Chemoenzymatic synthesis and biological evaluation of C-3 carbamate analogues of 1alpha,25-dihydroxyvitamin D3.
The synthesis of new analogues of 1alpha,25-dihydroxyvitamin D3 containing a carbamate function at the A-ring fragment has been described using the cross-coupling approach. The carbamate group was selectively introduced at the C-3 position by regioselective enzymatic alkoxycarbonylation of A-ring enyne 3 and subsequent treatment with ammonia, amines, amino alcohols, and amino acids. Biological studies to evaluate the potency of all five of these carbamate analogues were performed and demonstrated very low binding affinity for the vitamin D receptor compared with 1alpha,25-dihydroxyvitamin D3. Moreover, all the carbamate analogues were less active than 1alpha,25-dihydroxyvitamin D3 in inhibiting cell proliferation or stimulating cell differentiation. Of all the five analogues, the 3-O-carbamoyl-1alpha,25-(OH)2-D3 analogue 10a was the most potent one in vitro. However, all investigated carbamate analogues demonstrated lower calcemic effects in vivo than the parent compound.
Gotor-Fernández
Vicente
V
Departamento de Química Orgánica e Inorgánica, Facultad de Química, Universidad de Oviedo, 33071 Oviedo, Spain.
Fernández
Susana
S
Ferrero
Miguel
M
Gotor
Vicente
V
Bouillon
Roger
R
Verstuyf
Annemieke
A
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans
D000970:Antineoplastic Agents; D002219:Carbamates; D002117:Calcitriol