Novel quinolinylaminoisoquinoline bioisosteres of sorafenib as selective RAF1 kinase inhibitors: Design, synthesis, and antiproliferative activity against melanoma cell line

Abstract

Design and synthesis of a new series of quinolinylaminoisoquinoline derivatives as conformationally restricted bioisosteres of Sorafenib are described. Their in vitro antiproliferative activity against A375P melanoma cell line was tested. Compounds 1b, 1d, 1g, and 1j showed the highest potency against A375P cell line with IC50 values in sub-micromolar scale. In addition, compound 1d exerted high selectivity towards RAF1 serine/threonine kinase with 96.47% inhibition at 10 μM, and IC50 of 0.96 μM. This compound can possess antiproliferative activity against melanoma cells through inhibition of RAF1 kinase. © 2013 The Pharmaceutical Society of Japan.