A novel series of substituted 1,2,3‐triazoles as cancer stem cell inhibitors: Synthesis and biological evaluation

Abstract

An alarming increase in global death toll resulting from cancer incidents, particularly due to multidrug resistance and reduced efficacy as a consequence of target mutations, has compelled us to look for novel anticancer agents. Cancer stem cells (CSCs), contributing majorly to the chemoresistance and tumor relapse, seem to the main culprits. In the present investigation, new chemical entities (NCEs) belonging to four novel chemical series (A: 4′‐allyl‐2′‐methoxyphenoxymethyl‐1,2,3‐triazoles; B: 4′‐acetamidophenoxymethyl‐1,2,3‐triazoles; C: naphthalene‐1′‐yloxymethyl‐1,2,3‐triazoles, and D: naphthalene‐2′‐yloxymethyl‐1,2,3‐triazoles) were synthesized via Copper (I)‐catalyzed alkyne‐azide cycloaddition reaction and evaluated for in vitro anticancer activity. A total of 30 NCEs (39–68) were screened at 10 μM concentration in cell viability assay against cancer cell lines such as breast (MDA‐MB‐231), prostate (PC‐3), glioma (U87 MG), along with cervical (SiHa) and lung (A549). The NCEs from Series C (56–60) and D (61–68) were more potent than those in Series A (39‐45) and Series B (46–55) at the tested concentration. Furthermore, NCEs with >80% inhibition at 10 μM were evaluated for dose response. A total of five NCEs, 48, 56, 61, 65 and 66, were further assessed in soft‐agar assay and found to be relatively potent (IC50 < 10 μM). Finally, the hits were screened in sphere assay to identify potential CSC inhibitors against mammospheres (MDA‐MB‐231) and prostatospheres (PC‐3). More so, the hits were also evaluated to understand in vitro cytotoxicity against normal cells using mouse embryonic fibroblast cell line (NIH/3T3) and human peripheral blood mononuclear cells (hPBMCs). Overall, hits 56 and 61 exhibited potent anticancer as well as CSC inhibitory activities with notably less toxicity toward NIH/3T3 and hPBMCs. On the whole, our arduous study led to the identification of potential hits with anticancer and CSC inhibitory activities, with minimal or no toxicity to normal cells.

Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

“…The GBM cell line U-87MG was purchased from National Centre for Cell Sciences. The cell line was processed and maintained as per the supplier's protocols (Padhariya et al, 2021). Cytotoxic activity of the compounds (% inhibition at 10 μM) was evaluated using colorimetric…”

“…The cell line was processed and maintained as per the supplier's protocols (Padhariya et al, 2021). Cytotoxic activity of the compounds (% inhibition at 10 μM) was evaluated using colorimetric MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay with cisplatin as positive control (Padhariya et al, 2020, 2021). Cells were cultured in Dulbecco's Modified Eagle Medium/F‐12 (HiMedia; Catalogue No.…”

“…The GBM cell line U‐87MG was purchased from National Centre for Cell Sciences. The cell line was processed and maintained as per the supplier's protocols (Padhariya et al, 2021). Cytotoxic activity of the compounds (% inhibition at 10 μM) was evaluated using colorimetric MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay with cisplatin as positive control (Padhariya et al, 2020, 2021).…”

Cancer Stem Cell (CSC) Inhibitors in Oncology—A Promise for a Better Therapeutic Outcome: State of the Art and Future Perspectives

“…Extending the previous work on electrophilic chloroacetamides, Padhariya et al (2020) set out with the sole aim of discovering more drug-like and nontoxic hits by building up on the previous hits 66 and 67 . The search culminated in a new series of 1,2,3-triazoles . Initial cell viability assays for 30 NCEs were performed using breast (MDA-MB-231), prostate (PC-3), and glioma (U87 MG) cell lines along with cervical (SiHa) and lung (A549) cell lines.…”

“…The search culminated in a new series of 1,2,3-triazoles. 135 Initial cell viability assays for 30 NCEs were performed using breast (MDA-MB-231), prostate (PC-3), and glioma (U87 MG) cell lines along with cervical (SiHa) and lung (A549) cell lines. Furthermore, five potent hits were tested in soft-agar and sphere assays (MDA-MB-231 and PC-3).…”