article · RSC Advances
Researchers have synthesised a series of hexahydroquinoline derivatives by reacting 2-amino-3-cyano-1-cyclohexylhexahydroquinoline with oxalyl chloride and triethyl orthoformate. Laboratory evaluations tested the antiproliferative activity of these newly created chemical candidates against four human cancer cell lines, specifically targeting liver, breast, prostate, and colon cancers. Among the tested substances, derivatives containing hydrazide, thiosemicarbazide, and thiazolidinone groups displayed the strongest potency in inhibiting cancer cell growth across all four evaluated lines. Molecular docking investigations revealed that the thiosemicarbazide and thiazolidinone variants bound strongly to the Mcl-1 enzyme, displaying superior binding scores compared to the reference co-crystallised ligand LC3. In addition, computational pharmacokinetic analyses indicated that these lead compounds possess favourable oral bioavailability and drug-likeness profiles, demonstrating their consistency across both theoretical models and laboratory observations.
Finding effective treatments for common cancers such as liver, breast, prostate, and colon remains a significant healthcare challenge. By identifying new chemical structures that inhibit cancer cell proliferation and bind efficiently to key disease-associated enzymes, this research offers early foundational chemical candidates that could guide future oncology drug discovery, particularly where existing molecular targets like Mcl-1 are concerned.
This work could serve as an early starting point for pharmaceutical companies and medicinal chemists seeking novel lead compounds for cancer therapies. The primary users are preclinical drug discovery teams focused on Mcl-1 inhibition. Because the findings are based entirely on in vitro cell line assays and computational modelling, the compounds remain at an early discovery stage, far from clinical evaluation or commercial development.
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Some hexahydroquinoline candidates were prepared by reacting 2-amino-3-cyano-1-cyclohexylhexahydroquinoline with oxalyl chloride and triethyl orthoformate. The computational chemical approach agreed with the product-testing results. The produced substances were examined <i>in vitro</i> for their antiproliferative activity against liver carcinoma (HepG2), breast adenocarcinoma (MCF7), prostate cancer (PC3), and colon cancer (HCT116) cell lines. The highest potency against the four cell lines was exhibited by hydrazide, thiosemicarbazide, and thiazolidinone derivatives. The best docking score was presented by thiosemicarbazide and thiazolidinone derivatives as they showed the highest binding to the Mcl-1 enzyme with binding energies of -8.97 and -8.90 kcal mol<sup>-1</sup>, respectively, which were higher than that of the co-crystallized ligand (LC3) with a binding energy of -8.74 kcal mol<sup>-1</sup>. Besides, the modeling pharmacokinetics disclosed their desirable drug-likeness and oral bioavailability characteristics.
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DOI: 10.1039/d4ra02271h
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