4-氨甲基噻吨酮和5-氨甲基苯并噻吩并吲哚衍生物的合成及其抗肿瘤活性

Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives.

作者信息

Perni R B, Wentland M P, Huang J I, Powles R G, Aldous S, Klingbeil K M, Peverly A D, Robinson R G, Corbett T H, Jones J L, Mattes K C, Rake J B, Coughlin S A

机构信息

Departments of Medicinal Chemistry and Oncopharmacology, Sanofi Winthrop Inc., 9 Great Valley Parkway, Malvern, Pennsylvania 19355, USA.

出版信息

J Med Chem. 1998 Sep 10;41(19):3645-54. doi: 10.1021/jm9708083.

DOI:10.1021/jm9708083

PMID:9733489

Abstract

Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.

摘要

本文描述并比较了两类新型抗肿瘤药物，即4-氨甲基硫杂蒽酮（6-50）和5-氨甲基苯并硫代吡喃并吲哚（51-61）。尽管这两类药物之间几乎没有明显差异，但两类药物的几乎所有成员对小鼠胰腺腺癌03（Panc03）均显示出优异的体内活性。在这两类药物中，结构与体内疗效之间均无明显关联。对选定的类似物进行了体外评估；观察到所有类似物均通过嵌入作用与DNA具有中度至强结合力。然而，体外P388细胞毒性和拓扑异构酶II抑制作用存在不同程度的差异。一般来说，表现出强拓扑异构酶II抑制作用的分子比未表现出该作用的分子具有明显更强的细胞毒性。在这两类药物中，具有酚羟基取代的衍生物（48-50、60和61）表现出最有效的P388细胞毒性和拓扑异构酶II抑制作用。