Synthesis, CYP24A1-Dependent Metabolism and Antiproliferative Potential against Colorectal Cancer Cells of 1,25-Dihydroxyvitamin D2 Derivatives Modified at the Side Chain and the A-Ring

• Published in: International journal of molecular sciences Vol. 21; no. 2; p. 642
• Main Authors: Milczarek, Magdalena, Chodyński, Michał, Pietraszek, Anita, Stachowicz-Suhs, Martyna, Yasuda, Kaori, Sakaki, Toshiyuki, Wietrzyk, Joanna, Kutner, Andrzej
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 18.01.2020; MDPI
• Subjects: 1,25-dihydroxyergocalciferol analogs; 5-Fluorouracil; Absolute configuration; Analogs; antiproliferative activity in vitro; Antiproliferatives; Biological activity; Calciferol; Chains; Chirality; Clinical trials; Colorectal cancer; Colorectal carcinoma; Configurations; cyp24a1-dependent metabolism; double-point modified vitamin d2 analogs; human colorectal cancer cell lines; Low resistance; Metabolism; Metabolites; Vitamin D; vitamin d derivatives
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21020642

Experimental data indicate that low-calcemic vitamin D derivatives (VDDs) exhibit anticancer properties, both in vitro and in vivo. In our search for a vitamin D analog as potential anticancer agent, we investigated the influence of chirality in the side chain of the derivatives of 1,25-dihydroxyergocalciferol (1,25D2) on their activities. In this study, we synthesized modified analogs at the side chain and the A-ring, which differed from one another in their absolute configuration at C-24, namely (24S)- and (24R)-1,25-dihydroxy-19-nor-20a-homo-ergocalciferols (PRI-5105 and PRI-5106, respectively), and evaluated their activity. Unexpectedly, despite introducing double-point modifications, both analogs served as very good substrates for the vitamin D-hydroxylating enzyme. Irrespective of their absolute C-24 configuration, PRI-5105 and PRI-5106 showed relatively low resistance to CYP24A1-dependent metabolic deactivation. Additionally, both VDDs revealed a similar antiproliferative activity against HT-29 colorectal cancer cells which was higher than that of 1,25D3, the major biologically active metabolite of vitamin D. Furthermore, PRI-5105 and PRI-5106 significantly enhanced the cell growth-inhibitory activity of 5-fluorouracil on HT-29 cell line. In conclusion, although the two derivatives showed a relatively high anticancer potential, they exhibited undesired high metabolic conversion.