Difluoromethyl analogs of the natural hormone 1α,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation

Abstract

Three new Vitamin D analogs 3-5 incorporating a -CHF(2) group as an -OH surrogate have been prepared. Two of these new analogs (3 and 5) are strongly antiproliferative toward murine keratinocytes and are approximately 50 times less calciuric in vivo than the natural hormone calcitriol. The transcriptional activity of the 25-CHF(2) analog 3 is higher than that of the 1-CHF(2) analog 4.

Low-Calcemic, Highly Antiproliferative, 1-Difluoromethyl Hybrid Analogs of the Natural Hormone 1α,25-Dihydroxyvitamin D3: Design, Synthesis, and Preliminary Biological Evaluation

“…Chemistry: Syntheses of hybrid analogs 6 and 7 are outlined in Scheme 1, starting with the recently reported A-ring 1-CHF 2 7-phosphine oxide synthon (()-8. 17 Lythgoe-type coupling 18 of racemic phosphine oxide 8 with enantiomerically pure C,Dring C-8 ketone 9 led smoothly after desilylation to a mixture of diastereomers from which the major diasteromer analog (+)-6 was isolated via preparative HPLC. Similarly, coupling with C,D-ring C-8 ketone 10 led easily after desilylation and HPLC purification to analog (-)-7.…”

“…Analog 6. Racemic 1-CHF 2 phosphine oxide 8 17 and CD-ring ketone 9 11 were separately azeotropically dried with anhydrous benzene (4 × 5 mL) on a rotary evaporator and held under vacuum (ca. 0.1 mmHg) for at least 48 h prior to use.…”

“…[R] 24 D +54.2 (c 0.125, CHCl 3 ); IR (neat, cm -1 ) 3400 (br s), 2924 (m), 2861 (m), 2361 (s), 2339 (s), 1456 (w), 1373 (w), 1061 (w), 673 (w), 650 (w); 1 Analog 7. Racemic 1-CHF 2 phosphine oxide 8 17 and CD-ring ketone 10, 19 were separately azeotropically dried with anhydrous benzene (4 × 5 mL) on a rotary evaporator and held under vacuum (ca. 0.1 mmHg) for at least 48 h prior to use.…”

“…A flame-dried 10-mL recovery flask equipped with a magnetic stir bar and an Ar balloon was charged with phosphine oxide (()-8 17 (45 mg, 0.09 mmol). The reagent was dissolved in 2.0 mL freshly distilled THF and cooled to -78 °C.…”

“…A virtual docking of this analog into the binding pocket of hVDR indeed predicted that the bulkier difluoromethyl group at C1 (1-CHF 2 ) would form weaker hydrogen bonds than the natural 1-R hydroxyl group. 17 To determine if biological activities of analogs with this new type of modification in the C-1 position can be as effectively restored by incorporating potentiating side chains as were biological activities of analogs with the 1-hydroxymethyl group, 8 we have now designed and prepared new hybrid analog 6 (KSP-BCS-1RCHF 2 -1624F 2 -2) carrying 1-CHF 2 and 16-ene-24,24-difluoro structural units and also new hybrid analog 7 (KSP-BCS-1R-CHF 2 -20-epi-22-oxabishomo-26-OH) carrying a 1-CHF 2 group and a KH-1060-type 20-epi-22-oxa-27,28-bishomo-26-OH side chain. These new 1-CHF 2 hybrid analogs 6 and 7 are as transcriptionally active as calcitriol and are strongly antiproliferative in vitro but are low-calcemic in vivo.…”