Discovery of Novel Dimeric Pyridinium Bromide Analogues Inhibits Cancer Cell Growth by Activating Caspases and Downregulating Bcl-2 Protein

Abstract

Flexible dimeric substituted pyridinium bromides with primary and tertiary amines are prepared by conventional and solvent-free methods. The formation of compounds 2 and 4 is much easier than that of compounds 1 and 3 because of the benzyl carbon which is more electropositive than the primary alkyl carbon. The newly synthesized dimeric pyridinium compounds are optimized using p). The in vitro antiproliferative activity is studied in lung (A549) and breast cancer cell lines (MDA-MB 231). Among the four compounds, 1,1′-(1,3-phenylene bis(methylene)bis 2aminopyridinium bromide 4 showed potent anticancer activity when compared to the standard drug 5-fluorouracil. 1,1′-(1,3-Phenylene bis(methylene)bis 2aminopyridinium bromide 4 is not toxic to normal cell lines 3T3-L1 and MRC-5 cell lines. Also, 1,1′-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide 4-induced apoptosis in cancer cell lines is examined using AO/EB and Hoechst staining, which is further supported by cell cycle analysis. Western blot analysis showed that 1,1′-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide 4 induces apoptosis through the extrinsic apoptotic pathway by upregulating caspase 3 and caspase 9. This compound also downregulates intrinsic apoptotic proteins, including Bcl-2, Bcl-x, and Bad. From the present study results, it is confirmed that 1,1′-(1,3-phenylene bis(methylene)bis 2aminopyridinium bromide 4 has potent anticancer activity when compared to other compounds.

Synthesis of potent MDA-MB 231 breast cancer drug molecules from single step

“…Many researchers have demonstrated that many anticancer drugs induce apoptosis, which plays an important role in cancer drug development 33 . For this reason, we tested the morphological changes of our new compounds against MDA-MB-231 cells with acridine orange (AO) and ethidium bromide (EB) after 24 h. Morphological assessment demonstrates viable cells (control) with normal morphology and pale green nuclei.…”

“…Swiss drug design tools were used to predict the bioavailability of compounds ( 1 – 4 ) 33 . Applications of the Swiss ADME web tool has recently contributed greatly to the design and development of anticancer, tubercular, and antimicrobial agents 33 , 40 , 41 .…”

“…Swiss drug design tools were used to predict the bioavailability of compounds ( 1 – 4 ) 33 . Applications of the Swiss ADME web tool has recently contributed greatly to the design and development of anticancer, tubercular, and antimicrobial agents 33 , 40 , 41 . The bioavailability radar demonstrated six physicochemical indices such as lipophilicity (XLOGP3), size, polarity, solubility, saturation, and flexibility (Table 3 ; Fig.…”

“…MTT assay Ionic liquids have rarely or never been tested for anticancer studies and our previous ionic liquid compounds showed potent anticancer activity 33 . Therefore, it is very important to evaluate the anticancer activity of newly discovered compounds against various cancer cells.…”

2-Chloro-3-cyano-4-nitrobenzyl pyridinium bromide as a potent anti-lung cancer molecule prepared using a single-step solvent-free method

“…Almost 80-90 percent of novel drug molecules are made of derivatives of heterocyclic compounds. [3][4][5][6] Mohamed et al reported on derivatives of pyridone, thiazolidinone and pyrazolone and studied their anticancer properties against A-549 (lung) and MDA-MB-231 (breast) cancer cell lines using MTT assay. They tested the anticancer properties of nitro-, N,N-dimethyl amino-, methoxy-, and methyl-substituted pyridone derivatives.…”