Structure-Activity Relationships of Naturally Occurring Active forms of Vitamin D Analogues

Abstract We synthesized active forms of naturally occurring vitamin D analogues (vitamin D 2 , D 3 , D 4 , D 5 , D 6 and D 7 ) and investigated the biological activities and metabolism (especially for 1α,25-dihydroxyvitamin D 4 ). 1α,25-Dihydroxyvitamin D 4 showed the same affinity for vitamin D receptor as 1α,25-dihydroxyvitamin D 3 , but it had stronger affinity for vitamin D binding protein and more efficient biological activities, such as activation of vitamin D receptor and effect on cellular growth and differentiation than 1α,25-dihydroxyvitamin D 3 . 1α,25-Dihydroxyvitamin D 4 increased total bone mass content in animal models of osteoporosis without elevating plasma calcium level. The pharmacokinetic study on 1α,25-dihydroxyvitamin D 4 showed longer T 1/2 , higher C max and AUC values than those of 1α,25-dihydroxyvitamin D 3 . According to the metabolism study, 1α,25-dihydroxyvitamin D 4 is metabolized in a similar manner to 1α,25-dihydroxyvitamin D 2 but differently from 1α,25-dihydroxyvitamin D 3 , suggesting the importance of theside chain structure. The results indicate that 1α,25-dihydroxyvitamin D 4 is a promising therapeutic agent for osteoporosis, skin disease and immune disorders. The synthetic procedure developed for active forms of vitamin D analogues was applied to the synthesis of biologically active steroids such as dictyosterol possessing the neurite outgrowth activity and the intermediates in steroid biosynthesis.