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Synthesis of 6-s-cis and 6-s-trans A-Ring Modified Vitamin D Analogues

[ Vol. 14 , Issue. 21 ]

Author(s):

Susana Fernandez, Alba Hernandez-Martín, Tania Gonzalez-García and Miguel Ferrero   Pages 2424 - 2445 ( 22 )

Abstract:


Vitamin D, through its hormonally active form 1α,25-dihydroxyvitamin D3 [1α,25- (OH)2-D3], exhibits a much broader spectrum of bio logical activities than expected in the endocrine system. However, 1α,25-(OH)2-D3 causes hypercalcemia a t pharmacologically r elevant doses wh ich forms a major obstacle in the clinical development of this compound. As a result, considerable effort has been made toward the synthesis of potential chemotherapeutic structurally related congeners with dissociation of beneficial effects from their toxic effects. Most of the analogues prepared have modifications on the upper side chain, more accessible from a synthetic point of view. Modifications of the A-ring are less extensive, although A-ring analogues exhibit a unique biological profile. This seco steroid can undergo a rotation around the 6,7 carbon-carbon single bond generating a wide array of molecular shapes, extending from the 6-s-cis to the more stable extended 6-s-trans conformation, which plays an important role in modulating the different biological activities of vitamin D. We review here, the synthetic strategies for the preparation of Vitamin D analogues with modific ations on the A-ring, including 6-s-cis locked derivatives that became of interest to further probe the less well investigate membrane actions of 1α,25-(OH)2-D3 for structure-activity relationship studies.

Keywords:

6-s-cis Analogues, 6-s-trans Analogues, A-Ring Analogues, Previtamin D, Vitamin D, Synthesis.

Affiliation:

Departamento de Química Orgánica e Inorgánica and Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33006-Oviedo (Asturias), Spain.

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