Design and synthesis of new 2‐anilinoquinolines bearing N‐methylpicolinamide moiety as potential antiproliferative agents. (9th September 2016)

• Record Type: Journal Article
• Authors: El‐Damasy, Ashraf Kareem; Seo, Seon Hee; Cho, Nam‐Chul; Pae, Ae Nim; Kim, Eunice Eunkyeong; Keum, Gyochang
• Is Part Of: Chemical biology & drug design. Volume 89:Number 1(2017)
• Page Start: 98
• Page End: 113
• Publication Date: 2016-09-09
• Subjects: 2‐anilinoquinoline -- antiproliferative activity -- N‐methylpicolinamide -- RAF kinase; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12836
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : A series of new 2‐anilinoquinolines6a –o possessing the substantial N ‐methylpicolinamide motif at C5 has been designed and synthesized as sorafenib analogs. The antiproliferative activities of the target compounds were preliminarily appraised against a panel of three human cancer cell lines (MCF‐7, SK‐BR3, and HCT116), and a selected array was further tested over a panel of approximately 60 cancer cell lines at NCI at 10 μM concentration. Interestingly, compounds6c, 6d, 6j, 6k, and6l showed promising selective anticancer activities (growth inhibition >80%) toward certain cancer cells at 10 μM testing dose. Compounds6d and6j were advanced to five‐dose testing mode to determine their GI50 values and compared with our previously reported ureidoquinolineB and sorafenib as reference compounds. The 4‐chloro‐3‐trifluoromethylaniline derivative6j manifested superior potency than both compoundB and sorafenib over eleven and eight cell lines, respectively. It showed GI50 values of 0.36, 0.66, 0.68, and 0.60 μM against the breast MDA‐MB‐468, renal A498, and melanoma SK‐MEL‐5 and UACC‐62 cell lines, respectively. Moreover, both6d and6j exerted low cytotoxic effects against HFF‐1 normal cell line. Furthermore, compounds6d and6j were tested against both B‐Raf V600E and C‐Raf kinases and displayed modest inhibitory activities, which were justified by molecular docking study. Compound6j could serve as a promising candidate for further development of potent anticancer chemotherapeutics. Abstract : A series of new 2‐anilinoquinolines possessing N ‐methylpicolinamide motif has been designed, synthesized, and biologically evaluated as sorafenib analogues. All the tested compounds showed promising selective anticancer activities and the 4‐chloro‐3‐trifluoromethyl aniline derivative6j manifested superior potency than sorafenib over certain cell lines, with submicromolar GI50 values against four cell lines.