Structure-specific control of differentiation and apoptosis of human promyelocytic leukemia (HL-60) cells by A-ring diastereomers of 2-methyl- 1α,25-dihydroxyvitamin D 3 and its 20-epimer

Abstract

1α,25-Dihydroxyvitamin D 3 (1α,25(OH) 2D 3) has been shown to modulate not only proliferation and differentiation but also apoptosis of malignant cells, indicating that it would be useful for the treatment of hyperproliferative diseases such as cancer and psoriasis. Little information is available concerning structural motifs of the 1α,25(OH) 2D 3 molecule responsible for modulation of differentiation and apoptosis. We synthesized all possible A-ring diastereomers of the 2-methyl-1α,25(OH) 2D 3 and its 20-epimer and evaluated their biological activities in human promyelocytic leukemia (HL-60) cells. Surprisingly, the potent analogues could be clearly divided into two groups: (i) those bearing the 1α- and 3β-hydroxyl groups on the A-ring were potent inducers of differentiation and growth inhibitors of HL-60 cells and (ii) those bearing the 1β-hydroxyl group together with either 3α- or 3β-hydroxyl groups on the A-ring were potent stimulators of apoptosis in these cells. We have clearly identified for the first time the structural motifs on the basis of the stereochemistry of both hydroxyl groups at positions 1 and 3 of the A-ring of the 1α,25(OH) 2D 3 molecule responsible for the induction of differentiation and apoptosis of HL-60 cells. These findings provide useful information not only for structure–function studies of 1α,25(OH) 2D 3 analogues but also for the development of therapeutic agents for the treatment of leukemia and other cancers.