biostudies-literatureIvanenkov YARussian Science Foundation1325https://www.ebi.ac.uk/biostudies/studies/S-EPMC9919490biostudies-literatureUnknown28(3)Novel variously substituted thiohydantoin-based <i>dispiro</i>-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, HCT^wt, 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 <i>dispiro</i>-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 <b>29</b> 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 <b>29</b> 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.Molecules (Basel, Switzerland)Synthesis and Biological Evaluation of Novel <i>Dispiro</i>-Indolinones with Anticancer Activity.PMC991949021-13-00023Ivanenkov YAAyginin AAShafikov RRSerebryakova MSMajouga AGBeloglazkina AABarashkin AASkvortsov DATafeenko VAKukushkin MEBeloglazkina EKfalseSynthesis and Biological Evaluation of Novel <i>Dispiro</i>-Indolinones with Anticancer Activity.Novel variously substituted thiohydantoin-based <i>dispiro</i>-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, HCT^wt, 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 <i>dispiro</i>-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 <b>29</b> 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 <b>29</b> 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.2023-01-01T00:00:00Z2023 Jan2024-11-19T19:07:07.043Z2024-11-19T19:07:07.043ZS-EPMC99194903677099110.3390/molecules28031325