TY - JOUR T1 - 13,13-Dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D₃ (2MD): total synthesis, docking to the VDR, and biological evaluation JF - Bioorganic & Medicinal Chemistry Y1 - 2011 A1 - Katarzyna Plonska-Ocypa A1 - Izabela Sibilska A1 - Rafal R. Sicinski A1 - Wanda Sicinska A1 - Lori A. Plum A1 - Hector F. DeLuca KW - Animals KW - Calcitriol KW - Cell Differentiation KW - Crystallography, X-Ray KW - HL-60 Cells KW - Humans KW - Male KW - Models, Molecular KW - Molecular Conformation KW - Rats KW - Receptors, Calcitriol KW - Structure-Activity Relationship AB - As a continuation of our studies focused on the vitamin D compounds lacking the C,D-hydrindane system, 13,13-dimethyl-des-C,D analogues of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D(3) (2, 2MD) were prepared by total synthesis. The known cyclohexanone 30, a precursor of the desired A-ring phosphine oxide 11, was synthesized starting with the keto acetal 13, whereas the aldehyde 12, constituting an acyclic 'upper' building block, was obtained from the isomeric esters 34, prepared previously in our laboratory. The commercial 1,4-cyclohexanedione monoethylene ketal (13) was enantioselectively α-hydroxylated utilizing the α-aminoxylation process catalyzed by l-proline, and the introduced hydroxy group was protected as a TBS, TPDPS, and SEM ether. Then the keto group in the obtained compounds 15-17 was methylenated and the allylic hydroxylation was performed with selenium dioxide and pyridine N-oxide. After separation of the isomers, the newly introduced hydroxy group was protected and the ketal group hydrolyzed to yield the corresponding protected (3R,5R)-3,5-dihydroxycyclohexanones 30-32. The esters 34, starting compounds for the C,D-fragment 12, were first α-methylated, then reduced and the resulted primary alcohols 36 were deoxygenated using the Barton-McCombie protocol. Primary hydroxy group in the obtained diether 38 was deprotected and oxidized to furnish the aldehyde 12. The Wittig-Horner coupling of the latter with the anion of the phosphine oxide 11, followed by hydroxyl deprotection furnished two isomeric 13,13-dimethyl-des-C,D analogues of 2MD (compounds 10 and 42) differing in configuration of their 7,8-double bond. Pure vitamin D analogues were isolated by HPLC and their biological activity was examined. The in vitro tests indicated that, compared to the analogue 7, unsubstituted at C-13, the synthesized vitamin D analogue 10 showed markedly improved VDR binding ability, significantly enhanced HL-60 differentiation activity as well as increased transcriptional potency. Docking simulations provided a rational explanation for the observed binding affinity of these ligands to the VDR. Biological in vivo tests proved that des-C,D compound 10 retained some intestinal activity. Its geometrical isomer 42 was devoid of any biological activity. VL - 19 IS - 23 ER - TY - JOUR T1 - 2-Methylene analogs of 1alpha-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2004 A1 - Pawel Grzywacz A1 - Lori A. Plum A1 - Wanda Sicinska A1 - Rafal R. Sicinski A1 - Jean M. Prahl A1 - Hector F. DeLuca KW - Animals KW - Binding Sites KW - Calcitriol KW - Female KW - HL-60 Cells KW - Humans KW - Hydrocarbons KW - Ligands KW - Methane KW - Mice KW - Models, Molecular KW - Rats KW - Receptors, Calcitriol AB - In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1alpha-hydroxy-19-norvitamin D(3) analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann type ketones 9, possessing different 17beta-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) (1) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported. VL - 89-90 IS - 1-5 ER - TY - JOUR T1 - 2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain. JF - Journal of Medicinal Chemistry Y1 - 2002 A1 - Rafal R. Sicinski A1 - Piotr Rotkiewicz A1 - Andrzej Koliński A1 - Wanda Sicinska A1 - Jean M. Prahl A1 - Connie M. Smith A1 - Hector F. DeLuca KW - Animals KW - Binding Sites KW - Biological Transport KW - Calcitriol KW - Calcium KW - Cell Differentiation KW - Chromatography, High Pressure Liquid KW - HL-60 Cells KW - Humans KW - Intestinal Mucosa KW - Ligands KW - Magnetic Resonance Spectroscopy KW - Male KW - Models, Molecular KW - Molecular Conformation KW - Rats KW - Receptors, Calcitriol KW - Spectrophotometry, Ultraviolet KW - Structure-Activity Relationship KW - Swine AB - Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann's ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported. VL - 45 IS - 16 ER - SMTP Error: The following recipients failed: pledor@chem.uw.edu.pl SMTP Error: The following recipients failed: pledor@chem.uw.edu.pl SMTP Error: The following recipients failed: pledor@chem.uw.edu.pl Error | Laboratory of Theory of Biopolymers

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