Design, synthesis, and molecular docking studies of novel pyrazolyl 2-aminopyrimidine derivatives as HSP90 inhibitors.

Autor: Mettu A; Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Kukatpally, Hyderabad, India., Talla V; Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, India., Bajaj DM; Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, India., Subhashini NJP; Department of Chemistry, University College of Science, Osmania University, Hyderabad, India.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2019 Oct; Vol. 352 (10), pp. e1900063. Date of Electronic Publication: 2019 Aug 14.
DOI: 10.1002/ardp.201900063
Abstrakt: A series of novel pyrazolyl 2-aminopyrimidine derivatives (7a-t) were designed based on scaffold hopping techniques, synthesized and biologically evaluated for their HSP90 inhibition and anticancer activity. Several compounds exhibited potent HSP90 inhibition with IC 50 values less than that of the reference standard 17-AAG (1.25 µM). The most potent compound 7t displayed excellent HSP90 inhibition with an IC 50 of 20 nM and in vitro antiproliferative potential against three cancer cell lines (IC 50  < 5 µM). 7t also induced dose dependent degradation of client proteins (pHER2 and pERK1/2) in Western blot analysis. Several structural features of 7p-t oriented the molecules to retain all the essential binding interactions with HSP90, as observed by rationalized docking studies. Therefore, the para-nitrophenyl ring on the central pyrazole ring along with the 2-amino group on the pyrimidine ring are the crucial features in the development of novel HSP90 inhibitors based on this scaffold for targeted anticancer therapy.
(© 2019 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
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