Ring-A-seco analogs of 1α,25-dihydroxy-19-norvitamin D3

Abstract

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.

Total Synthesis of ent-Ascospiroketal B

“…Segment G would be prepared from L-(+)-tartaric acid. Thioacetal 7 corresponding to segment F was synthesized from diol 5 9 prepared by a known method from D-(+)-malic acid (Scheme 2). Selective protection of the primary hydroxy group in diol 5 was carried out as a Bn ether 10 (80% yield), and the secondary hydroxy group was protected as a THP ether.…”

“…The organic layer was washed with water and saturated aqueous NaCl, dried over Na 2 SO 4 , and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/EtOAc = 8:1) to afford thioacetal 7 (6.57 g, 91% yield) as a colorless oil: R f 0.51 (hexane/ EtOAc = 6:1); IR (neat) ν max = 2940, 2854, 1450 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.39−7.22 (5H, m), 4.82 (0.4H, dd, J = 3.0, 4.0 Hz), 4.66 (0.6H, dd, J = 3.0, 4.0 Hz), 4.60−4.48 (2H, m), 4.07 (0.4H, t, J = 6.8 Hz), 4.02 (0.6H, t, J = 6.1 Hz), 3.95−3.74 (2H, m), 3.62 (0.6H, dd, J = 4.9, 9.8 Hz), 3 (9). To a suspension of NaH (2.80 g, 64.0 mmol, 55% in oil) in THF (305 mL) was slowly added a solution of diol 8 (11.5 g, 61.0 mmol) in THF (305 mL) at 0 °C, and the mixture was stirred for 30 min.…”

Biocatalyzed transformation of progesterone by Geobacillus gargensis DSM 15378

“…13 C NMR spectra were recorded for CDCl 3 solu tions, on a Bruker 600 MHz NMR spectrometer (Germany) using 5 mm NMR tubes. A 5 mm dual probe was used for chemical shift measurements.…”

“…Investigations into seco steroids is an impor tant and progressive field that has resulted in the cleav age of a, b, or c ring in a steroid nucleus. Thus, several seco steroids with diverse biological activities have been recently reported [13,14]. The commonly known example of seco steroid is vitamin D3, which is involved in calcium and phosphorus metabolism.…”

Relation between Crystal Structures of Precursors and Final Products: Example of Vitamin D Intermediates

“…However, the simple structural fragments having their X-ray structures solved might be a valuable source of data in predicting the solid-state structure of the final vitamin D analogues. Despite broad applications and interests in the chemistry of vitamin D, less than 20 crystal structures of active metabolites and various analogues of vitamin D have been solved and deposited in the Cambridge Structural Database (CSD) [15][16][17][18], while ca. 20, 20, and 40 structures of widely used other pharmaceutical compounds were deposited, that is, ibuprofen, acetylsalicylic acid, and acetaminophen, respectively [19,20].…”