Synthesis and biological evaluation of novel steroidal pyrazole amides as highly potent anticancer agents.

ABSTRACT

A series of thirty-six steroidal pyrazole amides, divided into two categories based on their main skeletons were designed and synthesized via a five-step synthetic route. The final product is obtained through Pinnick oxidation of pyrazole aldehydes to yield the corresponding acids, which then underwent amidation to afford the target products efficiently under mild reaction conditions. Structures of the desired compounds were confirmed by 1H NMR, 13C NMR, high resolution mass spectrometry; X-ray structural characterization of compound 16n was also obtained. The synthesized compounds were screened for their antiproliferative activity against four cancer cell lines (Pc-3 A549, Hela, HepG2) using the SRB method. Amides 10n, 16n, and 16p-16t exhibited moderate to high cytotoxic activities with IC50 values ranging from 2.05 to 8.73 µM. Of note, the hydrochloride derivative 16p displayed the highest activity towards PC-3 cells with IC50 values of 2.05 µM. Analysis of structure-activity relationships indicated that the presence of the diamine moiety and the aqueous solubility of the derivatives were vital factors for antiproliferative potency. Furthermore, molecule 16p induced PC-3 cells apoptosis and arrested cell cycle at G1 phase in a dose-dependent manner.