Synthesis, Characterization, and Cytotoxicity of New Spirooxindoles Engrafted Furan Structural Motif as a Potential Anticancer Agent

Abstract

A new series of spirooxindoles based on ethylene derivatives having furan aryl moiety are reported. The new hybrids were achieved via [3 + 2] cycloaddition reaction as an economic one-step efficient approach. The final constructed spirooxindoles have four contiguous asymmetric carbon centers. The structure of 3a is exclusively confirmed using X-ray single crystal diffraction. The supramolecular structure of 3a is controlled by O···H, H···H, and C···C intermolecular contacts. It includes layered molecules interconnected weak C–H···O (2.675 Å), H···H (2.269 Å), and relatively short Cl···Br interhalogen interactions [3.4500(11)­Å]. Using Hirshfeld analysis, the percentages of these intermolecular contacts are 10.6, 25.7, 6.4, and 6.2%, respectively. The spirooxindoles along with ethylene derivatives having furan aryl moiety were assessed against breast (MCF7) and liver (HepG2) cancer cell lines. The results indicated that the new chalcone 3b showed excellent activity in both cell lines (MCF7 and HepG2) with IC50 = 4.1 ± 0.10 μM/mL (MCF7) and 3.5 ± 0.07 μM/mL (HepG2) compared to staurosporine with 4.3 and 2.92 folds. Spirooxindoles 6d (IC50 = 4.3 ± 0.18 μM/mL), 6f (IC50 = 10.3 ± 0.40 μM/mL), 6i (IC50 = 10.7 ± 0.38 μM/mL), and 6j (IC50 = 4.7 ± 0.18 μM/mL) exhibited potential activity against breast adenocarcinoma, while compounds 6d (IC50 = 6.9 ± 0.23 μM/mL) and 6f (IC50 = 3.5 ± 0.11 μM/mL) were the most active hybrids against human liver cancer cell line (HepG2) compared to staurosporine [IC50 = 17.8 ± 0.50 μM/mL (MCF7) and 10.3 ± 0.23 μM/mL (HepG2)]. Molecular docking study exhibited the virtual mechanism of binding of compound 3b as a dual inhibitor of EGFR/CDK-2 proteins, and this may highlight the molecular targets for its cytotoxic activity.

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…Analogously, compounds 70 were obtained in a similar synthetic protocol utilizing furyl-containing chalcones. Some of the synthesized agents exhibited potent antitumor properties against MCF-7 (breast) and HepG2 (liver) cancer cell lines (IC 50 = 4.3, 6.9; 4.7, 11.8, 17.8, 10.3 μM for 70a , 70b , and Staurosporine, respectively) [ 37 ] ( Scheme 18 ).…”

Synthesis and SARs study of novel spiro‐oxindoles as potent antiproliferative agents with CDK‐2 inhibitory activities

“…Recently, Barakat et al conducted a thorough study of this spirooxindole scaffold and have so far published several articles with an emphasis on drug discovery research focused on the anticancer reactivity of these scaffolds. [ 47–63 ]…”

“…In vitro studies have shown that these compounds have antitumor activity, with 5f increasing cytochrome C levels in the breast cancer cell line (MCF-7) human breast cancer cell line. [47,64] Moreover, numerous clinically approved inhibitors, such as the EGFR inhibitors erlotinib and gefitinib, have been found to be effective in breast cancer. [32] Spirooxindole derivatives have greater target specificity and lower toxicity against noncancerous cells and have been demonstrated to have potent anticancer activities in several models of human cancer cell lines.…”

“…[45,46] Recently, Barakat et al conducted a thorough study of this spirooxindole scaffold and have so far published several articles with an emphasis on drug discovery research focused on the anticancer reactivity of these scaffolds. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] F I G U R E 1 Some cyclin-dependent kinases (CDKs) inhibitors possessing pyrazole/iso-pyrazole in the clinical trial phases.…”

Pyrrolizine/indolizine-bearing (un)substituted isoindole moiety: design, synthesis, antiproliferative and MDR reversal activities, and in silico studies

“…38 Literature has many examples of multi-target molecules, such as EGFR/CDK-2 dual inhibitors as potent anticancer agents. 36,39,40…”