Synthesis of Sugar and Nucleoside Analogs and Evaluation of Their Anticancer and Analgesic Potentials

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-05, Vol.27 (11), p.3499
• Main Authors: Hussain, Fahad, Rahman, Fahad Imtiaz, Saha, Poushali, Mikami, Atsushi, Osawa, Takashi, Obika, Satoshi, Rahman, S M Abdur
• Format: Article
• Language: English
• Subjects: Acetic acid; Adenosine; Adenosine deaminase; Adenosine kinase; analgesic; Analgesics; Analogs; anticancer; Cancer; Carbohydrates; Chemical modification; Cholecystokinin; Cyclooxygenase-1; Cyclooxygenase-2; Cytidine deaminase; Cytotoxicity; Drug dosages; Glucose; Kinases; Molecular docking; Nucleoside analogs; Nucleosides; Pain perception; Protein kinase; Proteins; Selectivity; Severe acute respiratory syndrome coronavirus 2; Simulation; Sugar; sugar derivatives; synthesis; Therapeutic targets; Thymidine; Thymidine kinase; Thymidylate synthase; Tyrosine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27113499

Chemical modification of sugars and nucleosides has a long history of producing compounds with improved selectivity and efficacy. In this study, several modified sugars ( - ) and ribonucleoside analogs ( - ) have been synthesized from α-d-glucose in a total of 21 steps. The compounds were tested for peripheral anti-nociceptive characteristics in the acetic acid-induced writhing assay in mice, where compounds , , and showed a significant reduction in the number of writhes by 56%, 62%, and 63%, respectively. The compounds were also tested for their cytotoxic potential against human HeLa cell line via trypan blue dye exclusion test followed by cell counting kit-8 (CCK-8) assay. Compound demonstrated significant cytotoxic activity with an IC value of 54 µg/mL. Molecular docking simulations revealed that compounds , , and had a comparable binding affinity to cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. Additionally, the bridged nucleoside analogs and potently inhibited adenosine kinase enzyme as well, which indicates an alternate mechanistic pathway behind their anti-nociceptive action. Cytotoxic compound demonstrated strong docking with cancer drug targets human cytidine deaminase, proto-oncogene tyrosine-protein kinase Src, human thymidine kinase 1, human thymidylate synthase, and human adenosine deaminase 2. This is the first ever reporting of the synthesis and analgesic property of compound and the cytotoxic potential of compound .