Synthesis and Biological Activity of Fluorinated Vitamin D

Abstract

The active metabolite of vitamin D, 1 ,25-dihydroxyvitamin D3 (1), has a wide range of biological activities, making its analogues promising therapeutic agents for the treatment of cancer, psoriasis and osteoporosis. In particular, the stability of the carbonfluorine bond to oxidation has aided in the development of fluorinated vitamin D analogues as catabolism inhibitors. The analogues were synthesized either by classical steroidal approaches or by convergent methods, depending on the sites of fluorination. The incorporation of fluorine has provided numerous advantages for studying the structurally flexible hormone 1 ,25-dihydroxyvitamin D3 1, including helping to define its molecular mode of actions. Biological evaluation of the fluorinated analogues suggested that fluorine substitution would not only change the metabolism, but also have direct effects on the vitamin D receptor, resulting in compounds with unique activity profiles.

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

“…5,15 The same group proposed an alternative route that involved as a starting compound 1α,3β-bis[tert-butyldimethylsilyl)oxy]androst-5-ene to obtain 24,24-difluoro-1α,25-(OH) 2 D 3 in 4% total yield through 10 steps. 16 …”

“…Takayama et al synthesized 24,24-difluoro-1α,25-(OH) 2 D 3 starting from commercially available lithocholic acid and using (diethylamino)sulfur trifluoride (DAST) as a fluorinating reagent. , The same group proposed an alternative route that involved as a starting compound 1α,3β-bis­[ tert -butyldimethylsilyl)­oxy]­androst-5-ene to obtain 24,24-difluoro-1α,25-(OH) 2 D 3 in 4% total yield through 10 steps …”

“…Because of the C-F bond stability and a similar size of the hydrogen and fluorine atoms, fluorinated vitamin D analogues have been applied as catabolism inhibitors. 4,5 …”

“…The high electronegativity of fluorine, its small size, the good overlap of the 2s or 2p orbitals with corresponding orbitals of carbon as well as the presence of three lone pairs of electrons mean that bonds are always polarized from the sp 3 carbon (δ + ) to the fluorine (δ – ). Because of the C–F bond stability and a similar size of the hydrogen and fluorine atoms, fluorinated vitamin D analogues have been applied as catabolism inhibitors. , …”