D3 A-ring Research Articles

Evaluation of vitamin D3 A-ring analogues as Hedgehog pathway inhibitors

A structure-activity relationship study focusing on the A-ring of vitamin D3 (VD3) was undertaken to elucidate its role in inhibiting the Hedgehog pathway and in mediating anti-cancer effects. Analogues resulting from simple functional group substitution at 3' position of VD3 were evaluated in a variety of biological assays to determine their ability to selectively inhibit Hh signaling. Moderately active Hh inhibitors that have insignificant binding affinity for VDR were identified; however, these compounds also activate the traditional VDR pathway, presumably due to metabolites produced in the cultured cells. Thus, further structural modifications to the VD3 scaffold are required to yield potent, selective Hh inhibitors.

ChemInform Abstract: Stereoselective Synthesis of 1α-Hydroxyvitamin D3 A-Ring Synthons by Palladium-Catalyzed Cyclization.

Palladium-catalyzed cyclization of 8-bromo-2,8-nonadienoates proceeded stereoselectively to give 1α-hydroxyvitamin D3 A-ring synthons in good yields.

ChemInform Abstract: Asymmetric Intramolecular Diels-Alder Cycloadditions of 2-Pyrone-3-carboxylates and Synthesis of Vitamin D3 A-Ring Phosphine Oxide.

ChemInform Abstract: Asymmetric Intramolecular Diels-Alder Cycloadditions of 2-Pyrone-3-carboxylates and Synthesis of Vitamin D3 A-Ring Phosphine Oxide.

ChemInform Abstract: Asymmetric Synthesis of 1α,25-Dihydroxyvitamin D3 A-Ring Precursor Starting with 5-tert-Butyldimethylsiloxy-2-cyclohexenone.

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ChemInform Abstract: Chiral Synthons from Carvone. Part 40. A Simple, Enantiospecific Approach to Both Enantiomers of 1α,25-Dihydroxyvitamin D3 A-Ring Precursors from R-Carvone.

A simple and direct approach to both enantiomeric series of A-ring derivatives of 1 alpha,25-dihydroxyvitamin D-3 and the corresponding 1 alpha,3 alpha-derivatives, starting from the abundantly available R-carvone, is described. (C) 2000 Elsevier Science Ltd. All rights reserved.

Synthesis of monoacyl A-ring precursors of 1alpha,25-dihydroxyvitamin D3 through selective enzymatic hydrolysis.

An efficient synthesis of monoacylated 1alpha,25-dihydroxyvitamin D3 A-ring precursors 15, 16, 18, and 19 has been described through an enzymatic hydrolysis process. Candida antarctica A lipase (CAL-A) hydrolyzes the C-5 acetate ester in trans stereoisomers 9 and 13, with complete and high selectivity, respectively. In the case of cis isomers 11 and 14, Chromobacterium viscosum lipase (CVL) is the enzyme of choice, exhibiting opposite selectivity for these two enantiomers. This lipase selectively catalyzes the hydrolysis at the C-3 acetate in diester 11 and at C-5 position in diester 14. It is noteworthy that through a hydrolysis reaction CAL-A and CVL allow the synthesis of the four A-ring monoacetylated precursors of 1alpha,25-dihydroxyvitamin D3, precursors which are complementary to those obtained by the enzymatic acylation process. In addition, with excellent yield CVL selectively hydrolyzes the C-3 chloroacetate ester instead of the C-5 acetate in diester 22, a key intermediate in the synthesis of new A-ring modified 1alpha,25-dihydroxyvitamin D3 analogues.

Asymmetric catalytic ene-cyclization approach to 2-fluoro-19-nor-1,25-dihydroxyvitamin D(3) A-ring analog with significant transactivation activity.

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)2D3) has been shown to modulate not only proliferation and differentiation, but also apoptosis in malignant cells, indicating that it could be useful for the treatment of cancer and psoriasis. However, little information has been available on the binding conformation of the 1alpha,25(OH)2D3 molecule and its analogs with the vitamin D receptor (VDR). Therefore, we synthesized 2alpha-fluorinated A-ring analogs of 19-nor-1alpha,25(OH)2D3 in order to investigate the VDR-binding conformation of the A-rings on the basis of the (19)F NMR analysis. The 2alpha-fluoro-19-nor-1alpha,25-dihydroxyvitamin D3 A-ring analog thus synthesized via a asymmetric catalytic carbonyl-ene cyclization, shows significant activity in transactivation.

Catalytic asymmetric syntheses and biological activities of singly dehydroxylated 19-nor-1α,25-dihydroxyvitamin D3 A-ring analogs in cancer cell differentiation and apoptosis

Background: 1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) has been shown to modulate not only proliferation and differentiation, but also apoptosis in malignant cells, indicating that it could be useful for treating cancer. Little information is available concerning the structural motifs of the 1α,25(OH)2D3 molecule responsible for modulation of differentiation and apoptosis, however. We set out to synthesize singly dehydroxylated A-ring analogs of 19-nor-1α,25(OH)2D3 in a catalytic asymmetric fashion, and to investigate their biological activities in leukemia HL-60 cells.Results: A series of singly dehydroxylated 19-nor-1α,25-dihydroxyvitamin D3 A-ring analogs were synthesized using a combinatiorial sequence of regioselective propiolate-ene reaction and catalytic asymmetric carbonyl-ene cyclization. Surprisingly, the analogs could be clearly divided into two categories; one group, bearing 1α-hydroxy or 3β-hydroxy groups in the A-ring, were potent differentiators and the second group, bearing 1β-hydroxy or 3α-hydroxy groups, were potent stimulators of apoptosis.Conclusions: We have clearly identified the structural motifs of 19-nor-1α,25(OH)2D3 analogs responsible for differentiation and apoptosis in HL-60 cells. These findings will provide useful information not only for development of therapeutic agents for treatment of leukemia and other cancers, but also for structure–function studies of 1α,25(OH)2D3. Supplementary material

1α,25-Dihydroxyvitamin D3 A-Ring Precursors: Studies on Regioselective Enzymatic Alkoxycarbonylation Reactions of Their Stereoisomers. Chemoenzymatic Synthesis of A-Ring Synthon Carbamate Derivatives, Including Carbazates and Polyamino Carbamates

The stereoisomers of 1α,25-dihydroxyvitamin D3 A-ring synthon 3a, named 3b−d, were subjected to a very comprehensive regioselective enzymatic study with Candida antarctica lipase (CAL). From this, it emerged that 3b, the enantiomer of the natural A-ring synthon, was a very good substrate for CAL in toluene, dioxane, or THF, showing in all cases conversions close to 100% and regioselectivities between 95% and 99% toward the C-5-(S) hydroxyl group. The best results for the regioselective enzymatic transformation of stereoisomer 3c were achieved with toluene at 30 °C or with THF at 60 °C. The regioselectivity displayed a preference toward the C-5-(S) hydroxyl group. The 1:10 ratio (3c:4) was mandatory so as to obtain an acceptable degree of conversion (in dioxane or THF). The A-ring synthon 3d has a surprising conduct, suffering C-5-(R) enzymatic alkoxycarbonylation, whereas in the acylation process with Chromobacterium viscosum lipase, it showed behavior opposite to that observed for 3a−c. In addition to th...

An asymmetric synthesis of a 1α,25-dihydroxyvitamin D3 A-ring synthon

An efficient asymmetric synthesis of the A-ring of 1α,25-dihydroxyvitamin D 3 from α-bromoacrolein is described. The key steps of the synthesis are the Evans type syn-selective asymmetric aldol reaction of bromoacrolein with the boron enolate of 3-chloroacetyl-4(S)-isopropyl oxazolidinone and ring closure by Heck type reaction of a vinyl bromide onto an α,β-unsaturated ester in the exo-mode. Graphic The synthesis of 1 is achieved in high yield by intramolecular Heck reaction of 2 which in turn was prepared from α-bromoacrolein via the Evans aldol 3 .