Highly active analogs of 1α,25-dihydroxyvitamin D 3 that resist metabolism through C-24 oxidation and C-3 epimerization pathways
The secosteroid hormone 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2D 3] is metabolized in its target tissues through modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the main side chain modification pathway is initiated by hydroxylation at C-24 of the side chain and leads...
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Published in | Steroids Vol. 66; no. 3; pp. 463 - 471 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
01.03.2001
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Subjects | |
Online Access | Get full text |
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Summary: | The secosteroid hormone 1α,25-dihydroxyvitamin D
3 [1α,25(OH)
2D
3] is metabolized in its target tissues through modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the main side chain modification pathway is initiated by hydroxylation at C-24 of the side chain and leads to the formation of the end product, calcitroic acid. The C-23 and C-26 oxidation pathways, the minor side chain modification pathways are initiated by hydroxylations at C-23 and C-26 of the side chain and lead to the formation of the end product, calcitriol lactone. The C-3 epimerization pathway, the newly discovered A-ring modification pathway is initiated by epimerization of the hydroxyl group at C-3 of the A-ring to form 1α,25(OH)
2-3-epi-D
3. A rational design for the synthesis of potent analogs of 1α,25(OH)
2D
3 is developed based on the knowledge of the various metabolic pathways of 1α,25(OH)
2D
3. Structural modifications around the C-20 position, such as C-20 epimerization or introduction of the 16-double bond affect the configuration of the side chain. This results in the arrest of the C-24 hydroxylation initiated cascade of side chain modifications at the C-24 oxo stage, thus producing the stable C-24 oxo metabolites which are as active as their parent analogs. To prevent C-23 and C-24 hydroxylations, cis or trans double bonds, or a triple bond are incorporated in between C-23 and C-24. To prevent C-26 hydroxylation, the hydrogens on these carbons are replaced with fluorines. Furthermore, testing the metabolic fate of the various analogs with modifications of the A-ring, it was found that the rate of C-3 epimerization of 5,6-trans or 19-nor analogs is decreased to a significant extent. Assembly of all these protective structural modifications in single molecules has then produced the most active vitamin D
3 analogs 1α,25(OH)
2-16,23-E-diene-26,27-hexafluoro-19-nor-D
3 (Ro 25–9022), 1α,25(OH)
2-16,23-Z-diene-26,27-hexafluoro-19-nor-D
3 (Ro 26–2198), and 1α,25(OH)
2-16-ene-23-yne-26,27-hexafluoro-19-nor-D
3 (Ro 25–6760), as indicated by their antiproliferative activities. |
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ISSN: | 0039-128X 1878-5867 |
DOI: | 10.1016/S0039-128X(00)00226-9 |