No abstract

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 IC50 values less than that of the reference standard 17‐AAG (1.25 µM). The most potent compound 7t displayed excellent HSP90 inhibition with an IC50 of 20 nM and in vitro antiproliferative potential against three cancer cell lines (IC50 < 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.

A simple and efficient one‐pot protocol for the synthesis of a library of 3‐hydroxy‐oxindolino‐dithiocarbamate hybrids has been developed and evaluated for their in vitro cytotoxicity potential against selected human cancer cell lines. This one‐pot reaction takes place via regiospecific spiro‐epoxide ring‐opening with concomitant C–S bond formation by an in situ generation of dithiocarbamate intermediate. Gratifyingly, the reaction has been accelerated efficiently in water medium without using any catalyst or base and enable higher yields, atom‐economy, greener synthesis and offers diverse substrate scope. Among the tested compounds, one of the representative compounds 4 p with a chloro substitution and N‐p‐CN‐benzyl on oxindole nucleus displayed potent in vitro cytotoxicity against MCF‐7 (breast cancer cells) with an IC50 value of 2.1 ± 0.4 μM. Moreover, the promising candidate 4 p induce G2/M phase cell cycle arrest and apoptosis on MCF‐7 cells, as determined by AO‐EB and DAPI staining as well as annexin binding studies