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 language | English (US) |
|---|---|
| Pages (from-to) | 4529-4537 |
| Number of pages | 9 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 38 |
| Issue number | 22 |
| State | Published - 1995 |
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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 journal › Article
}
TY - JOUR
T1 - 1α,25-Dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings
T2 - Design, synthesis, and preliminary biological testing
AU - Posner, Gary H.
AU - Li, Zhengong
AU - White, M. Christina
AU - Vinader, Victoria
AU - Takeuchi, Kazuhiro
AU - Guggino, Sandra E.
AU - Dolan, Patrick
AU - Kensler, Thomas W
PY - 1995
Y1 - 1995
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0028970494&partnerID=8YFLogxK
M3 - Article
C2 - 7473581
AN - SCOPUS:0028970494
VL - 38
SP - 4529
EP - 4537
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 22
ER -