Ring-A-seco analogs of 1α,25-dihydroxy-19-norvitamin D3.
The steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2D3] is the most active metabolite of vitamin D3 which exerts its control over a multitude of biological processes related to calcium and phosphorus homeostasis, cell proliferation and differentiation, and immune regulation. Unfortunately, the therapeutic application of 1α,25-(OH)2D3 is limited by induction of hypercalcemia. The need for vitamin D compounds with selective biological profiles has stimulated the synthesis of more than three thousand analogs of 1α,25-(OH)2D3. Most of these compounds have structural modifications in the side chain and A-ring; there is also an increasing number of modifications in the CD-rings and limited number in the triene system (seco-B ring). Herein, we report the synthesis and biological evaluation of seco-A-19-nor analogs of 1α,25-dihydroxyvitamin D3, developed to study the role of ring A in the biological activity of 1α,25-(OH)2D3. Interestingly, compounds 2 and 4 show substantial ability to bind the vitamin D receptor and the former is also characterized by selective intestinal calcium transport activity. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
Agnieszka
A
Glebocka
Rafal R
RR
Sicinski
Lori A
LA
Plum
Hector F
HF
Deluca
D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium