1. Synthesis and Biological Evaluation of Novel Dispiro -Indolinones with Anticancer Activity.
- Author
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Ivanenkov YA, Kukushkin ME, Beloglazkina AA, Shafikov RR, Barashkin AA, Ayginin AA, Serebryakova MS, Majouga AG, Skvortsov DA, Tafeenko VA, and Beloglazkina EK
- Subjects
- Humans, Animals, Mice, Structure-Activity Relationship, Oxindoles pharmacology, Molecular Docking Simulation, Mice, Nude, HEK293 Cells, Cell Proliferation, Drug Screening Assays, Antitumor, Cell Line, Tumor, Molecular Structure, Antineoplastic Agents chemistry
- Abstract
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, 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 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.- Published
- 2023
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