Search

Novel vitamin D receptor (VDR) antagonists, la-hydroxy-24-phenylvitamin D 3 -26,23-lactones were synthesized by Trost's methodology. The biological evaluation revealed that both the binding affinity for VDR and antagonistic activity were affected by the orientation of the phenyl group on the lactone ring. The modification of the 2a-position of the 24-phenylvitamin D 3 lactones improved the antagonistic activity up to 41 times higher than that of TEI-9647.

Synthesis of 25-hydroxy-19-norvitamin D 3 derivatives as prohormone type agents for anti-prostate diseases was accomplished utilizing Julia-type olefination. Synthesized compounds showed potent antiproliferative activity on an immortalized normal prostate cell line, PZ-HPV-7, which has high la-hydroxylase activity. Furthermore, we demonstrated that 25-hydroxy-19-norvitamin D 3 was hydroxylated at the la position to form la,25-dihydroxy-19-norvitamin D 3 by a recombinant human la-hydroxylase (CYP27B1) in a cell-free system.

Schiff base formation between the 5-formyl group of 5-formyl-2'-deoxyuridine, which is an oxidative thymidine lesion, and the e-amino group of lysine at both monomer and oligomer levels is reported.

The diene system of 1α,25-dihydroxy-19-norvitamin D 3 was replaced by a stable amide bond. A 3-hydroxypropoxy group, which was effective on enhancing binding affinity of 1α,25-dihydroxyvitamin D 3 for vitamin D receptor (VDR), was introduced to the C2-position of the amide type analogue of 1α,25-dihydroxy-19-norvitamin D 3 . The amide analogue was found to be not suitable for binding to the ligand binding domain of the bovine thymus VDR, and additional modification at the C2-position did not improve the affinity. Potency in induction of HL-60 cell differentiation was evaluated for the novel amide analogues (3a-c).

Single 6-formyl-2'-O-methyluridine or 2'-Omethyluridine was introduced into oligonucleotides (9-23 mers), which have simple base-sequences, as a substituent for thymidine to compare the ability of duplex formation and thethermal stability of the resulting duplexes.