A new synthetic approach for pyrazolo[1,5-a]pyrazine-4(5H)-one derivatives and their antiproliferative effects on lung adenocarcinoma cell line.

Starting from the 3,5-dimethyl pyrazole ring and acetophenone derivatives, five different N-propargylated C-3 substituted pyrazoles were obtained. These derivatives were reacted with different amine derivatives using Cs2CO3 in methanol and 11 different pyrazolo [1,5-a] pyrazine-4(5H)-one derivatives were obtained, which are not found in the literature. The cytotoxic effects of these derivatives in the A549 cell line were investigated. The 160 µM concentration of two derivatives was found to increase cell death rate to 50%, and two derivatives increased cell death rate by up to 40%. The structure-activity relationship (SAR) study revealed an amide group with a long alkyl chain and benzene ring with a p-CF3 group could be important for efficiency. With theoretical ADMET studies of pyrazolopyrazine derivatives, pharmacokinetic phases were predicted to be suitable.

Flavopiridol's antiproliferative effects in glioblastoma multiforme.

AIM OF STUDY: Glioblastoma multiforme (GBM) is largely refractory to surgical operation, radiotherapy, and chemotherapy in use today. Remaining lifetime accounting for the GBM-affected patients varies between 12 and 16 months generally. The most frequently altered genes in GBM are p53, epidermal growth factor receptor, PTEN, and cyclin-dependent kinase inhibitor 2A. Our aim is to investigate the antiproliferative and apoptotic effects of flavopiridol, a cyclin-dependent kinases and specific phosphokinase inhibitor, on glioblastoma cell lines having different genetic profiles: U87MG, U118MG, and T98G. MATERIALS AND METHODS: Cell viability and IC50 values were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, protein expressions were determined by Western blot and caspase activities were analyzed by activity kit. RESULTS: Western blot analysis showed down-regulation of the cyclin D1, c-Myc, and p53 protein activities, and up-regulation of p27KIP1 activity after flavopiridol treatment. Additionally, flavopiridol diminished p-Akt protein levels generally which induces inhibition of proliferation. CONCLUSION: The present study demonstrated that flavopiridol did not induce caspase-3/7 activation, BIM, and BAX pro-apoptotic proteins but it leads to the expression changes of various proteins that inhibit proliferation and eternity in glioblastoma cell lines which have different genetic alterations.