Calcitriol Derivatives with Two Different Side Chains at C-20. II. Diastereoselective Syntheses of the Metabolically Produced 24(R)-Hydroxygemini

Abstract

Vitamin D derivatives containing two side chains emanating at C-20 are known as gemini. We have recently synthesized two gemini which are related to calcitriol and 19-norcalcitriol containing two identical side chains. The metabolism of these species involves 24(R)-hydroxylation on one of the side chains. To determine the outcome of this diastereospecific transformation, we synthesized both C-20 epimeric pairs containing the 24(R)-hydroxy group in the gemini and 19-norgemini series. On the basis of the availability of these reference compounds, it was shown that the metabolic hydroxylation occurred at the pro-R side chain in both gemini compounds. In comparison to the parent compounds, the 24-hydroxygemini required higher doses to increase blood calcium levels in mice and to suppress INF-gamma release in MLR.

Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

“…11,12 The discovery that 20-epi vitamin D analogs can exhibit higher potencies 13,14 engendered the synthesis of Gemini, distinguished by two identical side chains emanating at C-20. 15,16 In a second generation of Gemini compounds, chain-modifications aimed at metabolic retardation and enhanced differentiation were introduced stereoselectively 17,18 and their effects evaluated. 19,20 Increased anti-proliferative activities of 20-desmethyl-20-cyclopropyl-cholecalciferol analogs have also been reported, 21 and an additional modification in the form of an unsaturated chain containing terminal trifluoromethyl groups and a 19-nor A-ring 22 has demonstrated enhanced transcriptional activity while maintaining low hypercalcemia-induction potential when compared to 1,25D.…”

Steroids: partial synthesis in medicinal chemistry

“…Calcitriol analogues with two different side chains at C (20) have been synthesized 121 and their use as probes of the vitamin D receptor has been explored. 122 The crystal structure of the vitamin D nuclear receptor liganded with the vitamin D side chain analogue calcipotriol 45, has been determined 123 in order to provide an insight into the biological activity of these analogues.…”

Structure–function study of gemini derivatives with two different side chains at C-20, Gemini-0072 and Gemini-0097

“…These chemical features have been shown to prevent or delay biological degradation initiated by 24-hydroxylation. 8,10 Deuteration of the geminal methyl groups also extends the half-life 10,11 and was expected to stabilize the interactions within the VDR complex. The two C-20 epimeric Gemini-0072 and Gemini-0097 (Fig.…”

“…6 New gemini derivatives were subsequently synthesized with chemical modifications designed to enhance their biological activity by increasing their resistance toward metabolic degradation. [7][8][9] These modifications include a 19-nor A-ring and two different side chains, one side chain similar to the natural one wherein the geminal methyl groups are replaced by trideuteromethyls, and the second side chain with trifluoromethyl groups and C-23 unsaturation. These chemical features have been shown to prevent or delay biological degradation initiated by 24hydroxylation.…”