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Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification.

ABSTRACT: The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions.

PROVIDER: S-EPMC5004205 | BioStudies |

REPOSITORIES: biostudies

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Concise Total Synthesis of (-)-Affinisine Oxindole, (+)-Isoalstonisine, (+)-Alstofoline, (-)-Macrogentine, (+)-Na -Demethylalstonisine, (-)-Alstonoxine?A, and (+)-Alstonisine.

Project description:A highly enantio- and diastereoselective strategy to access any member of the sarpagine/macroline family of oxindole alkaloids via internal asymmetric induction was developed from readily available d-(+)-tryptophan. At the center of this approach was the diastereospecific generation of the spiro[pyrrolidine-3,3'-oxindole] moiety at an early stage via a tert-butyl hypochlorite-promoted oxidative rearrangement of a chiral tetrahydro-?-carboline derivative. This key branching point determined the spatial configuration at the C-7 spiro center to be entirely 7R or 7S. Other key stereospecific processes were the asymmetric Pictet-Spengler reaction and Dieckmann cyclization, which were scalable to the 600 and 150?gram levels, respectively. Execution of this approach resulted in first enantiospecific total synthesis of (+)-isoalstonisine and (-)-macrogentine from the chitosenine series (7R), as well as (+)-alstonisine, (+)-alstofoline, (-)-alstonoxine?A and (+)-Na -demethylalstonisine from the alstonisine series (7S).

| S-EPMC6168078 | BioStudies

In vitro Mechanistic Exploration of Novel Spiropyrrolidine Heterocyclic Hybrids as Anticancer Agents.

Project description:Novel spiro acenaphthylene pyrrolo[1,2-b]isoquinoline/pyrrolidine hybrids have been achieved through Pictet-Spengler/Eschweiler-Clarke reactions depending on the substitution in the benzyl ring. The in vitro biological efficacy of N-methyl spiropyrrolidine derivatives toward different cancer and non-cancer cell lines revealed that these novel spiro heterocyclic hybrids induced cancer cell death at moderate concentrations, while slight reduction in non-cancer cell viability at the higher concentrations. The analysis of cancer cells proved that the major pathway of cell death is apoptosis and in addition, the role of caspases is confirmed by the appearance of fluorescent cells in microscopic images. Therefore, this study indicates a sustainable way of treating cancer cells by inducing apoptotic pathways and associated caspases, while simultaneously protecting the non-cancer cells.

| S-EPMC7283928 | BioStudies

Diethyl 1-acetyl-4'-(4-chloro-phen-yl)-5'-(4-nitro-phen-yl)-2-oxospiro-[indoline-3,3'-pyrrolidine]-2',2'-dicarboxyl-ate.

Project description:In the title compound, C(31)H(28)ClN(3)O(8), the pyrrolidine ring exhibits an envelope conformation, with the spiro C atom located at the flap position. A spiro junction links the oxindole ring system and the pyrrolidine ring. The planar oxindole ring system is twisted with respect to the nitro-benzene and chloro-benzene rings, with dihedral angles of 62.34?(11) and 75.93?(9)°, respectively. In the crystal, a weak C-H?O interaction links the molecules into chains and two intramolecular C-H?O close contacts are seen.

| S-EPMC2970347 | BioStudies

Palladium asymmetric allylic alkylation of prochiral nucleophiles: horsfiline.

Project description:[reaction; see text] The asymmetric synthesis of the oxindole alkaloid horsfiline is described. A palladium-catalyzed asymmetric allylic alkylation (AAA) is used to set the spiro(pyrrolidine-oxindole) stereogenic center.

| S-EPMC2565574 | BioStudies

A Facile One-Pot Construction of Succinimide-Fused Spiro[Pyrrolidine-2,3'-Oxindoles] via 1,3-Dipolar Cycloaddition Involving 3-Amino Oxindoles and Maleimides.

Project description:Increasing interests have been invested in the development of synthetic strategies toward the construction of spiro[pyrrolidine-2,3'-oxindole], which is the core structural skeleton in some compounds with diverse biological activities. In this work, an efficient diastereoselective 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from 3-amino oxindoles and aldehydes with maleimides has been described. The protocol provides a facile and efficient access to structurally diverse succinimide-fused spiro[pyrrolidine-2,3'-oxindole] compounds in good to high yields (up to 93%) with moderate to excellent diastereoselectivities (up to >95:5). The relative stereochemistry of cycloaddition products has been assigned by X-ray diffraction analysis.

| S-EPMC6017913 | BioStudies

Unnatural spirocyclic oxindole alkaloids biosynthesis in Uncaria guianensis.

Project description:Spiro-oxindole scaffolds have been studied due to their promising therapeutic potential. In the Amazon rainforest there are two important Uncaria species known as "cat's claw", which biosynthesize spirocyclic oxindole alkaloids; Uncaria tomentosa (Willd. ex Schult.) DC. and Uncaria guianensis (Aublet) Gmell. We carried out a precursor-directed biosynthesis approach with U. guianensis and successfully obtained oxindole alkaloid analogues with molecular mass corresponding to the addition of a methyl or fluorine group on the oxindole ring using tryptamine analogue precursors. Two of these novel oxindole alkaloid analogues (3b-7-methyl-isomitraphylline and 3c-6-fluoro-isomitraphylline) were isolated and characterized by NMR spectroscopy and ESI-QTOF-MS/MS. Having established a substrate feeding protocol for these plantlets, the biosynthetic route for mitraphylline (1), rhynchophylline (2), isomitraphylline (3) and isorhynchophylline (4) was also investigated using 13C-precursors (1-13C-D-glucose, 2-13C-tryptophan, 1-13C-DL-glyceraldehyde, and methyl-13C-D-methionine).

2019-01-01 | S-EPMC6683290 | BioStudies

Synthesis, Evaluation and Proposed Binding Pose of Substituted Spiro-Oxindole Dihydroquinazolinones as IRAP Inhibitors.

Project description:Insulin-regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non-peptide IRAP inhibitors derived from a spiro-oxindole dihydroquinazolinone screening hit (pIC50 5.8). The compounds were synthesized either by a simple microwave (MW)-promoted three-component reaction, or by a two-step one-pot procedure. For decoration of the oxindole ring system, rapid MW-assisted Suzuki-Miyaura cross-couplings (1?min) were performed. A small improvement of potency (pIC50 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the S-configuration of the spiro-oxindole dihydroquinazolinones accounts for the inhibition of IRAP.

| S-EPMC7050655 | BioStudies

Flavin-Dependent Monooxygenases NotI and NotI' Mediate Spiro-Oxindole Formation in Biosynthesis of the Notoamides.

Project description:The fungal indole alkaloids are a unique class of complex molecules that have a characteristic bicyclo[2.2.2]diazaoctane ring and frequently contain a spiro-oxindole moiety. While various strains produce these compounds, an intriguing case involves the formation of individual antipodes by two unique species of fungi in the generation of the potent anticancer agents (+)- and (-)-notoamide A. NotI and NotI' have been characterized as flavin-dependent monooxygenases that catalyze epoxidation and semi-pinacol rearrangement to form the spiro-oxindole center within these molecules. This work elucidates a key step in the biosynthesis of the notoamides and provides an evolutionary hypothesis regarding a common ancestor for production of enantiopure notoamides.

| S-EPMC7483341 | BioStudies

A diastereoselective synthesis of Cebranopadol, a novel analgesic showing NOP/mu mixed agonism.

Project description:A diastereoselective synthesis of the title compound as a single E diastereomer has been efficiently accomplished by assembling the featured pyrano-indole scaffold of the spiro[cyclohexane-dihydropyrano[3,4-b]-indole]-amine framework through an oxa-Pictet-Spengler reaction, promoted by a cheap and green Zeolite catalyst. Basic pharmacological experiments demonstrate that Cebranopadol acts as a mixed nociception/orphanin FQ (NOP) and mu (MOP) opioid receptor agonist useful for treatment of chronic pain.

| S-EPMC5445067 | BioStudies

Biomimetic Phosphate-Catalyzed Pictet-Spengler Reaction for the Synthesis of 1,1'-Disubstituted and Spiro-Tetrahydroisoquinoline Alkaloids.

Project description:Tetrahydroisoquinoline (THIQ) alkaloids are an important group of compounds that exhibit a range of bioactivities. Here, a phosphate buffer-catalyzed Pictet-Spengler reaction (PSR) using unreactive ketone substrates is described. A variety of 1,1'-disubstituted and spiro-tetrahydroisoquinoline alkaloids were readily prepared in one-step and high yields, highlighting the general applicability of this approach. This study features the role of phosphate in the aqueous-based PSR and provides an atom-efficient, sustainable route to new THIQs.

| S-EPMC7007230 | BioStudies

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