Synthesis and crystallographic study of 1,25-dihydroxyergocalciferol analogs

Abstract

The hybrid analogs of 1,25-dihydroxyergocalciferol (PRI-5201 and PRI-5202) were synthesized as potential anticancer agents using a convergent strategy. The analogs were designed by combining a 19-nor modification of the A-ring with the homologated and rigidified ergocalciferol-like side-chain of the previously obtained analogs PRI-1906 and PRI-1907. The strategy also allowed the novel efficient synthesis of 19-nor-1,25-dihydroxyergocalciferol (paricalcitol, PRI-5100) and its (24R)-diastereomer (PRI-5101). The single crystal X-ray structures of the 19-nor analogs (PRI-5100 and PRI-5101) were solved and refined. The A-ring of both analogs adopts exclusively chair β-conformation in the solid state. The side-chain of these analogs is coplanar with the CD-ring plane, while it is perpendicular in 1,25-dihydroxycholecalciferol.

Keywords: 19-nor vitamin D analogs; A-ring synthon; CD-ring fragment; Convergent synthesis; Paricalcitol; Single crystal X-ray structure.