the cytotoxic potency.

摘要

合成了一系列新型吡咯并[2,1-c][1,4]苯并二氮杂卓（PBD）-聚酰胺缀合物（1和2）以及2,2'-PBD二聚体（3、4和5），并在60多种人类肿瘤细胞系中评估了它们的细胞毒性。总体而言，与2,2'-PBD二聚体（3、4和5）相比，PBD-聚酰胺缀合物（1和2）表现出更高的细胞毒性效力。化合物2对六个癌症组中的17种细胞系具有广泛的抗癌活性，半数致死浓度（LC50）值<9微摩尔，尤其对结肠癌、黑色素瘤、肾癌和乳腺癌有效。化合物1选择性地影响肾癌A 498细胞系的细胞生长，化合物4影响乳腺癌MDA-MB-231/ATCC细胞系的细胞生长，LC50值为0.06微摩尔。2,2'-PBD二聚体中连接子链长度的增加显著提高了细胞毒性效力，PBD-聚酰胺缀合物中吡咯基团数量的增加同样提高了细胞毒性效力。