Synthesis and Biological Evaluation of Novel Dispiro -Indolinones with Anticancer Activity.
Yan A IvanenkovMaxim E KukushkinAnastasia A BeloglazkinaRadik R ShafikovAlexander A BarashkinAndrey A AygininMarina S SerebryakovaAlexander G MajougaDmitry A SkvortsovViktor A TafeenkoElena K BeloglazkinaPublished in: Molecules (Basel, Switzerland) (2023)
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.
Keyphrases
- cell cycle arrest
- molecular docking
- cell death
- pi k akt
- induced apoptosis
- high fat diet induced
- molecular dynamics simulations
- emergency department
- signaling pathway
- endoplasmic reticulum stress
- cardiovascular events
- big data
- coronary artery disease
- cell proliferation
- cardiovascular disease
- quantum dots
- risk factors
- south africa
- oxidative stress
- electronic health record
- adipose tissue
- machine learning
- insulin resistance
- dna binding
- data analysis
- artificial intelligence
- living cells
- squamous cell
- single molecule