Design, Synthesis, Anticancer Activity and Molecular Docking of New 1,2,3-Triazole-Based Glycosides Bearing 1,3,4-Thiadiazolyl, Indolyl and Arylacetamide Scaffolds.

New 1,3,4-thiadiazole thioglycosides linked to a substituted arylidine system were synthesized via heterocyclization via click 1,3-dipolar cycloaddition. The click strategy was used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycoside-based indolyl systems as novel hybrid molecules by reacting azide derivatives with the corresponding acetylated glycosyl terminal acetylenes. The cytotoxic activities of the compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds, the triazole glycosides linked to p-methoxyarylidine derivatives and the free hydroxyl glycoside had potent activity comparable to the reference drug, doxorubicin, against MCF-7 human cancer cells. Docking simulation studies were performed to check the binding patterns of the synthesized compounds. Enzyme inhibition assay studies were also conducted for the epidermal growth factor receptor (EGFR), and the results explained the activity of a number of derivatives.

Synthesis and Cytotoxic Properties of New Substituted Glycosides-Indole Conjugates as Apoptosis Inducers in Cancer Cells.

BACKGROUND & OBJECTIVE: Glycosyl heterocycles, being as nucleoside analogs with modified glycon and hybrid heterocycle motifs, are of considerable interest, and thus, the targeted compounds were synthesized via a convenient and efficient approach. METHODS: New indolyl-thiadiazolyl thioglycosides scaffolds were synthesized, starting with the reaction of indole-3-carbaldehyde with 2-aminothiadiazole-5-thiole followed by glycosylation and deprotection. Likewise, new molecular hybrids comprising indole, thiadiazole, triazole and glycosyl moieties were synthesized utilizing click chemistry strategy. The cytotoxic activities of the newly synthesized compounds were studied on colon carcinoma HCT116, breast carcinoma MCF-7, lung carcinoma A549 and hepatocellular carcinoma HepG2 cell lines using Sulphorhodamine-B (SRB) assay. RESULTS: The 1,3,4-thiadiazole thioglycoside and the 1,2,3-triazole N1-glycoside possessing xylose moiety, compounds 8 and 15 revealed the most potent bio-activity among the new chemical entities; therefore, they undertook for further analysis of apoptosis. CONCLUSION: IC50s of Compound 8 were 38, 36, 33 and 158µg/ml, while they were 41, 44, 32 and 25µg/ml for compound 15 on HepG2, MCF7, HCT116 and A549 cell lines, respectively; furthermore, the total apoptosis rate (%) for control untreated cells were 9.63, 28.4, 25.4 (%), compounds 8 and 15 respectively, they produced a significant increase in total and early apoptosis rate (%) compared to control (P=0.0001). At the same time, no significant difference was detected in the late apoptosis rate (%), which means that both derivatives have the potential to be developed into potent anticancer agents.

Synthesis and Cytotoxic Activity of New 1,3,4-Thiadiazole Thioglycosides and 1,2,3-Triazolyl-1,3,4-Thiadiazole N-glycosides.

New 1,3,4-thiadiazole thioglycosides linked to substituted arylidine systems were synthesized via glycosylation of the prepared 1,3,4-thiadiazole thiol compounds. Click strategy was also used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycosides by reaction of the acetylenic derivatives with different glycosyl azids followed by deacetylation process. The cytotoxic activities of the prepared compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds 2 and 3, the triazole glycosides linked to p-methoxyarylidine derivatives 14 and 15 in addition to the free hydroxyl glycoside 20 were found potent in activity comparable to the reference drug doxorubicin against MCF-7 human cancer cells. The acetylenic derivative 2 and glycoside 20 were also found highly active against HCT-116 cell lines.