Methyl-introduced A-ring analogues of 1alpha,25-dihydroxyvitamin D3: synthesis and biological evaluation

The hormonally-active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1), has a wide variety of biological activities, which makes it a promising therapeutic agent for the treatment of cancer, psoriasis and osteoporosis. Insights into the structure-activity relationships of the A-ring of 1 are needed to assist the development of more potent and selective analogues, as well as to define the molecular mode of action. All possible A-ring stereoisomers of 2-methyl-1,25-dihydroxyvitamin D3 and 2,2-dimethyl-1,25-dihydroxyvitamin D3, which differ in stereochemistry at the C1-, C2- and C3-positions, were designed and efficiently synthesized by employing the convergent method. Biological evaluation of the analogues, in terms of the vitamin D receptor-binding affinity and HL-60 cell differentiation-inducing activity, as well as the transcriptional potency in ROS 17/2.8 cells, revealed the importance of substituents at the C2-position in certain orientations.