Autor: |
Ivanenkov YA; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia.; The Federal State Unitary Enterprise Dukhov Automatics Research Institute (VNIIA), 22. ul. Sushchevskaya, 127055 Moscow, Russia., Kukushkin ME; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia., Beloglazkina AA; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia., Shafikov RR; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia.; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, GSP-7, Ulitsa Mklukho-Maklaya 16/10, 17997 Moscow, Russia.; A. N. Belozersky Research Institute of Physico-Chemical Biology MSU, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia., Barashkin AA; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia., Ayginin AA; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia., Serebryakova MS; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia., Majouga AG; College of New Materials and Nanotechnologies, National University of Science and Technology MISiS, 119049 Moscow, Russia., Skvortsov DA; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia., Tafeenko VA; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia., Beloglazkina EK; Chemistry Department, Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia. |
Abstrakt: |
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. |