Bile-Acid-Appended Triazolyl Aryl Ketones: Design, Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats

Abstract

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents.

Mode of Actions of Bile Acids in Avoidance of Colorectal Cancer Development; and their Therapeutic Applications in Cancers - A Narrative Review

“…Thirdly Agarwal et al [16], illustrated that Bile acid appended triazoyl aryl ketones 6af as well as 6cf resulted in apoptosis induction in MCF7 cells breast cancer cells (Figure 3D). Specifically substance 6cf led to apoptosis induction by 46.09% in MCF7 cells whereas substance 6af led to apoptosis induction by 33.89%, illustrating that 6cf possesses greater effectiveness regarding apoptosis induction.…”

“…Additionally, various laboratories have generated innovative Bile Acid obtained substance for evaluation of the tumor suppressive actions of bile acids. These substances were illustrated to result in induction of programmed cell death (PCD) in different cancer cells besides possess tumor repressive action [14][15][16][17][18][19][20][21][22][23][24]. Cell death possesses a key part in embryonic formation, sustenance of homeostasis, as well as elimination of injured cells.…”

Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review

“…Third, Agarwal et al [24] showed that the bile acid-added triazolyl aryl ketones 6af and 6cf induced apoptosis in MCF-7 breast carcinoma cells (Figure 3D). In particular, compound 6cf induced apoptosis by 46.09% in MCF-7 cells, and compound 6af induced apoptosis by 33.89%, showing that 6cf was more effective in inducing apoptosis.…”

“…In addition, several laboratories have synthesized novel bile acid derivatives to explore the tumor-suppressive function of bile acids. These derivatives were shown to induce programmed cell death in several cancer cells, and have tumor-suppressive effects [22][23][24][25][26][27][28][29][30][31][32].…”

Oral sorafenib-loaded microemulsion for breast cancer: evidences from the in-vitro evaluations and pharmacokinetic studies

“…The results obtained from optical density values were utilised to calculate the percentage cell viability. The samples were also analysed for microscopic observation using an optical microscope 35 .…”