分子内水素結合骨格導入によるキノリン系mTOR阻害剤の設計・合成・生物学的評価
A series of quinoline derivatives incorporating an intramolecular hydrogen bonding scaffold (iMHBS) were designed and synthesized, then assessed for mTOR inhibitory potency and antiproliferative activity against HCT-116, PC-3, and MCF-7 cancer cell lines. Six compounds achieved IC50 values below 35 nM against mTOR. Among them, compound 15a showed the strongest mTOR inhibition (IC50 = 14 nM) and favorable cellular potency, with IC50 values of 0.46, 0.61, and 0.24 μM against HCT-116, PC-3, and MCF-7, respectively. Several compounds demonstrated selectivity over class I PI3Ks. Western blot analysis of compound 16b revealed that dual inhibition of mTORC1 and mTORC2 circumvented the S6K/IRS1/PI3K negative feedback loop. Compound 15a also exhibited acceptable metabolic stability in simulated gastric and intestinal fluids and liver microsomes, supporting its suitability for further in vivo studies.
Quinoline derivatives with an intramolecular hydrogen bonding scaffold dually inhibit mTORC1 and mTORC2, thereby bypassing the S6K/IRS1/PI3K negative feedback loop and suppressing cancer cell proliferation.
This is basic research at the cellular or molecular level. For human application, inhalation is the most promising delivery route, but inhalation carries explosion risk and concentration matters (empirical LFL of 10%; high-concentration devices are not recommended).
See also:
https://h2-papers.org/en/papers/26596710