article · Journal of Enzyme Inhibition and Medicinal Chemistry
New hydrazonoindolin-2-one chemical compounds have been designed, synthesised, and evaluated in laboratory tests as prospective anticancer agents. When screened against human lung, colon, and breast cancer cell lines, four specific derivatives, designated 5b, 5c, 7b, and 10e, demonstrated stronger anti-proliferative effects than the reference drug Sunitinib. Further investigation of compounds 7b and 10e examined their impact on cell cycle progression and the regulation of phosphorylated retinoblastoma protein within lung cancer cells. Both compounds also curtailed cell growth in a multidrug-resistant lung cancer cell line. In addition, tests against non-cancerous intestinal, breast, and fibroblast cell lines revealed that compounds 7b and 10e had higher tumour selectivity indices than Sunitinib, indicating a potentially better ability to target cancer cells while sparing healthy tissue.
Developing cancer treatments that overcome drug resistance while minimising toxicity to healthy cells is a major healthcare challenge. Identifying synthetic compounds that outperform standard reference therapies in laboratory cell cultures, particularly against resistant lung cancer variants, provides valuable candidate structures for the ongoing search for more effective and selective cancer therapies.
This research represents early-stage preclinical drug discovery. The identified compounds could serve as starting scaffolds for pharmaceutical companies and oncology researchers seeking to develop new small-molecule cancer drugs. Because the findings are limited to in vitro cell culture evaluations, the work remains at an early laboratory stage, requiring extensive pharmacokinetic optimisation, in vivo efficacy studies, and safety profiling before any clinical or commercial viability can be determined.
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In connection with our research program on the development of novel indolin-2-one-based anticancer candidates, herein we report the design and synthesis of different series of hydrazonoindolin-2-ones 3a-e, 5a-e, 7a-c, and 10a-l. The synthesised derivatives were in vitro evaluated for their anti-proliferative activity towards lung A-549, colon HT-29, and breast ZR-75 human cancer cell lines. Compounds 5b, 5c, 7b, and 10e emerged as the most potent derivatives with average IC<sub>50</sub> values of 4.37, 2.53, 2.14, and 4.66 µM, respectively, which are superior to Sunitinib (average IC<sub>50</sub> = 8.11 µM). Furthermore, compounds 7b and 10e were evaluated for their effects on cell cycle progression and levels of phosphorylated retinoblastoma (Rb) protein in the A-549 cancer cell line. Moreover, 7b and 10e inhibited the cell growth of the multidrug-resistant lung cancer NCI-H69AR cell line with IC<sub>50</sub> = 16 µM. In addition, the cytotoxic activities of 7b and 10e were assessed towards three non-tumorigenic cell lines (Intestine IEC-6, Breast MCF-10A, and Fibroblast Swiss-3t3) where both compounds displayed mean tumor selectivity index (1.6 and 1.8) higher than that of Sunitinib (1.4).
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DOI: 10.1080/14756366.2018.1462802
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