Abstract

In continuity of our search for novel anticancer agents acting as procaspase activators, we have designed and synthesised two series of (E)-N′-benzylidene-carbohydrazides (4a–m) and (Z)-N'-(2-oxoindolin-3-ylidene)carbohydrazides (5a–g) incorporating 1-(4-chlorobenzyl)-1H-indole core. Bioevaluation showed that the compounds, especially compounds in series 4a–m, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Within series 4a–m, compounds with 2-OH substituent (4g–i) exhibited very strong cytotoxicity in three human cancer cell lines assayed with IC₅₀ values in the range of 0.56–0.83 µM. In particular, two compounds 4d and 4f bearing 4-Cl and 4-NO₂ substituents, respectively, were the most potent in term of cytotoxicity with IC₅₀ values of 0.011–0.001 µM. In caspase activation assay, compounds 4b and 4f were found to activate caspase activity by 314.3 and 270.7% relative to PAC-1. This investigation has demonstrated the potential of these simple acetohydrazides, especially compounds 4b, 4d, and 4f, as anticancer agents.

摘要

在我们的用于充当胱天蛋白酶原激活剂新的抗癌剂搜索的连续性，我们设计并合成了两个系列的（ë） - ñ ' -苄基碳酰肼（4A-4M）和（Z）-N” - （2- oxoindolin-结合了1-（4-氯苄基）-1 H-吲哚核的3-yylne）carbohydrides（5a–g）。生物评估表明，这些化合物，尤其是4a–m系列化合物，对三种人类癌细胞系（SW620，结肠癌； PC-3，前列腺癌； NCI-H23，肺癌）表现出有效的细胞毒性。在系列4a–m中，带有2-OH取代基的化合物（4g–i）在三种人类癌细胞系中表现出非常强的细胞毒性，其中IC ₅₀值在0.56-0.83 µM范围内。特别是，在细胞毒性方面，两种分别带有4-Cl和4-NO ₂取代基的化合物4d和4f最有效，IC ₅₀值为0.011-0.001 µM。在半胱天冬酶激活试验中，发现化合物4b和4f相对于PAC-1激活caspase活性为314.3和270.7％。这项研究证明了这些简单的乙酰肼的潜力，尤其是化合物4b，4d和4f，作为抗癌药。