Stereoselective Synthesis of Spirooxindole Derivatives Using One-Pot Multicomponent Cycloaddition Reaction and Evaluation of Their Antiproliferative Efficacy

Abstract

A highly stereoselective, one-pot, multicomponent method has been developed to synthesize pyrrolizidine- and N -methyl pyrrolidine-substituted spirooxindole derivatives. The [3 + 2] cycloaddition reaction involves the reaction between the dipole azomethine ylides, generated in situ from the reaction between isatin and secondary amino acids such as L-proline or sarcosine, and α,β-unsaturated carbonyl compounds as the dipolarophile. The reaction condition was optimized to achieve excellent regio- and stereoselectivity. Products were obtained in good yield using ethanol as a solvent at the reflux temperature. The newly synthesized spirooxindole derivatives were evaluated for their antiproliferative efficacy against National Cancer Institute (NCI)-60 cancer cell lines and DNA G-quadruplex (G4) interaction capacity. Compound 14b produced selective cytotoxicity against leukemia, renal, colon, and prostate cancer cell lines at a 10 μM concentration. The G4 interaction studies further suggested that these spirooxindole derivatives were devoid of any activity as DNA G4 ligands.

Expeditious entry into carbocyclic and heterocyclic spirooxindoles

“…Acharya's group reported the diastereoselective 1,3-dipolar cycloaddition of azomethine ylides generated from isatin 5a and amino acids 89 with enones 90 under mild conditions (Scheme 58). 55…”

“…Acharya's group reported the diastereoselective 1,3-dipolar cycloaddition of azomethine ylides generated from isatin 5a and amino acids 89 with enones 90 under mild conditions (Scheme 58). 55 All the compounds were subjected to an in vitro cytotoxicity assay on National Cancer Institute (NCI) guided 60 cancer cell lines. One of the cycloadducts (R 1 = 4-Cl, R 2 = 4-Br) exhibited selective toxicity against leukemia, renal, colon, and prostate cancer cell lines at 10 μM concentration.…”

Novel Functionalized Spiro [Indoline-3,5′-pyrroline]-2,2′dione Derivatives: Synthesis, Characterization, Drug-Likeness, ADME, and Anticancer Potential

“…The MCRs are usually catalyzed in a “single pot reaction” manner in which two or more components react by sequential addition in the same reaction settings. All components in MCRs either assemble in linear form (i.e., Michael addition reaction) or undergo further cyclization (as in 3 + 2 cycloaddition) to give complex molecules, i.e., SOXs [ 41 , 42 ]. Recent studies have widely used the MCRs for the synthesis of novel functionalized SOXs and assessed their therapeutic efficacy against a range of diseases, particularly cancer.…”

“…Recent studies have widely used the MCRs for the synthesis of novel functionalized SOXs and assessed their therapeutic efficacy against a range of diseases, particularly cancer. Moreover, most of these studies were focused on the assessment of the antiproliferative effect of SOXs against breast cancer, hepatocellular carcinoma, and prostate cancer [ 41 , 43 , 44 , 45 ]. Based on the here-mentioned studies, in the current study, we used three different active compounds, namely dioxindoles (DOXs), primary arylamines, and dimethyl acetylenedicarboxylate for the formation of spirooxindole-pyrroline derivatives ( 4a – h ).…”

Synthesis, characterization, antibacterial activity and cytotoxicity of (1′R,2′S,7a′S)‐2′‐(2,5‐dichlorothiophene‐3‐carbonyl)‐1′‐(aryl)‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizin]‐2‐one derivatives

“…Several research groups readily synthesized spirooxindole-based compounds using a 1,3-dipolar cycloaddition reaction. For example, the combination of an electron deficient alkene, isatin and an amino acid [6][7][8]. Some other spiro[indoline-3,3 0 -indolizine]s synthesized by the reaction between isatins, pipecolic acid and an electron-deficient alkene [9].…”