Abstract
1α,25-Dihydroxyvitamin D3 [1α,25-(OH)2-D3], the hormonally active form of vitamin D3, classically regulates bone formation, calcium, and phosphate homeostasis. In addition, this hormone also exerts non-classical effects in a wide variety of target tissues and cell types, such as inhibition of the proliferation and stimulation of the differentiation of normal and malignant cells. However, to produce these actions, supraphysiological doses are required resulting in calcemic effects that limit the use of this natural hormone. During the past 30 years, many structurally modified analogs of the 1α,25-(OH)2-D3 have been synthesized in order to find derivatives that can dissociate the beneficial antiproliferative effects from undesired calcemic effects. Among these candidates, 1α,25-(OH)2-19-nor-D3 analogs have shown promise as good derivatives since they show equal or better activity relative to the parent hormone but with reduced calcemic effects. In this review, we describe the synthetic strategies to obtain the 19-nor-D3 derivatives and briefly describe their physiological activities.
Highlights
The steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2-D3] (2, Figure 1) is the active form of vitamin D3 (1), which can be synthesized in the skin or obtained from dietary sources [1]
50 years have passed since the discovery of calcitriol (1α,25-dihydroxyvitamin D3), the hormonally active form of vitamin D
Many hundreds of vitamin D analogs have been synthesized in an attempt to segregate these two opposite effects
Summary
The steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2-D3] (2, Figure 1) is the active form of vitamin D3 (1), which can be synthesized in the skin or obtained from dietary sources [1]. The new synthesis entails the independent preparation of a phosphine oxide A-ring precursor and the CD-ring/side chain ketone and their eventual condensation through a Wittig–Horner reaction to obtain the 19-nor-vitamin D derivative 25, which, after deprotection, yielded the desired compound 3a They chose (−)-quinic acid (18) as the starting material since it features the correct hydroxy stereochemistry and is commercially available. The objective was to synthesize new analogs with potential applications as drugs for osteoporosis but with no calcemic effects They were prepared through a convergent route, starting from (−)-quinic acid (18) and 25-hydroxy-protected Grundmann’s ketone (21) followed by the Wittig–Horner coupling approach using the phosphine oxide precursors 30. Preparation of 1α,25-(OH)2-19-nor-vitamin D3 A-ring C1- and C3-epi analogs
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