Potent 19-norvitamin D analogs for prostate and liver cancer therapy

The active form of vitamin D-3, 1 alpha,25(OH)(2)D-3 or calcitriol, is known to inhibit the proliferation and invasiveness of many types of cancer cells, including prostate and liver cancer cells. These findings support the use of 1 alpha,25(OH)(2)D-3 for prostate and liver cancer therapy. However, 1 alpha,25(OH)(2)D-3 can cause hypercalcemia, thus, analogs of 1 alpha,25(OH)(2)D-3 that are less calcemic but exhibit potent antiproliferative activity would be attractive as therapeutic agents. We have developed 2 alpha-functional group substituted 19-norvitamin D-3 analogs with and without 14-epimerization. Among them, 2 alpha- and 2 beta-(3-hydroxypropyl)-1 alpha,25-dihydroxy-19-norvitamin D-3 (MART-10 and -11, respectively) and 14-epi-2 alpha- and 14-epi-2 beta-(3-hydroxypropyl)-1 alpha,25-dihydroxy-19-norvitam in D-3 (14-epi-MART-10 and 14-epi-MART-11, respectively) were found to be the most promising. In this review, we discuss the synthesis of this unique class of vitamin D analogs, the molecular mechanism of anticancer actions of vitamin D, and the biological evaluation of these analogs for potential application to the prevention and treatment of prostate and liver cancer.