Synthesis and in vitro evaluation of side chain-unsaturated analogs of 24a,24b-dihomo-1,25-dihydroxycholecalciferol

• Published in: Steroids 1997-07, Vol.62 (7), p.546-553
• Main Authors: Chodyński, Michał, Wojciechowska, Wanda, Halkes, Sebastian J., van de Velde, Jan-Paul, Kutner, Andrzej
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Calcitriol - analogs & derivatives; Calcitriol - chemical synthesis; Calcitriol - metabolism; Calcitriol - pharmacology; Calcium - metabolism; calcium activity; cell differentiation; Cell Differentiation - drug effects; Drug Evaluation, Preclinical; Enzymes. Coenzymes. Vitamins. Pigments; Fundamental and applied biological sciences. Psychology; HL-60 Cells - drug effects; Humans; Intestinal Mucosa - metabolism; Intestines - drug effects; Isomerism; Kidney - drug effects; Kidney - metabolism; Metabolisms and neurohumoral controls; Receptors, Calcitriol - drug effects; Receptors, Calcitriol - metabolism; Structure-Activity Relationship; Vertebrates: anatomy and physiology, studies on body, several organs or systems; vitamin D analogs; vitamin D receptor; vitamin D-binding protein; Vitamin D-Binding Protein - blood; Vitamin D-Binding Protein - drug effects; Vitamin D-Binding Protein - metabolism
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(97)00040-8

A synthesis and an in vitro evaluation of side chain-unsaturated analogs 3 and 4 of 24a,24b-dihomo-1,25-dihydroxycholecalciferol ( 1) are described. Novel C 23a,24-vitamin D synthons (sulfone 10 and aldehyde 11) were used for the synthesis of analog 4 and for the efficient preparation of the parent compound 1. The synthetic approach developed allows the use of easily available side chain fragments, such as oxirane 12 or Witting reagent 15 for the preparation of compound 1 and analog 4, respectively. Introduction of a 4a E double bond results in a selective, 1000-fold increase in the binding affinity of analog 4 for the vitamin D receptor, compared to the affinity of 1, whereas the affinity of 4 for the vitamin D-binding protein and the activity in stimulating the differentiation of human promyelocytic leukemia HL-60 cells remained largely unchanged.