Design, Synthesis, and In Vitro Mitotic Evaluation of 3‐Amino‐Isoquinolinones as Anticancer Agents

Abstract

Dedicated to Professor Robert A. Holton for his contributions to anticancer drug developmentIn this study, a series of N-(3-amino-1-oxo-2(1H)isoquinolinyl)benzamides and butyramides were designed and synthesized, and several of them showed mitotic therapeutic activity against renal and breast tumors. The most effective compounds were N-(3-amino-1-oxo-2(1H)isoquinolinyl)benzamides bearing an electron-withdrawing group on their benzamide moieties. N,N-Carbonyldiimidazole promotes cross-coupling between 2-(cyanomethyl)benzoic acids and commercial acyl hydrazides, followed by intra-molecular cyclization to afford these compounds via a twostage protocol. This process is enhanced through addition of imidazole ⋅ HCl which serves as a catalyst for the production of the acyl imidazole/imidazolium intermediate through the first stage. Gentle overnight heating at 60 °C after the addition of the acyl hydrazide during the second stage affords a final product that either precipitates from the solution or forms as a pure compound upon addition of a small amount of water.