In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers

Abstract

A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synthesized compounds were characterized by NMR and elemental analysis. Results revealed that all the synthesized compounds displayed significant inhibition towards the tested cell lines. Among them, 2g and 2f, which differ only by the presence of an ester group at the C-3 position and small EDG (methyl) at the C-5 position of the phenyl ring (2g), were the most active derivatives in attenuating the growth of the three cells in a dose-dependent manner. The IC50 for 2g were 17.7 ± 1 µM (MCF-7), 12.1 ± 1.1 µM (A-549), and 13.9 ± 0.7 µM (SKOV3), and for 2f were 9.7 ± 1.3µM (MCF-7), 9.7 ± 0.7µM (A-549), and 6.5 ± 0.9µM (SKOV3), respectively, which were comparable to the standard drug, doxorubicin. The enzymatic inhibition of 2f and 2g against EGFR afforded good inhibitory activity with IC50 of 0.298 ± 0.007 μM and 0.484 ± 0.01 µM, respectively, close to the positive control, Afatinib. Compound 2f arrested the cell cycle in the S phase in MCF-7 and SKOV3 cells, and in the G2/M phase in the A549 cell; however, 2g induced G0/G1 phase cell cycle arrest, and inhibited the progression of the three cancer cells, together with significant apoptotic effects. The docking study of compounds 2f and 2g into EGFR ATP-active site revealed that it fits nicely with good binding affinity. The pharmacokinetic and drug-likeness scores revealed notable lead-like properties. At 100 ns, the dynamic simulation investigation revealed high conformational stability in the EGFR binding cavity.

In Silico Design, Synthesis, and Evaluation of Novel Enantiopure Isoxazolidines as Promising Dual Inhibitors of α-Amylase and α-Glucosidase

“…The stereochemistry of compounds 2 and 6 was determined in a recent work by Alminderej et al [ 24 ]. The structures of the synthesized compounds 5a–g and the most relevant coupling constants are illustrated in Table 1 .…”

“…Hydrazide 8 was condensed with p-bromophenyl isocyanate and p-fluorophenyl isocyanate to yield the semicarbazides 5f and 5g (Supplementary Materials, pages from 16 to 19), respectively (Scheme 2). The stereochemistry of compounds 2 and 6 was determined in a recent work by Alminderej et al [24]. The structures of the synthesized compounds 5a-g and the most relevant coupling constants are illustrated in Table 1.…”

“…The structures of the synthesized compounds 5a-g and the most relevant coupling constants are illustrated in Table 1. The stereochemistry of compounds 2 and 6 was determined in a recent work by Alminderej et al [24]. The structures of the synthesized compounds 5a-g and the most relevant coupling constants are illustrated in Table 1.…”

“…A recent study showed that compounds containing an isoxazolidine ring can be antidiabetic [ 11 , 20 ]. Additionally, some natural isoxazolidine derivatives are known for their diverse biological activities [ 21 , 22 , 23 ] ( Figure 1 ), such as anticancer [ 24 ], antibacterial [ 25 ], antifungal [ 26 ], and antioxidant [ 27 ] properties. Isoxazolidine analogs have also been used as a key intermediate to obtain natural compounds of high biological importance [ 28 , 29 , 30 ], such as 4-hydroxyisoleucine [ 31 ], a natural hypoglycemic agent.…”

Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches

“…Molecular docking was performed using Schrödinger glide, and MD simulation was performed using Schrödinger's Desmond program. The same technique as described in our earlier article for Molecular docking and MD simulation methods is used here [ 85 ].…”