Novel [1,2,3]triazoles, [1,2,3]triazolo[4,5-d]Pyrimidines, and Some of Their Glycoside Derivatives: Synthesis and Molecular Modeling as Potential Apoptotic Antitumor Agents
Creators: name: Mohamed, Ashraf M.
name: El-Bayaa, Mohamed N.
name: Elnaggar, Dina H.
name: Abdel-Hafez, Naglaa A.
name: Mohamed, Salwa F.
name: Elsayed, Mohamed A.
name: Abou-Amra, Eman S.
name: Omran, Mervat M.
name: El-Sayed, Wael A.
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Cancer
subject: Hematology

description: Two new series of 4,5-difunctionalized 1-bromobenzyl[1,2,3]triazole (<b>2a</b>, <b>3a</b>, <b>4a</b>, <b>5a</b>, and <b>6a)</b> and 4,5-difunctionalized 1-(2-oxo-2-(<i>p</i>-tolylamino)ethyl-[1,2,3]triazole (<b>2b</b>, <b>3b</b>, <b>4b</b>, <b>5b</b>, and <b>6b)</b> were synthesized using related 1-(azidomethyl)-4-bromobenzene <b>1a</b> and <i>p</i>-tolylcarbamoyl azide <b>1b</b> respectively. The substituted [1,2,3]triazolo[4,5-d]pyrimidine-7-one derivatives (<b>7a</b>, <b>7b, 8a,</b> and <b>8b)</b> were synthesized by the reaction of [1,2,3]triazolo derivatives <b>2a</b> and <b>2b</b> with carbon disulfide in the presence of 10% sodium hydroxide/dimethylformamide and/or by the reaction with formic acid respectively. The <i>S</i>-glucoside derivatives (<b>9–12)</b> of newly synthesized [1,2,3]triazolo[4,5-d]pyrimidines were also synthesized. By using several spectroscopic methods, including IR, <sup>1</sup>H NMR, <sup>13</sup>C NMR, and elemental analysis, the chemical structures of the novel derivatives were confirmed. The synthetic compounds’ cytotoxicity and <i>in vitro</i> anticancer activity were examined vs. human breast carcinoma (MCF-7), human laryngeal carcinoma (HEP-2), and human colorectal carcinoma (HCT-116) cell lines. According to the findings, HEP-2 and HCT-116 cells are more sensitive to the tested compounds than the other cell lines. In the HEP-2 and MCF-7 cell lines, respectively, compounds <b>5b</b> and <b>11</b> showed potential anticancer activity when compared to the effect of the commonly used anticancer medication, doxorubicin. The selectivity of compounds against the cancer cell line was confirmed by testing their cytotoxicity on VERO (African Green Monkey kidney) normal cells. The anticancer activity of those compounds is suggested to be due to nuclear damage generated by a high generation of reactive oxygen species (ROS). In addition, the induction of apoptosis by significantly upregulating the apoptotic genes PAR-4 and BAX while substantially downregulating the anti-apoptotic genes BCL-2 and BCL-xl. Molecular docking research was undertaken to predict the probable binding poses of the most effective drugs in the active site of CDK-2. The more active compounds (<b>2a, 3a,b, 4a,b, 5a,b, 6b, 11,</b> and <b>12</b>) have been docked on the CDK-2 enzyme to demonstrate their mode of action as anticancer medicines. The compounds exert many interactions and showed high binding to the CDK-2 receptor. Finally, a hypothetical pharmacophore model was created using the Molecular Operating Environment (MOE) software and five compounds that are structurally similar to the synthesized ones with known anticancer action.