1α,25-Dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings: Design, synthesis, and preliminary biological testing

Gary H. Posner, Zhengong Li, M. Christina White, Victoria Vinader, Kazuhiro Takeuchi, Sandra E. Guggino, Patrick Dolan, Thomas W Kensler

Research output: Contribution to journalArticle

Abstract

Aromatic compounds 2a-c, analogs of 1α,25-dihydroxyvitamin (calcitriol, 1), and heteroaromatic compounds 4a-c and 5a-c, analogs of 19-nor-1α,25-dihydroxyvitamin D3 (3), were designed to simulate the topology of their biologically potent parent compounds while avoiding previtamin D equilibrium. Convergent and facile total syntheses of the analogs (+)-2b, (+)-2c, (-)-4b, and (-)-5b were achieved via carbonyl addition of regiospecifically formed organolithium nucleophiles to the enantiomerically pure C,D-ring ketone (+)-17, characteristic of natural calcitriol (1). Likewise, hybrid analogs 20a-c were prepared to determine whether incorporation of a known potentiating side chain would lead to increased biological activity. Preliminary in vitro biological testing showed that aromatic analogs (+)-2b, (+)-2c, and 20a-c as well as heteroaromatic analogs (-)-4b and (-)-5b have very low affinities for the calf thymus vitamin D receptor but considerable antiproliferative activities in murine keratinocytes at micromolar concentration. No biological advantage was observed in this keratinocyte assay for the doubly modified hybrid analogs 20a-c over the singly modified parent (+)-2b. Analog (+)-2b, but surprisingly not the corresponding analog 20b differing from (+)-2b only in the side chain, showed considerable activity in nongenomic opening of calcium channels in rat osteosarcoma cells.

Original languageEnglish (US)
Pages (from-to)4529-4537
Number of pages9
JournalJournal of Medicinal Chemistry
Volume38
Issue number22
StatePublished - 1995

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Calcitriol
Keratinocytes
Thymus
Nucleophiles
Calcitriol Receptors
Aromatic compounds
Testing
Osteosarcoma
Calcium Channels
Bioactivity
Ketones
Thymus Gland
Rats
Assays
Topology
19-nor-1,25-dihydroxyvitamin D3
In Vitro Techniques

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

1α,25-Dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings : Design, synthesis, and preliminary biological testing. / Posner, Gary H.; Li, Zhengong; White, M. Christina; Vinader, Victoria; Takeuchi, Kazuhiro; Guggino, Sandra E.; Dolan, Patrick; Kensler, Thomas W.

In: Journal of Medicinal Chemistry, Vol. 38, No. 22, 1995, p. 4529-4537.

Research output: Contribution to journalArticle

Posner, GH, Li, Z, White, MC, Vinader, V, Takeuchi, K, Guggino, SE, Dolan, P & Kensler, TW 1995, '1α,25-Dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings: Design, synthesis, and preliminary biological testing', Journal of Medicinal Chemistry, vol. 38, no. 22, pp. 4529-4537.
Posner, Gary H. ; Li, Zhengong ; White, M. Christina ; Vinader, Victoria ; Takeuchi, Kazuhiro ; Guggino, Sandra E. ; Dolan, Patrick ; Kensler, Thomas W. / 1α,25-Dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings : Design, synthesis, and preliminary biological testing. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 22. pp. 4529-4537.
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