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Synthesis and Biological Evaluation of Novel Dispiro-Indolinones with Anticancer Activityстатья
- Авторы: Ivanenkov Yan A., Kukushkin Maxim E., Beloglazkina Anastasia A., Shafikov Radik R., Barashkin Alexander A., Ayginin Andrey A., Serebryakova Marina V., Majouga Alexander G., Skvortsov Dmitry A., Tafeenko Viktor A., Beloglazkina Elena K.
- Журнал: Molecules
- Том: 28
- Номер: 3
- Год издания: 2023
- Издательство: MDPI
- Местоположение издательства: Basel, Switzerland
- Номер статьи: 1325
- DOI: 10.3390/molecules28031325
- Аннотация: Novel variously substituted thiohydantoin-based dispiro-indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCTwt, and HCT(−/−). Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC50 = 1.2–3.5 µM) and a reasonable selectivity index (SI = 3–10). Confocal microscopy revealed that the conjugate of propargyl-substituted dispiro-indolinone with the fluorescent dye Sulfo-Cy5-azide was mainly localized in the cytoplasm of HEK293 cells. P388-inoculated mice and HCT116-xenograft BALB/c nude mice were used to evaluate the anticancer activity of compound 29 in vivo. Particularly, the TGRI value for the P388 model was 93% at the final control timepoint. No mortality was registered among the population up to day 31 of the study. In the HCT116 xenograft model, the compound (170 mg/kg, i.p., o.d., 10 days) provided a T/C ratio close to 60% on day 8 after the treatment was completed. The therapeutic index—estimated as LD50/ED50—for compound 29 in mice was ≥2.5. Molecular docking studies were carried out to predict the possible binding modes of the examined molecules towards MDM2 as the feasible biological target. However, such a mechanism was not confirmed by Western blot data and, apparently, the synthesized compounds have a different mechanism of cytotoxic action.
- Добавил в систему: Белоглазкина Елена Кимовна