title: Regioselective chemical and rapid enzymatic synthesis of a novel redox – Antiproliferative molecular hybrid.
abstract: Recent science evidenced the interlinkage of oxidative stress and cancer. Due to the inherent complexity of cancer and its accompanying effect of oxidative stress, novel molecules, containing combinatorial functionalities should be targeted. Herein, we synthesized gemcitabine-5'-O-lipoate derived from a regioselective coupling of the chemotherapeutic drug gemcitabine (GEM), a first-line agent for cancer therapy and α-lipoic acid (LA), a potent antioxidant. gemcitabine-5'-O-lipoate was obtained in 4 chemical steps. To avoid the tedious and laborious chemical steps we also utilized biocatalysis using immobilized Candida antarctica lipase B (CALB), and the optimum conditions for the regioselective and one-pot synthesis of gemcitabine-5'-O-lipoate were established by exploiting different solvents (organic solvents and ionic liquids) and enzyme immobilization (acrylic resin and carbon nanotubes). Cytotoxic activity of co-administrating GEM and LA was proven to be synergistic against non-small cell lung cancer cells whereas antagonistic for bladder cancer cells. In contrast, the gemcitabine-5'-O-lipoate hybrid was found to be superior to the parent compounds against both non-small cell lung cancer and bladder cancer cells as also was found to preserve the redox activity of the parent compound LA. The regioselective biotransformation mediated synthesis of the anticancer-antioxidant hybrid illustrates the capacity of biocatalysis to act as an asset in molecular hybridization techniques.
authors: Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, 45110, Greece; Symeonidion Research Center, "Theagenion" Cancer Hospital, Thessaloniki, 54007, Greece.
authors: Elena
authors: E
authors: Geromichalou
authors: Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, 45110, Greece.
authors: Nisar
authors: N
authors: Sayyad
authors: Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, 45110, Greece.
authors: Eleni
authors: E
authors: Kyriakou
authors: Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, 45110, Greece.
authors: Alexandra V
authors: AV
authors: Chatzikonstantinou
authors: Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patras, 26504, Greece.
authors: Efstathia
authors: E
authors: Giannopoulou
authors: Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 84005, Bratislava 45, Slovak Republic.
authors: Norbert
authors: N
authors: Vrbjar
authors: Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patras, 26504, Greece.
authors: Haralabos P
authors: HP
authors: Kalofonos
authors: Laboratory of Biotechnology, Department of Biological Applications and Technologies, University of Ioannina, Ioannina, 45110, Greece.
authors: Haralambos
authors: H
authors: Stamatis
authors: Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, 45110, Greece; Cancer Biobank Center, University of Ioannina, Ioannina, 45110, Greece. Electronic address: agtzakos@gmail.com.
authors: Andreas G
authors: AG
authors: Tzakos
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D055162:Biocatalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004800:Enzymes, Immobilized / Q000737:chemistry / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism*; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D004800:Enzymes, Immobilized; D005656:Fungal Proteins; D003841:Deoxycytidine; D008049:Lipase; C431349:lipase B, Candida antarctica; D000093542:Gemcitabine
keywords: Antiproliferative activity; Biotransformation; Bladder cancer; Gemcitabine; Molecular hybrid; Non-small cell lung cancer; Synergism; α-lipoic acid