Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting V600EBRAF

• Published in: Bioorganic & medicinal chemistry 2020-06, Vol.28 (11), p.115493-115493, Article 115493
• Main Authors: Abdel-Maksoud, Mohammed S., Ali, Eslam M.H., Ammar, Usama M., Mersal, Karim I., Yoo, Kyung Ho, Oh, Chang-Hyun
• Format: Article
• Language: English
• Subjects: Anticancer; B-RAF inhibitors; Kinase inhibitor; Pyrrolo[2,3-b]pyridine; SAR
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115493

[Display omitted] •Two sets of pyrrolo[2,3-b]pyridine- based derivatives were designed and synthesized.•The synthesized compounds were evaluated for their V600EBRAF Enzyme inhibitory activity.•Compounds 34d and 34e emerged as the most potent enzyme inhibitors.•The cytotoxicity assay was performed against NCI-60 cell line panel.•Compound 35 exhibited the highest cytotoxic agent. Several pyrrolo[2,3-b]pyridine-based B-RAF inhibitors are well known and some of them are currently FDA approved as anticancer agents. Based on the structure of these FDA approved V600EB-RAF inhibitors, two series of pyrrolo[2,3-b]pyridine scaffold were designed and synthesized in attempt to develop new potent V600EB-RAF inhibitors. The 38 synthesized compounds were biologically evaluated for their V600EB-RAF inhibitory effect at single dose (10 μM). Compounds with high percent inhibition were tested to determine their IC50 over V600EB-RAF. Compounds 34e and 35 showed the highest inhibitory effect with IC50 values of 0.085 µM and 0.080 µM, respectively. Headed for excessive biological evaluation, the synthesized derivatives were tested over sixty diverse human cancer cell lines. Only compound 35 emerged as a potent cytotoxic agent against different panel of human cancer cell lines.