Design and Synthesis of an Anticancer Diarylurea Derivative with Multiple-Kinase Inhibitory Effect

Abstract

A diarylurea compound 1 possessing pyrrolo[3,2-c]pyridine nucleus was designed and synthesized with structure similarity to Sorafenib. Compound 1 was tested over 60-cancer cell line panel at a single dose concentration of 10 µM and showed high activity. It was further tested in a five-dose mode to determine its IC 50 , TGI, and LC 50 values over the 60 cell lines. Compound 1 showed high potency and good efficacy, and was accordingly tested at a single dose concentration of 10 µM over a panel of 40 kinases. At this concentration, it completely inhibited the enzymatic activities of a number of oncogenic kinases, including ABL, ALK, c-RAF, FLT3, KDR, and TrkB. The target compound was subsequently tested over these 6 kinases in 10-dose testing mode in order to determine its IC 50 values.

Pyridazinones: A versatile scaffold in the development of potential target‐based novel anticancer agents

“…B-Raf protein belongs to serine-threonine receptor that showed a vital role in signaling pathway by activating RAS-RAF-MEK-ERK and helps in encouraging the normal progression of cell. Nearly 90% of B-Raf muted cancer cells consist of common V600E oncogenic mutation which involves mutation at codon 600 by substitution of valine in place of glutamic acid and almost 7% of all human cancer cells consist of this muted B-Raf kinase [102][103][104][105][106]. The deregulation of signaling pathway of B-Raf resulted in the upregulation of various types of cancers; comprising hepatocellular (14%), melanoma (60%), colorectal (15%), mammary gland (10%), and prostate cancer (10%).…”

Synthesis and Antiproliferative Activity of New Aminoisoquinolinylurea Derivatives against Melanoma Cell Line

“…7 In addition, a number of reports have recently highlighted diarylureas as potential antiproliferative agents against melanoma cell lines. [8][9][10][11][12][13][14][15][16][17][18][19] Encouraged by the interesting antiproliferative activity of diarylurea derivatives, we report a new series of diarylureas containing 5-aminoisoquinoline scaffold in the present investigation ( Fig. 1).…”

Synthesis and Characterization of New Biologically Active Pyrrolo[2,3-b]Pyridine Scaffolds

“…[2]. They are displaying interesting chemical reactions and important biological actions such as antibacterial [3], antimycobacterial [4], anti-inflammatory [5], antifungal [6], antiparkinson's [7], antitumor [8], antiproliferative [9], antiviral [10], muscarinic antagonist [11], antimicrobial [12], anticancer [13][14][15]. In light of the above all, it was the target to design and synthesize the expected biologically active structures of pyrrolo [2,3-b] An essential component of the search for new leads in drug designing program is the synthesis of molecules, which are novel still resembling known biologically active molecules by virtue of the presence of some critical structural features.…”