An overview of spirooxindole as a promising scaffold for novel drug discovery

Zhou, Liming; Qu, Ren‐Yu; Yang, Guang‐Fu

doi:10.1080/17460441.2020.1733526

Cited by 217 publications

(89 citation statements)

References 193 publications

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“…As a promising scaffold for drug discovery, the stereochemical restriction on the spiro center (3R or 3S) could not only achieve specific binding to their respective targets, but also potentially improve drug oral bioavailability and metabolic stability 12,13 . Moreover, the three-dimensional structure of spiro scaffolds in spirooxindoles plays a critical role in their bioactivities 14 . However, enantioselective and efficient construction of chiral spirooxindole frameworks is very challenging in organic synthesis 15 .…”

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confidence: 99%

Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins

Liu

Zhao

et al. 2021

Nat Commun

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Prenylated indole alkaloids featuring spirooxindole rings possess a 3R or 3S carbon stereocenter, which determines the bioactivities of these compounds. Despite the stereoselective advantages of spirooxindole biosynthesis compared with those of organic synthesis, the biocatalytic mechanism for controlling the 3R or 3S-spirooxindole formation has been elusive. Here, we report an oxygenase/semipinacolase CtdE that specifies the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A. High-resolution X-ray crystal structures of CtdE with the substrate and cofactor, together with site-directed mutagenesis and computational studies, illustrate the catalytic mechanisms for the possible β-face epoxidation followed by a regioselective collapse of the epoxide intermediate, which triggers semipinacol rearrangement to form the 3S-spirooxindole. Comparing CtdE with PhqK, which catalyzes the formation of the 3R-spirooxindole, we reveal an evolutionary branch of CtdE in specific 3S spirocyclization. Our study provides deeper insights into the stereoselective catalytic machinery, which is important for the biocatalysis design to synthesize spirooxindole pharmaceuticals.

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confidence: 99%

Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins

Liu

Zhao

et al. 2021

Nat Commun

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“…In particular, a series of spiro-oxindole-tethered benzo[ b ]thiophene scaffolds consisting of a single regio- and diastereo-selective isomer were synthesized from benzo[ b ]thiophene-based chalcones ( 2a – e ), which were in turn prepared through an aldol condensation of the corresponding substituted acetophenones ( 1a – e ) with benzo[ b ]thiophene-2-carboxaldehyde. Following the 1,3-dipolar cycloaddition reaction protocol [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], 2a – e reacted with 5-substituted isatins ( 3a – c ) and secondary amino acids, such as thioproline ( 4a ) and octahydro-1 H -indole-2-carboxylic acid ( 4b ), forming the corresponding spiro-oxindole analogs IIa–n in high yields after purification by short column chromatography. The chemical features of the target compounds were assigned based on the NMR spectrum.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of a New Class of Spirooxindole–Benzo[b]Thiophene-Based Molecules as Acetylcholinesterase Inhibitors

et al. 2020

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A series of new oxindole-based spiro-heterocycles bearing the benzo[b]thiophene motif were synthesized via a 1,3-dipolar cycloaddition reaction and their acetylcholinesterase (AChE) inhibitory activity was evaluated. All the synthesized compounds exhibited moderate inhibitory activities against AChE, while IIc was found to be the most active analog with an IC50 value of 20,840 µM·L−1. Its molecular structure was a 5-chloro-substituted oxindole bearing benzo[b]thiophene and octahydroindole moieties. Based on molecular docking studies, IIc was strongly bound to the catalytic and peripheral anionic sites of the protein through hydrophilic, hydrophobic, and π-stacking interactions with Asp74, Trp86, Tyr124, Ser125, Glu202, Ser203, Trp236, Trp286, Phe297, Tyr337, and Tyr341. These interactions also indicated that the multiplicity of the IIc aromatic core significantly favored its activity.

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“…The spirooxindole moiety is a key bioactive fragment of various natural products (Fig. 1), series of derivatives already being used in medicinal practice (Zhou et al, 2020).…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure and Hirshfeld surface analysis of ethyl 6′-amino-2′-(chloromethyl)-5′-cyano-2-oxo-1,2-dihydrospiro[indoline-3,4′-pyran]-3′-carboxylate

et al. 2021

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The molecular conformation of the title compound, C17H14ClN3O4, is stabilized by an intramolecular C—H...O contact, forming an S(6) ring motif. In the crystal, the molecules are connected by N—H...O hydrogen-bond pairs along the b-axis direction as dimers with R 2 2(8) and R 2 2(14) ring motifs and as ribbons formed by intermolecular C—H...N hydrogen bonds. There are weak van der Waals interactions between the ribbons. The most important contributions to the surface contacts are from H...H (34.9%), O...H/H...O (19.2%), C...H/H...C (11.9%), Cl...H/H...Cl (10.7%) and N...H/H...N (10.4%) interactions, as concluded from a Hirshfeld surface analysis.

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An overview of spirooxindole as a promising scaffold for novel drug discovery

Cited by 217 publications

References 193 publications

Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins

Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins

Synthesis of a New Class of Spirooxindole–Benzo[b]Thiophene-Based Molecules as Acetylcholinesterase Inhibitors

Crystal structure and Hirshfeld surface analysis of ethyl 6′-amino-2′-(chloromethyl)-5′-cyano-2-oxo-1,2-dihydrospiro[indoline-3,4′-pyran]-3′-carboxylate

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