|
Abstract
|
Novel anti-cancer agents are much needed to expand the available pharmacological tools for patients suffering
from this deadly disease. In this study, a series of 3′H-spiro[indoline-2,1′-isobenzofuran]-3,3′‑dione derivatives
were synthesized via a new efficient procedure based on one-pot synthesis and oxidation of 4b,9b-dihydroxy-
4b,5-dihydroindeno[1,2-b]indol-10(9bH)-ones. The chemical structures of compounds were established by
spectroscopic methods including 1H- and 13C NMR. Cytotoxicity was evaluated against HT-29 (colorectal
adenocarcinoma), Mia-Paca-2 (pancreatic ductal adenocarcinoma), and MDA-MB-231 (breast adenocarcinoma)
human cancer cell lines as well as Vero non-cancer cell line. The compound 4f with ethoxy and ninhydrin
moieties on the indoline ring showed antiproliferative activity against tested cell lines, while it relatively spared
the non-cancer cells. The active derivatives 4a, 4f and 4 g slightly increased the percentage of cells in the G0/G1
phase of the cell cycle and also induced apoptosis in cancer cells. Molecular docking and dynamics simulations
studies showed extensive interactions of synthesized compounds with epidermal growth factor receptor (EGFR),
an important oncogenic kinase. In silico studies performed to determine the absorption, distribution, metabolism,
and excretion (ADME) of studied compounds also showed their favorable profiles. In conclusion, the findings of
this study show that spiro[indoline-2,1′-isobenzofuran] derivatives may be promising anticancer agents with
EGFR inhibitory potential.
|