Lee, Ju-Hyeon El-Damasy, Ashraf K. Seo, Seon Hee Gadhe, Changdev G. Pae, Ae Nim Jeong, Nakcheol Hong, Soon-Sun Keum, Gyochang 2024-01-19T21:30:47Z 2024-01-19T21:30:47Z 2021-09-05 2018-11-15 0968-0896 https://pubs.kist.re.kr/handle/201004/120674 Two new series of 5-subtituted and 5,6-disubstituted pyrrolo [2,3-d]pyrimidine octamides (4a-o and 6a-g) and their corresponding free amines 5a-m and 7a-g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d-g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI(50) values over the tested cancer cells, and low cytotoxic effects (GI(50) > 10.0 mu M) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-c]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI(50) and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10 mu M concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC50 = 2.25 mu M), FGFR4 (IC50 = 6.71 mu M) and Tie2 (IC50 = 6.84 mu M) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents. English PERGAMON-ELSEVIER SCIENCE LTD NERVE GROWTH-FACTOR ANTICANCER AGENTS INHIBITORS DESIGN MOIETY CANCER PROTEIN TRKA IDENTIFICATION EXPRESSION Novel 5,6-disubstituted pyrrolo[2,3-d]pyrimidine derivatives as broad spectrum antiproliferative agents: Synthesis, cell based assays, kinase profile and molecular docking study Article 10.1016/j.bmc.2018.10.004 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.26, no.21, pp.5596 - 5611 BIOORGANIC & MEDICINAL CHEMISTRY 26 21 5596 5611 scie scopus 000450102200002 2-s2.0-85055632377 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article NERVE GROWTH-FACTOR ANTICANCER AGENTS INHIBITORS DESIGN MOIETY CANCER PROTEIN TRKA IDENTIFICATION EXPRESSION Pyrrolo[2,3-d]pyrimidine octamides Mannich reaction Antiproliferative activity FGFR4 kinase Tie2 TrKA Molecular docking