Thiophene Derivative‐Loaded Nanoparticles Mediate Anticancer Activity Through the Inhibition of Kinases and Microtubule Assembly

Abstract

Different tetrahydrobenzo[b]thiophene derivatives are explored as new tubulin polymerization destabilizers to arrest tumor cell mitosis. A series of compounds incorporating the tetrahydrobenzo[b]thiophene scaffold are synthesized, and their biological activities are investigated. The cytotoxicity of each of the synthesized compounds is assessed against a range of cell lines. Specifically, the benzyl urea tetrahydrobenzo[b]thiophene derivative, 1-benzyl-3-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)urea (BU17), is identified as the most potent compound with broad-spectrum antitumor activity against several cancer cell lines. The potential mechanism(s) of action are investigated where dose-dependent G2/M accumulation and A549 cell cycle arrest are detected. Additionally, A549 cells treated with BU17 express enhanced levels of caspase 3 and 9, indicating the induction of apoptosis.Furthermore, it is found that BU17 inhibits WEE1 kinase and targets tubulin by blocking its polymerization. BU17 is also formulated into PLGA nanoparticles, and it is demonstrated that BU17-loaded nanoparticles can significantly enhance antitumor activity compared to the soluble counterpart.

A decade's overview of 2‐aminothiophenes and their fused analogs as promising anticancer agents

“…Somaya et al designed a series of 2‐aminotetrahydrobenzo[ b ]thiophene derivatives as inhibitors of WEE1 kinase and microtubule assembly. [ 95 ] The cytotoxicity assay demonstrated that compound 28 having the benzyl urea moiety is the most potent with broad‐spectrum anticancer activity against various cancer cell lines where dose‐dependent G2/M accumulation and A549 cell cycle arrest are the possible mechanism of action with apoptosis indicated by the increased levels of caspase 3 and 9. Furthermore, compound 28 inhibits WEE1 kinase and targets tubulin by inhibiting its polymerization.…”

Cationic nanoparticles enhance T cell tumor infiltration and antitumor immune responses to a melanoma vaccine

“…Plates were then incubated at 37°C with 5% CO 2 for 48 hours. Next, Cell Titer 96 aqueous MTS reagent [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, purchased from Promega Corporation, San Luis Obispo, CA] was added to the cells following the manufacturer's instructions (63,(68)(69)(70). After incubation for 2 hours, cell viability (%) was calculated on the basis of the absorbance measured at 490 nm using a SpectraMax Plus spectrophotometer (Molecular Devices, San Jose, CA).…”

Employing acetoacetamide as a key synthon for synthesizing novel thiophene derivatives and assessing their potential as antioxidants and antimicrobial agents

“…Indeed, many heterocyclics bearing thiophene (e.g., AZD-7762, OSI-930, and PF-4989216) have been known to target cancer-specific proteins, leading to inhibition or activation of specific signaling pathways in cancer cells [13][14][15][16][17][18][19]. Another thiophene-bearing drug, nocodazole, has been shown to have antimitotic effects by binding to tubulin and arresting the cell cycle at the G2/M phase [20,21].…”

“…13 C NMR spectrum (DMSO-d 6 ), showed several carbon signals at δ C 14.3 ppm (CH 3 ), 15.1 ppm (CH 3 ),19.8 ppm (CH 3 ), 55.3 ppm (O-CH 3 ), and 60.7 ppm (CH 2 ). Furthermore, the signals for aromatic carbon atoms were indicated by their chemical shifts at δ C 113.8 ppm (2C), 116.1, 121.9 ppm (2C), and 157.7 ppm.…”