Versatile synthesis and biological evaluation of 1,3-diamino-substituted 1alpha,25-dihydroxyvitamin D3 analogues.
A concise route to 1alpha,3beta-diamino-25-hydroxy-3-deoxyvitamin D(3) (5) and 1beta,3alpha-diamino-25-hydroxy-3-deoxyvitamin D(3) (6) has been developed starting from (R)- or (S)-carvone for the construction of the modified A-ring fragments. The conversion of the hydroxyl group to amine function with complete inversion of the configuration was efficiently accomplished by Mitsunobu reaction using phthalimide as nucleophile or activation of the hydroxyl group as mesylate followed by reaction with NaN(3). Diamino 5 and 6 as well as monoamino 3, 4, 30, and 31 vitamin D(3) derivatives have shown poor binding to VDR compared with 1alpha,25-dihydroxyvitamin D(3). The most active compound in the inhibition of MCF-7 cell proliferation and HL 60 cell differentiation was 1alpha-amino analogue 3. Also, very low in vivo calcemic effects of derivatives 3 and 4 were found.
Oves
Daniel
D
Departamento de Química Orgánica e Inorgánica, Facultad de Química, Universidad de Oviedo, Spain.
Fernández
Susana
S
Ferrero
Miguel
M
Bouillon
Roger
R
Verstuyf
Annemieke
A
Gotor
Vicente
V
D000586:Amination; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C118756:dihydroxy-vitamin D3; D014807:Vitamin D