Antitumor properties of (5E,7E) analogs of vitamin D sub(3)

Geometric isomers (5E,7E) of major active metabolites of vitamin D sub(3) [1a,25(OH) sub(2)D sub(3) and (24R)-1,24(OH) sub(2)D sub(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 1a,25(OH) sub(2)D sub(3) or to (24R)-1,24(OH) sub(2)D sub(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 1a,25(OH) sub(2)D sub(3) or (24R)-1,24(OH) sub(2)D sub(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 1a,25(OH) sub(2)D sub(3), as well as than PRI-2191 and PRI-2209.