Synthesis and biological activity of 1 alpha-hydroxy vitamin D5 and derivatives

In continuing efforts of finding novel, potent vitamin D analogs active as cancer chemopreventive agents, displaying low-calcemic or non-calcemic activity, five vitamin D₅ derivatives have been synthesized: lα-hydroxy vitamin D₅, (24R,S)-1α,24-dihydroxy vitamin D₅, (24R)-1α,24-dihydroxy vitamin D ₅, (25R,S)-1α,26 dihydroxy vitamin D₅ and 1α-24-epi-hydroxy vitamin D₅. An improved synthetic strategy involving the use of the two wavelength photolysis process in conjunction with the 1α-hydroxylation of the trans-vitamin D ₅ derivative, obtained via the sulfur dioxide adduct of the corresponding vitamin D₅ derivative, was employed to obtain 1α-hydroxy vitamin D₅, (24R,S)-1α,24-dihydroxy vitamin D₅, (24R)-1α,24-dihydroxy vitamin D ₅, and (25R,S)-1α,26-dihydroxy vitamin D ₅.; The novel vitamin D₅ derivative, 1α-24-epi-hydroxy vitamin D₅, has been synthesized via a convergent synthesis involving the copper (I) mediated coupling reaction of two independently generated moieties: a “triene” system moiety, as a tosylate, obtained from vitamin D₂ and a side chain moiety, as a Grignard reagent, obtained by asymmetric synthesis.; The biological activity tested in vitro for 1α-hydroxy vitamin D₅ and its analogs, namely (25R,S)-1α,26 dihydroxy vitamin D₅ and 1α-24-epi-hydroxy vitamin D ₅ showed that although their antiproliferative activity is comparable, the parent 1α-hydroxy vitamin D₅ derivative is slightly more active and less toxic. These data qualify 1α-hydroxy vitamin D ₅ analogs as promising candidates for further clinical cancer chemopreventive studies and justify the effort of synthesizing novel derivatives in vitamin D₅ series.; The biological activity determined in vivo, revealed that 1α-hydroxy vitamin D₅ was able to reduce the tumor incidence up to 47% and tumor multiplicity up to 50% in chemically-induced mammary carcinogenesis experiments. This compound is on track for human clinical trials by January 2002 for breast cancer.