Indenoquinoxaline-Based Spiro-Heterocycles: Synthesis, Structural Characterization, MEDT Study, and Dual Inhibition of Kinase-Related Enzymes EGFR and VEGFR2
A new series of spiro-heterocycles derived from pyrazole–indenoquinoxaline scaffolds 4a–n and 5a–m was designed and
synthesized via one-pot multi-component reaction-based a [3 + 2] cycloaddition reaction (32CA). The Molecular Electron Density
Theory (MEDT) has been used to theoretically study the 32CA reaction between azomethine ylide (AY) 6a and the electrophilic
ethylene 1a. This 32CA reaction, which proceeds via a two-stage one-step mechanism, yields the spiro-cycloadduct 4a with high
ortho/endo selectivity. The newly pyrazole-tethered indenoquinoxaline-based spiro-heterocycles 4a–n and 5a–m were evaluated
for their anticancer activities againstMCF-7 and HepG-2 cancer cell lines. These compoundswere targeted as dual EGFR/VEGFR-
2 kinase inhibitors. Interestingly, 4l exhibited the most substantial inhibitory effect, with a potent effect on HepG2 cells (1.35 μM)
and poor cytotoxicity on MCF-7 (≥50 μM). However, compound 4f displayed a unique antiproliferative potency on HepG2 cells
(7.9 μM) and a promising cytotoxicity in MCF-7 (13.5 μM), compared to sorafenib with IC50 values of 2.1 and 2.3 μMagainstMCF-7
and HepG-2 cancer cells. Compound 4f treatment induced total apoptosis in the HepG2 cancer cells by 36.3-fold, arresting the
cell proliferation at the G1-phase by 83.4%. Accordingly, compounds 4l and 4f exhibited target-oriented chemotherapeutic activity
against liver cancer.
Hybrids of spirooxindole and 1,2,3-triazole have been the subject of extensive research because of their potential
as multitarget anticancer pharmaceuticals. Potential novel anticancer…
A new series of spiro-heterocycles derived from pyrazole–indenoquinoxaline scaffolds 4a–n and 5a–m was designed and
synthesized via one-pot multi-component reaction-based a [3 + 2]…
Several aspects of apoptosis signaling have been explored for
managing non-small cell lung cancer (NSCLC). While inhibiting
oncogenic kinases like PIM-1 and CDK2 has shown promise,…