ChemInform Abstract: VITAMIN D3 METABOLITES PART 1, SYNTHESIS OF 25‐HYDROXYCHOLESTEROL

Partridge, John J.; Faber, Stephanie; Uskoković, Milan R.

doi:10.1002/chin.197427438

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“…The analogue 8d was obtained employing a different strategy (Scheme 5). The following steps were involved starting from the mixture of 38Rd and 38βd: (i) substitution of the corresponding tosylate 45 with the sodium salt derived from the ethoxyethyl ether of 2-methyl-3-butyn-2-ol (NaH, DMSO); 28 (ii) desilylation (TBAF, THF) of 46d; (iii) hydrogenation of 47d using 5% Rh/Al 2 O 3 in ethyl acetate (90%) to alcohol 48d. Subsequent oxidation with PDC led to a mixture of 49d and deprotected 43d.…”

Section: Synthesismentioning

confidence: 99%

Synthesis, Biological Activity, and Conformational Analysis of Fourseco-d-15,19-bisnor-1α,25-Dihydroxyvitamin D Analogues, Diastereomeric at C17 and C20

et al. 1999

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The synthesis of four CD-ring-modified 19-nor-1alpha, 25-dihydroxyvitamin D(3) derivatives lacking C15, referred to as 6C analogues, and diastereomeric at C17 and C20 is described. The synthesis involves an Ireland-Claisen rearrangement of a 3-methyl-substituted ester of (1R)-3-methyl-2-cyclohexen-1-ol as the key step, followed by elaboration of the side chain, transformation into a C8 cyclohexanone derivative, and final Wittig-Horner coupling with the 19-nor A-ring phosphine oxide. Despite possessing a more flexible side chain than the parent hormone, biological evaluation showed an unexpected superagonistic antiproliferative and prodifferentiating activity (10-50 times higher as compared to that of 1alpha,25(OH)(2)D(3)) for the diastereomer with the "natural" configuration at C17 and C20. The other diastereomers exhibit a 25-90% decrease in activity. All four analogues show a decreased binding affinity (45% or less), and their calcemic activity is 4-400 times less than that of 1alpha,25(OH)(2)D(3). The conformational behavior of their side chain was studied using molecular mechanics calculations, and the result is presented as volume maps. A relative activity volume was determined by subtraction of the volume map of the least active analogue from the volume map of the most active one. This shows three regions corresponding to preferred orientations in space of the side chain of the active analogue. One of these regions was found to overlap with the region that is preferentially occupied by the most active of the four diastereomeric 22-methyl-substituted 1alpha,25(OH)(2)D(3) analogues.

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Section: Synthesismentioning

confidence: 99%

Synthesis, Biological Activity, and Conformational Analysis of Fourseco-d-15,19-bisnor-1α,25-Dihydroxyvitamin D Analogues, Diastereomeric at C17 and C20

et al. 1999

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ChemInform Abstract: VITAMIN D3 METABOLITES PART 1, SYNTHESIS OF 25‐HYDROXYCHOLESTEROL

Abstract: Das aus Stigmasterin und p‐Tosylchlorid in Pyridin erhaltene Tosylat (I) liefert beim Erhitzen mit Methanol neben Stigmasterylmethyläther überwiegend den Isostigmasteryläther (II), der in den Alkohol (IIIa) übergeführt wird.

Cited by 1 publication

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Synthesis, Biological Activity, and Conformational Analysis of Fourseco-d-15,19-bisnor-1α,25-Dihydroxyvitamin D Analogues, Diastereomeric at C17 and C20

Synthesis, Biological Activity, and Conformational Analysis of Fourseco-d-15,19-bisnor-1α,25-Dihydroxyvitamin D Analogues, Diastereomeric at C17 and C20

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