Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D3 analogues with aromatic side chains attached at C-17

Abstract Two new analogues of the steroid hormone 1α,25-dihydroxyvitamin D 3 with aromatic side chains attached at C-17 were designed to investigate their effects on VDR, HL-60 cell differentiation and tumor cell proliferation. These analogues were prepared by the classical photochemical ring opening approach. After the protection of both the 1α- and 3β-hydroxyl in 1α-hydroxydehydroepiandrosterone with TBS groups, followed by bromination with NBS and debromination in the presence of γ-collidine, the diene intermediate was obtained. Hydrazone formation followed by iodine oxidation gave a vinyl iodide. The aromatic side chain at C-17 was introduced via the Negishi coupling of the resulting intermediate with an in situ generated zinc reagent with the substituted aryl bromide (CD-side chain) in the presence of catalytic amount of Pd(PPh 3 ) 4 . After the removal of the TBDMS and MOM protective groups, followed by UV irradiation and the subsequent thermal reaction, the 1α,25-(OH) 2 -D 3 analogues with a substituted phenyl ring attached at C-17 to replace the C-20 and C-21 were prepared. In the VDR competitive binding assay, compounds 2 and 3 almost lost their binding ability, and were only 0.01% and 0.015% as potent as the 1α,25-dihydroxyvitamin D 3 . However, compounds 2 and 3 were as potent as 1α,25-(OH) 2 -D 3 in inducing HL-60 cell differentiation at concentrations of 30, 100, 300, 1000 nM, respectively. Moreover, compounds 2 and 3 exhibited similar or better antiproliferative potency against MCF-7 human breast cancer cells, the IC 50 values for analogues 2 , 3 and the natural hormone were 7.08, 7.56, and 12.5 μM, respectively.