Removal of C-ring from the CD-ring skeleton of 1α,25-dihydroxyvitamin D3 does not alter its target tissue metabolism significantly

It is now well established that 1 alpha,25(OH)(2)D-3 is metabolized in its target tissues through the modifications of both side chain and A-ring. The C-24 oxidation pathway is the side chain modification pathway through which 1 alpha,25(OH)(2)D-3 is metabolized into calcitroic acid. The C-3 epimerization pathway is the A-ring modification pathway through which 1 alpha,25(OH)(2)D-3, is metabolized into 1 alpha,25(OH)(2)-3-epi-D-3. During the past two decades, a great number of vitamin D analogs were synthesized by altering the structure of both side chain and A-ring of 1 alpha,25(OH)(2)D-3 with the aim to generate novel vitamin D compounds that inhibit proliferation and induce differentiation of various types of normal and cancer cells without causing, significant hypercalcemia. Previously, we used some of these analogs as molecular probes to examine how changes in 1 alpha,25(OH)(2)D-3 structure would affect its target tissue metabolism. Recently, several nonsteroidal analogs of 1 alpha,25(OH)(2)D-3 with unique biological activity profiles were synthesized. Two of the analogs, SL 117 and WU 515 lack the C-ring of the CD-ring skeleton of 1 alpha,25(OH)(2)D-3- SL 117 contains the same side chain as that of 1 alpha,25(OH)(2)D-3, while WU 515 contains an altered side chain with a 23-yne modification combined with hexafluorination at C-26 and C-27. Presently, it is unknown how the removal of Gring from the CD-ring skeleton of 1 alpha,25(OH)(2)D-3 would affect its target tissue metabolism. In the present study, we compared the metabolic fate of SL 117 and WU 515 with that of 1 alpha,25(OH)(2)D-3 in both the isolated perfused rat kidney, which expresses only the C-24 oxidation pathway and rat osteosarcoma cells (UMR 106), which express both the C-24 oxidation and C-3 epimerization pathways. The results of our present study indicate that SL 117 is metabolized like 1 alpha l,25(OH)(2)D-3,D- into polar metabolites via the C-24 oxidation pathway in both rat kidney and UMR 106 cells. As expected, WU 515 with altered side chain structure is not metabolized via the C-24 oxidation pathway. Unlike in rat kidney, both SL 117 and WU 515 are also metabolized into less polar metabolites in UMR 106 cells. These metabolites displayed GC and MS characteristics consistent with A-ring epimerization and were putatively assigned as C-3 epimers of SL 117 and WU 515. In summary, we report that removal of the C-ring from the CD-ring skeleton of 1 alpha,25(OH)(2)D-3 does not alter its target tissue metabolism significantly. (c) 2006 Elsevier Inc. All rights reserved.