Antitumor properties of (5E,7E) analogs of vitamin D3

Geometric isomers (5E,7E) of major active metabolites of vitamin D-3 [1 alpha,25(OH)(2)D-3 and (24R)-1,24(OH)(2)D-3] were synthesized by a new convenient procedure. Vitamin D triene system of the metabolites was first derivatized as a Diels-Alder adduct. Removal of the triene protecting group, in a key synthetic step, yielded the title compounds PRI-2208 and PRI-2209, respectively. The analogs were examined for their antiproliferative activity in vitro against human breast cancer cells (MCF-7) and promyelocytic leukemia (HL-60) cells. The activity was compared with one of the parent compounds. Both analogs examined revealed similar or higher antiproliferative activity compared to 1 alpha,25(OH)(2)D-3 or to (24R)-1,24(OH)(2)D-3. The studies of calcemic activity in vivo showed that analogs PRI-2208 and PRI-2209 did not influence the serum calcium level in doses, in which la,25(OH)(2)D-3 or (24R)-1,24(OH)(2)D-3 significantly increased this level. The antitumor activity of these analogs in the LLC mice tumor model was studied. Analog PRI-2208 was found to be more active in inhibiting LLC tumor growth than 1 alpha,25(OH)(2)D-3, as well as than PRI-2191 and PRI-2209. (C) 2010 Elsevier Ltd. All rights reserved.