Synthesis of Gemini analogs of 19-norcalcitriol and their platinum(II) complexes

• Published in: Bioorganic chemistry 2020-07, Vol.100, p.103883-103883, Article 103883
• Main Authors: Brzeminski, Pawel, Fabisiak, Adrian, Berkowska, Klaudia, Rárová, Lucie, Marcinkowska, Ewa, Sicinski, Rafal R.
• Format: Article
• Language: English
• Subjects: 19-Norcalcitriol; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Calcitriol - analogs & derivatives; Calcitriol - chemical synthesis; Calcitriol - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Drug delivery systems; Drug Design; Gemini compounds; Humans; Molecular Docking Simulation; Neoplasms - drug therapy; Neoplasms - metabolism; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Platinum(II) complexes; Receptors, Calcitriol - metabolism; Vitamin D receptor; Vitamins - chemical synthesis; Vitamins - chemistry; Vitamins - pharmacology; Wittig-Horner reaction
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103883

[Display omitted] •The building blocks required for the synthesis were prepared from natural compounds.•Epimeric at C-25 Gemini compounds with elongated side chains were synthesized.•Conjugate-type Pt(II) complexes of vitamin D analogs were obtained for the first time.•Cytotoxic activities of the synthesized 19-norcalcitrol analogs were evaluated. Hormonally active vitamin D3 metabolite, calcitriol, plays an important role in calcium-phosphate homeostasis, immune system actions and cell differentiation. Although anticancer activity of calcitriol is well documented and thousands of its analogs have been synthesized, none has been approved as a potential drug against cancer. Therefore, we attempted to introduce the cytotoxic effect to the calcitriol molecule by its linking to cisplatin. Herein, we present the synthesis of vitamin D compounds, designed on the basis of molecular modeling and docking experiments to the vitamin D receptor, and characterized by the presence of significantly different two side chains attached to C-20. In this study, a new synthetic approach to Gemini analogs was developed. Preparation of the target 19-norcalcitriol compounds involved separate syntheses of several building blocks (the A-ring, C/D-rings and side-chain fragments). The convergent synthetic strategy was used to combine these components by the different coupling processes, the crucial one being Wittig-Horner reaction of the Grundmann ketone analog with the known 2-methylene A-ring phosphine oxide. Due to the nature of the constructed steroidal side chains (bidentate ligands), which allowed coordination of metal ions, the first conjugate-type platinum(II) complexes of the vitamin D analogs were also successfully prepared and characterized. The target vitamin D compounds, displaying significant affinity for a vitamin D receptor, were assessed in vitro for their anti-proliferative activities towards several cell lines.