Hydrophosphinylation of <i>α</i> ‐Ketimino Esters to Access Unnatural Tetrasubstituted <i>α</i> ‐Phosphinyl <i>α</i> ‐Amino Acids: Cytotoxicity against Cancer Cells

An efficient and concise synthesis of tetrasubstituted α-phosphinyl α-amino acids (AAs) by hydrophosphinylation of α-ketimino esters under catalyst-free conditions is revealed. The strategy is simple, highly atom-economic and environmentally benign (E-factor = 0.03-0.38). Among the synthesized tetrasubstituted phosphinyl α-AA derivatives, compounds 3ab, 3ac, and 3ad exhibit potent anticancer activity in HepG2 (liver) and MCF7 (breast) cancer cells, whereas compound 3ah displays marked activity against A549 (lung) cancer cells. Notably, these compounds show more than twofold selectivity index toward MCF-7 cells compared to normal HEK-293 cells (kidney). Further, mechanistic studies reveal that these compounds effectively induce G1 or G2/M phase cell cycle arrest and promote significant apoptosis in a dose-dependent manner. Furthermore, compounds 3ab, 3ac, 3ad, and 3ah markedly downregulate the expression of anti-apoptotic genes (BCL-2 and Survivin), thereby enhancing their overall anticancer efficacy. These findings highlights the therapeutic potential of this class of compounds and encourage their further development as promising candidates for liver, breast, and lung cancer treatment.