Biological Evaluation of Double Point Modified Analogues of 1,25-Dihydroxyvitamin D₂ as Potential Anti-Leukemic Agents.

Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D₂ (1,25D₂) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi) at C-24 of 1,25D₂.

Antiproliferative Activity of Double Point Modified Analogs of 1,25-Dihydroxyvitamin D₂ Against Human Malignant Melanoma Cell Lines.

Vitamin D is a lipid soluble steroid hormone with pleiotropic biological properties, including regulation of cell proliferation, differentiation and apoptosis. As to these desirable anticancer actions, 1,25-dihydroxyvitamins D and analogs have been reported to inhibit the proliferation and to induce differentiation of a wide variety of cancer cell types, including human malignant melanoma. However, there is a need for novel and more efficacious vitamin D analogs, and how best to design such is still an open issue.

Convergent synthesis of double point modified analogs of 1α,25-dihydroxyvitamin D for biological evaluation.

There is a long lasting controversy over the biological activity of vitamin D as compared to vitamin D in terms of maintaining of calcium homeostasis and raising the level of circulating 25-OH-D. To shed more light on this relationship we synthesized 1α,25-dihydroxyvitamin D, by a novel convergent strategy, to compare this compound directly with the activity of 1α,25-dihydroxyvitamin D. The same synthetic strategy also provided a series of (5E,7E) geometric isomers of the natural 1α,25-dihydroxyvitamin D as well as a series of double point modified analogs of its (24R)-epimer, including C-22 hydroxy derivatives.

Double point modified analogs of vitamin d as potent activators of vitamin D receptor.

Rational design, chemical synthesis, structural analysis, molecular modeling and biological evaluation are reviewed for all the double point modified vitamin D analogs that have been developed as potential therapeutics over the last several years. The idea of double modifications was based on the 3D structure of the ligand binding domain of the model of the vitamin D receptor. It was recently proved that structural modifications in the two remote parts of the vitamin D molecule might have additive biological effects resulting in an increased functional activity and lowered calcemic side effect.