Synthetic analogs of 1alpha,25-dihydroxycholecalciferol [1alpha,25-(OH)2D3] and 1alpha,25-dihydroxyergocalciferol [1alpha,25-(OH)2D2] have long been considered as key regulators of calcium and phosphate homeostasis. These analogs have been recently investigated as potential therapeutics against a number of pathological states, including metabolic, dermatological, immune and hyperproliferative diseases. Analogues of 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, modified in the cyclohexane A-ring and in the aliphatic side-chain, potentiated the efficiency of cytostatics and/or cooperated efficiently with polyphenol in human myeloid leukemia cells (HL60, U937 and MOLM-13) and in several animal models of leukemias and solid tumours. The therapeutic effect resulted from the thorough combination of several key factors, including the selection of vitamin D-sensitive cancer model, type of cytostatic, the right scheme and route of administration of both therapeutics, correlation with vitamin D receptor level and managing of the hypercalcemic side effect of vitamin D. In this work our synthesis and biological evaluation is outlined of a novel generation of vitamin D analogs as well as our investigation of their anticancer profile in vitro and in vivo. Our convergent synthesis started from vitamin D-like advanced intermediates and separately prepared side-chain fragments. This way, in an over twenty-step syntheses, a series of analogs were obtained containing, compared to the parent vitamin D hormones, 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, an additional chiral center or conjugated diene system in the side-chain and/or modified 5,6-trans or 19-nor A-ring. Some of the new analogs, pre-selected in a number of in vitro models, showed, in the combined treatment with cytostatics, the beneficial activity profile in both, murine colon cancer MC38 and in human colon cancer HT-29 cells. Our analogues also modulated expression of genes related to stem-like phenotype in vitamin D receptor (VDR) positive colon cancer cells, HT-29 and HCT-116, at different differentiation states, undergoing renewal after the treatment with 5-FU. The analogs induced differentiation of VDR positive A375 and VDR negative SK-MEL 188b human melanoma cells. Some of our analogs also displayed moderate cytotoxic and pro-apoptotic activity in diffuse large B-cell lymphoma (DLBCL) and concentration and time-dependent antiproliferative action upon stimulated B-cells from healthy donors. Data available from the protein data bank were used for the rational design of the next generation of analogs by minimizing the electrostatic interaction energies, after the reconstruction of a charge densities using pseudoatom databank. Due to a low calcemic activity and anticancer profile in vivo, selected new analogues might be considered as promising candidates for further preclinical evaluation as potential anticancer agents.
Synthesis and Biological Evaluation of Analogs of Didehydroepiandrosterone as Potential New Anticancer Agents
