Synthesis, In Vitro and in Cell Study of a New Spirooxindoles-Based N-Alkylated Maleimides Targeting HER2/3 Signaling Pathway

Abstract

A series of spirooxindoles-based N-alkylated maleimide derivatives (AMIs) were synthesized and their inhibition profile also reported. Three component, one-pot [3 + 2] cycloaddition (32CA) reactions of isatin, amino acids and AMIs were found to proceed via syn-anti-azomethine ylides (AYs) to endo-addition of AMIs. These 32CA reactions present a very low activation enthalpy, 5.1 kcal·mol⁻¹, as a consequence of the supernucleophilic character of AYs and the strong nucleophilic character of AMIs. The favorable electrostatic interactions taking place at the zwitterionic endo transition state structure are responsible for the endo stereoselectivity found in these polar 32CA reactions. The new hits of spirooxindoles-based AMIs were screened for their anticancer activity. Compounds 4e and 4f revealed the best anti-cancer activity against breast cancer cell line (MCF-7) that highly expressed human epidermal growth factor receptor (HER)-3 with the lowest IC₅₀ < 6 µM. 4e and 4f were able to induce apoptosis by 47.26% and 55.36% with suppression of serine/threonine kinase (Akt). The latter is crucial mediator in the enhancement HER-3 which has essential function in HER-2-mediated tumor progression. Moreover, 4e and 4f were able to repress Akt-downstream genes (NF-kB and Bcl-2) expression and upregulating the expression of p21 in treated MCF-7 cells. Further, the newly synthesized spirooxindoles-based AMIs (4e and 4f) exhibited inhibitory potency for Akt and HER-2 that was supported by good binding affinity and docking interaction. Thus, 4e and 4f represent promising proapoptotic agents for breast cancer treatment.

Keywords:

• Spirooxindole
• N-alkylated maleimides
• HER2/3
• Akt
• PI3K

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Conceptualization, A.B.; and A.E-F.; synthesis and characterization, A.B.; M.A.; A.M.A-M.; H.A.A.; and A.E-F.; computational investigation: S.A.; K.Z.; Z.U.H.; and L.R.D.; Biological activity assays: M.M.A-S.; and A.A-D.; All authors have participated in the writing-original manuscript, editing, revision and agreed to the published version of the manuscript.

Additional information

Funding

The authors would like to extend their sincere appreciation to the Researchers Supporting Project [RSP-2021/64], King Saud University, Riyadh, Saudi Arabia, and project [number PID2019-110776GB-I00] (AEI/FEDER, UE), Ministerio de Ciencias, Innovación y Universidades of the Spanish Government.