| Title: |
Synthesis and Biological Evaluation of Novel Dispiro -Indolinones with Anticancer Activity |
| Authors: |
Yan A. Ivanenkov; Maxim E. Kukushkin; Anastasia A. Beloglazkina; Radik R. Shafikov; Alexander A. Barashkin; Andrey A. Ayginin; Marina S. Serebryakova; Alexander G. Majouga; Dmitry A. Skvortsov; Viktor A. Tafeenko; Elena K. Beloglazkina |
| Source: |
Molecules, Vol 28, Iss 3, p 1325 (2023) |
| Publisher Information: |
MDPI AG |
| Publication Year: |
2023 |
| Collection: |
Directory of Open Access Journals: DOAJ Articles |
| Subject Terms: |
dispiro -indolinones; MDM2; p53; PPI; molecular docking; cytotoxicity; Organic chemistry; QD241-441 |
| Description: |
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 (IC 50 = 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 LD 50 /ED 50 —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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://www.mdpi.com/1420-3049/28/3/1325; https://doaj.org/toc/1420-3049; https://doaj.org/article/4d2af309e9a245a297407ee7d7a93b9a |
| DOI: |
10.3390/molecules28031325 |
| Availability: |
https://doi.org/10.3390/molecules28031325; https://doaj.org/article/4d2af309e9a245a297407ee7d7a93b9a |
| Accession Number: |
edsbas.3D88D07D |
| Database: |
BASE |