TY - JOUR
T1 - Discovery and SAR of Novel Disubstituted Quinazolines as Dual PI3Kalpha/mTOR Inhibitors Targeting Breast Cancer
AU - Al-Ashmawy, Aisha A.K.
AU - Elokely, Khaled M.
AU - Perez-Leal, Oscar
AU - Rico, Mario
AU - Gordon, John
AU - Mateo, George
AU - Omar, Abdelsattar M.
AU - Abou-Gharbia, Magid
AU - Childers, Wayne E.
N1 - Publisher Copyright:
©
PY - 2020/11/12
Y1 - 2020/11/12
N2 - The dual PI3Kα/ m TOR inhibitors represent a promising molecularly targeted therapy for cancer. Here, we documented the discovery of new 2,4-disubstituted quinazoline analogs as potent dual PI3Kα/sm TOR inhibitors. Our structure based chemistry endeavor yielded six excellent compounds 9e, 9f, 9g, 9k, 9m, and 9o with single/double digit nanomolar IC50 values against both enzymes and acceptable aqueous solubility and stability to oxidative metabolism. One of those analogs, 9m, possessed a sulfonamide substituent, which has not been described for this chemical scaffold before. The short direct synthetic routes, structure-Activity relationship, in vitro 2D cell culture viability assays against normal fibroblasts and 3 breast cancer cell lines, and in vitro 3D culture viability assay against MCF7 cells for this series are described.
AB - The dual PI3Kα/ m TOR inhibitors represent a promising molecularly targeted therapy for cancer. Here, we documented the discovery of new 2,4-disubstituted quinazoline analogs as potent dual PI3Kα/sm TOR inhibitors. Our structure based chemistry endeavor yielded six excellent compounds 9e, 9f, 9g, 9k, 9m, and 9o with single/double digit nanomolar IC50 values against both enzymes and acceptable aqueous solubility and stability to oxidative metabolism. One of those analogs, 9m, possessed a sulfonamide substituent, which has not been described for this chemical scaffold before. The short direct synthetic routes, structure-Activity relationship, in vitro 2D cell culture viability assays against normal fibroblasts and 3 breast cancer cell lines, and in vitro 3D culture viability assay against MCF7 cells for this series are described.
KW - 4-Morpholinoquinazolines
KW - PI3Kα
KW - breast cancer cell lines
KW - mTOR. dual inhibitors
KW - mammalian target of rapamycin
UR - http://www.scopus.com/inward/record.url?scp=85095613287&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.0c00289
DO - 10.1021/acsmedchemlett.0c00289
M3 - Article
AN - SCOPUS:85095613287
SN - 1948-5875
VL - 11
SP - 2156
EP - 2164
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 11
ER -