Design, synthesis and biological evaluation of novel 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives as potent...

A series of 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives were designed, synthesized and evaluated for their in vitro inhibitory activities against PI3Kα and antiproliferative activities against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cancer cell lines. Inhibitory activities against PI3Kα evaluation indicated that some compounds showed excellent PI3Kα activity in vitro, and IC₅₀ values of eight compounds (17c, 17e, 17f, 17h, 17l, 17m, 17o, 17p) were less than 100 nM. The most promising compound 17f (PI3Kα: IC₅₀ = 0.039 microM) showed remarkable antiproliferative against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cell lines with IC₅₀ values of 3.48 microM, 1.06 microM, 2.21 microM and 0.93 microM, respectively. Furthermore, 17f effectively reduced p-PI3K protein expression and inhibited the activation of downstream signaling AKT and mTOR proteins in MDA-MB-453 cells. In addition, 17f induced cell apoptosis by down-regulating the expression levels of anti-apoptotic proteins Bcl-XL and Bcl-2 and up-regulating the expression of anti-apoptotic protein BAX, and in MDA-MB-453 cells. All these results indicated the potential of compound 17f to develop as potent anticancer agent.