ABSTRACT
The active form of vitamin D3, 1α,25(OH)2D3, plays a major role in maintaining calcium/phosphate homeostasis. In addition, it is a potent antiproliferative and pro-differentiating agent. Unfortunately, it usually causes hypercalcemia in vivo when effective antitumour doses are used. It has therefore been found necessary to synthesise new analogues that retain or even increase the antitumour effects but preclude hypercalcemia. This report presents the synthesis of a novel Gemini vitamin D analogue (UVB1) and its biological evaluation. We demonstrate that this compound has potent antitumoural effects over a wide panel of tumour cell lines while showing lack of hypercalcemic activity and toxicity effects in in vivo assays.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Hypercalcemia/chemically induced , Neoplasms/drug therapy , Vitamin D/analogs & derivatives , Vitamin D/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Calcium/blood , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Design , Female , Humans , Hypercalcemia/blood , Inhibitory Concentration 50 , Male , Mice , Mice, Nude , Molecular Structure , Neoplasms/pathology , Structure-Activity Relationship , Time Factors , Vitamin D/chemical synthesis , Vitamin D/toxicityABSTRACT
The Gemini analogs are the last significant contribution to the family of vitamin D derivatives in medicine, for the treatment of cancer. The first Gemini analog was characterized by two symmetric side chains at C-20. Following numerous modifications, the most active analog bears a C-23-triple bond, C-26, 27- hexafluoro substituents on one side chain and a terminal trideuteromethylhydroxy group on the other side chain. This progression was possible due to improvements in the synthetic methods for the preparation of these derivatives, which allowed for increasing molecular complexity and complete diastereoselective control at C-20 and the substituted sidechains.
Subject(s)
Vitamin D/analogs & derivatives , Animals , Humans , Models, Molecular , Structure-Activity Relationship , Vitamin D/pharmacologyABSTRACT
The synthesis of the clinically important drug calcipotriol (2, MC903) is described as an example of a new and efficient approach to C24-hydroxylated analogs and metabolites of vitamin D3 (1). The key step of the process is the generation of the C24 stereocenter by DAIB [(-)-3-exo-(dimethylamino)isoborneol]-catalyzed addition of the alkenylzinc derivative of alkyne 3 to cyclopropylcarboxaldehyde.
Subject(s)
Calcitriol/analogs & derivatives , Chemistry, Pharmaceutical/methods , Dihydroxycholecalciferols/chemistry , Dihydroxycholecalciferols/chemical synthesis , Psoriasis/drug therapy , Alcohols/chemistry , Calcitriol/chemistry , Catalysis , Cell Differentiation , Drug Design , Humans , Models, Chemical , Molecular Conformation , StereoisomerismABSTRACT
The crystal structures of vitamin D nuclear receptor (VDR) have revealed that all compounds are anchored by the same residues to the ligand binding pocket (LBP). Based on this observation, a synthetic analog with a locked side chain (21-nor-calcitriol-20(22),23-diyne) has been synthesized in order to gain in entropy energy with a predefined active side chain conformation. The crystal structure of VDR LBD bound to this locked side chain analogue while confirming the docking provides a structural basis for the activity of this compound.
Subject(s)
Calcitriol/chemistry , Receptors, Calcitriol/chemistry , Binding Sites , Calcitriol/analogs & derivatives , Calcitriol/metabolism , Entropy , Humans , Ligands , Protein Binding , Protein Structure, Tertiary , Receptors, Calcitriol/metabolism , Structure-Activity RelationshipABSTRACT
[structure: see text]. We describe the synthesis of the first locked side-chain analogues of the natural hormone 1alpha,25-(OH)2-D3 and their effects on gene transcription in human colon cancer cells. Analogue 2 was more potent than 1alpha,25-(OH)2-D3 at inducing vitamin D receptor (VDR) transcriptional activity. Analogues 3a and 3b show potency similar to that of 1alpha,25-(OH)2-D3, whereas 3c was less active. The novel analogues efficiently bind VDR in vivo to induce transcription from a consensus vitamin D responsive element (VDRE).
