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

Abstract

Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferative in vitro but are low-calcemic in vivo.

A Methylene Group on C-2 of 24,24-Difluoro-19-nor-1α,25-dihydroxyvitamin D3 Markedly Increases Bone Calcium Mobilization in Vivo

“…7 Numerous other modifications on the fluorinated side chain (e.g., a double 8-10 and a triple 9 bonds, sulfone, 8 a carbonyl group, 10 oxetan 11 ) as well as introduction of a fluorine atom on the A ring of vitamin D 3 have also been investigated. 12 …”

“…Falecalcitriol (26,27-hexafluorocalcitriol) marketed for the treatment of hypocalcemia, rickets, and osteomalacia was found several times more potent then calcitriol in both in vitro and in vivo systems, with a longer duration of its action in vivo . Numerous other modifications on the fluorinated side chain (e.g., a double − and a triple bond, sulfone, a carbonyl group, oxetane) as well as introduction of a fluorine atom on the A ring of vitamin D 3 have also been investigated …”

Catalytic Asymmetric Construction of Tertiary Carbon Centers Featuring an α-Difluoromethyl Group with CF2H-CH2-NH2 as the “Building Block”

“…4−7 For instances, upon replacement of 1α-OH groups with 1-CF 2 H of calcitriol derivatives, the toxic calcemic activity of target compounds could be greatly decreased (≤20-fold). 3 In addition, the improvement of the inhibition of hepatitis C virus NS3 protease has been successfully achieved through the exchange of a sulfhydryl group and a difluoromethyl group. 8 A growing amount of attention being paid to difluoromethyl groups in the field of pharmaceutical chemistry has inspired substantial research efforts that aimed to develop general methods for the controlled introduction of difluoromethyl groups into a wide scope of substrates, yet only a handful of effective strategies for the construction of enantioenriched tertiary and quaternary centers bearing CF 2 H groups have emerged.…”

“…It is gratifying that the difluoromethyl group (CF 2 H) has exhibited useful properties as a chemically inert surrogate of alcohols, thiols, and other polar functional groups . The incorporation of a difluoromethyl group into various molecules could not only avoid adverse reactions caused by original polar groups and retain a key recognition element for biologic targets but also provide additional benefits due to the effect of fluoroalkyl groups on the physical and biological properties of molecules. − For instances, upon replacement of 1α-OH groups with 1-CF 2 H of calcitriol derivatives, the toxic calcemic activity of target compounds could be greatly decreased (≤20-fold) . In addition, the improvement of the inhibition of hepatitis C virus NS3 protease has been successfully achieved through the exchange of a sulfhydryl group and a difluoromethyl group …”

Chemoenzymatic Synthesis of (S)-Hexafluoroleucine and (S)-Tetrafluoroleucine

“…The difluoromethyl group (CF 2 H) has been exploited in the development of bioactive compounds. − This group has been used as a bioisostere for the hydroxyl group because of similar hydrogen bond donating capability . Nonetheless, the CF 2 H group was incorporated as difluoromethionine into the interior of a protein to probe the environment near the fluorines, demonstrating the compatibility of CF 2 H with the hydrophobic core of proteins.…”