Abstract by Reuben Dass
Chemistry and Biochemistry
Synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidines: Discovery of a selective inhibitor of JAK1 JH2 pseudokinase and VPS34
A series of novel 3,6-di-substituted or 3-substituted pyrazolo[1,5-a]pyrimidines were prepared via a microwave-assisted approach that generated a broad array of derivatives in good yields (average = 59%). The synthesized compounds were screened for antimitotic activities against MCF7 breast cancer and/or A2780 ovarian
cancer cell lines in vitro. The most active compounds exhibited EC50 values ranging from 0.5 - 4.3μM, with two derivatives (34e and 35a) being two-three fold more active than Compound C (Dorsomorphin) in A2780 and MCF7 assays, respectively. A monosubstituted 3-(benzothiazol-2-yl) derivative (13) was equipotent with the more synthetically challenging 3,6-disubstituted derivatives (34 a–e and 35 a–e) and exhibited a promising and unique selectivity profile when screened against a panel consisting of 403 protein kinases (Kinomescan™) selectivity score = 0.005, Kd = 0.55 ± 0.055μM and 0.410 ± 0.20μM for JAK1 JH2 pseudokinase and VPS34, respectively).