A One-Pot Three-Component Synthesis and Investigation of the In Vitro Mechanistic Anticancer Activity of Highly Functionalized Spirooxindole-Pyrrolidine Heterocyclic Hybrids

Abstract

With an aim to develop more effective and affordable anticancer agents possessing a unique mechanism of action, we designed and synthesized derivatives of spirooxindole-pyrrolidine heterocyclic hybrids in good yields through a one-pot three-component (3+2) cycloaddition strategy. The synthesized compounds were characterized thoroughly for the physicochemical properties by making use of FT-IR, NMR spectroscopy, and mass spectrometry. Further, these compounds have been evaluated for the influence of anticancer activity against HepG2 cells up to 200 µg/mL concentration. The highly active molecular scaffold was tested for the in-depth mechanistic studies, and it was found that the major pathway of cell death is apoptosis which occurs through the induction of reactive oxygen species followed by the involvement of caspases.

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…Even though there have been several important breakthroughs and encouraging results on spirooxindoles as potential therapeutic agents as discussed above, challenges and opportunities remain for medicinal chemistry research. Several investigations on spirooxindole scaffolds were reported and studied in recent years [ 73 , 74 , 75 , 76 , 77 ]. The current compiled synthetic protocols of pharmacologically active spirooxindole scaffolds will provide an efficient platform to create a new generation of potential spirooxindole analogues for various diseases.…”

Design of Novel Enantiopure Dispirooxindolopyrrolidine-Piperidones as Promising Candidates toward COVID-19: Asymmetric Synthesis, Crystal Structure and In Silico Studies

“…Similarly, piperidone and their α,β-unsaturated ketones were previously reported to display a plethora of biological properties [38,39] (Figure 1). Recent investigations revealed spirooxindolopyrrolidine cores embedded with 4-piperidone rings as a new class of bioactive polyheterocyclic spiro-compounds with promising anti-cholinesterase [40], antifungal [41], and anti-inflammatory activities [36], in addition to their remarkable anticancer properties [42] (Figure 1). Based on these findings, the racemic forms of the aforementioned spiroheterocycles were constructed by multicomponent [3+2] cycloaddition of achiral arylidene-piperidones as dipolarophiles with isatin-derived azomethine ylides as dipoles.…”

Five-Membered Nitrogen Heterocycles as New Lead Compounds in Drug Discovery

“…This molecular hybridization triggers diverse targets by a single molecule, thus increasing the drug's therapeutic effectiveness and bioavailability while reducing its side effect. 10 This strategy has been used in the development of several pyrrolidine-based drug candidates, such as for antidiabetic (coumarin-proline-sulfonamide hybrids), 11 anticancer (pyrazoline-pyrrolidine-2,5-dione hybrids), 12 antiepileptics (dioxopyrrolidine-methoxypropanamides hybrids), 13 and antimalarial (N-benzylpyrrolidine-carboxamides hybrids). 14 The success of this strategy cannot be separated from the current development of the new synthetic methodology, which permits scientists to design compounds through bypassing traditional synthetic procedures.…”