{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ivanenkov YA"],"funding":["Russian Science Foundation"],"pagination":["1325"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9919490"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["28(3)"],"pubmed_abstract":["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<sup>wt</sup>, and HCT<sup>(-/-)</sup>. Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC<sub>50</sub> = 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 LD<sub>50</sub>/ED<sub>50</sub>-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."],"journal":["Molecules (Basel, Switzerland)"],"pubmed_title":["Synthesis and Biological Evaluation of Novel <i>Dispiro</i>-Indolinones with Anticancer Activity."],"pmcid":["PMC9919490"],"funding_grant_id":["21-13-00023"],"pubmed_authors":["Ivanenkov YA","Ayginin AA","Shafikov RR","Serebryakova MS","Majouga AG","Beloglazkina AA","Barashkin AA","Skvortsov DA","Tafeenko VA","Kukushkin ME","Beloglazkina EK"],"additional_accession":[]},"is_claimable":false,"name":"Synthesis and Biological Evaluation of Novel <i>Dispiro</i>-Indolinones with Anticancer Activity.","description":"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<sup>wt</sup>, and HCT<sup>(-/-)</sup>. Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC<sub>50</sub> = 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 LD<sub>50</sub>/ED<sub>50</sub>-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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2024-11-19T19:07:07.043Z","creation":"2024-11-19T19:07:07.043Z"},"accession":"S-EPMC9919490","cross_references":{"pubmed":["36770991"],"doi":["10.3390/molecules28031325"]}}