Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3'-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury.

Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.

Accraspiroketides A-B, Phenylnaphthacenoid-Derived Polyketides with Unprecedented [6 + 6+6 + 6] + [5 + 5] Spiro-Architecture.

Two novel polyketides, accraspiroketides A (1) and B (2), which feature unprecedented [6 + 6+6 + 6] + [5 + 5] spiro chemical architectures, were isolated from Streptomyces sp. MA37 ΔaccJ mutant strain. Compounds 1-2 exhibit excellent activity against Gram-positive bacteria (MIC = 1.5-6.3 µg/mL). Notably, 1 and 2 have superior activity against clinically isolated Enterococcus faecium K60-39 (MIC = 4.0 µg/mL and 4.7 µg/mL, respectively) than ampicillin (MIC = 25 µg/mL).

C3-Spirooxindoles: Divergent chemical synthesis and bioactivities (2018-2023).

This scientific review documents the recent progress of C3-spirooxindoles chemistry (synthesis and reaction mechanism) and their bioactivities, focusing on the promising results as well as highlighting the biological mechanism via the reported molecular docking findings of the most bioactive derivatives. C3-Spirooxindoles are attractive bioactive agents and have been found in a variety of natural compounds, including alkaloids. They are widely investigated in the field of medicinal chemistry and play a key role in medication development, such as antivirals, anticancer agents, antimicrobials, etc. Regarding organic synthesis, several traditional and advanced strategies have been reported, particularly those that started with isatin derivatives.

Dissipation, residues, and evaluation of processing factor for spirotetramat and its formed metabolites during kiwifruit growing, storing, and processing.

Spirotetramat is widely used around the world to control sucking pests and may form in agricultural products. In the current study, the dissipation, residues, and evaluation of processing factor (PF) for spirotetramat and its formed metabolites were investigated during kiwifruit growing, storing, and processing. The residue analysis method was established based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) combined with a QuEChERS method to detect the residues of spirotetramat and its metabolites in kiwifruit and its processed products. The method provided recoveries of 74.7-108.7%, and the relative standard deviations (RSDs) were 0.6-13.1%. The LOQs of spirotetramat and its four metabolites were 1 µg kg-1. The degradation of spirotetramat was best fitted for the first-order kinetics model with a half-life of 9.90-10.34 days in the field and 24.75-30.13 days during storage. Residues of spirotetramat and its formed metabolites in kiwifruit would not pose dietary risk to consumers. Moreover, the peeling and fermentation were the highest removal efficiency for the spirotetramat and its formed metabolite residues during processing. The PF values calculated after each individual process were < 1, indicating a significant reduction of residues in different processing processes of kiwifruit. The spirotetramat was degraded during kiwifruit wine-making process with half-lives of 3.36-4.91 days. B-enol and B-keto were the main metabolites detected in kiwifruit and its processed products. This study revealed the residues of spirotetramat and its formed metabolites in kiwifruit growing, storing, and processing, which helps provide reasonable data for studying the dietary risk factors of kiwifruits and products.

Synthesis of portimines reveals the basis of their anti-cancer activity.

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

6-Azaspiro[2.5]octanes as small molecule agonists of the human glucagon-like peptide-1 receptor.

Activation of the glucagon-like peptide-1 (GLP-1) receptor stimulates insulin release, lowers plasma glucose levels, delays gastric emptying, increases satiety, suppresses food intake, and affords weight loss in humans. These beneficial attributes have made peptide-based agonists valuable tools for the treatment of type 2 diabetes mellitus and obesity. However, efficient, and consistent delivery of peptide agents generally requires subcutaneous injection, which can reduce patient utilization. Traditional orally absorbed small molecules for this target may offer improved patient compliance as well as the opportunity for co-formulation with other oral therapeutics. Herein, we describe an SAR investigation leading to small-molecule GLP-1 receptor agonists that represent a series that parallels the recently reported clinical candidate danuglipron. In the event, identification of a benzyloxypyrimidine lead, using a sensitized high-throughput GLP-1 agonist assay, was followed by optimization of the SAR using substituent modifications analogous to those discovered in the danuglipron series. A new series of 6-azaspiro[2.5]octane molecules was optimized into potent GLP-1 agonists. Information gleaned from cryogenic electron microscope structures was used to rationalize the SAR of the optimized compounds.

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold.

Spirooxindoles occupy an important place in heterocyclic chemistry. Many natural spirooxindole-containing compounds have been identified as bio-promising agents. Synthetic analogs have also been synthesized utilizing different pathways. The present article summarizes the recent development of both natural and synthetic spirooxindole-containing compounds prepared from isatin or its derivatives reported in the last five years. The spirooxindoles are categorized based on their mentioned biological properties.

Stereoselective synthesis of the spirocyclic core of 13-desmethyl spirolide C using an aza-Claisen rearrangement and an exo-selective Diels-Alder cycloaddition.

13-Desmethyl spirolide C is a marine natural product of the cyclic imine class that demonstrates remarkable bioactivity against several biomarkers of Alzheimer's Disease, which renders its [7,6]-spirocyclic imine pharmacophore of significant synthetic interest. This work describes a facile and efficient synthesis of the [7,6]-spirocyclic core of 13-desmethyl spirolide C from inexpensive starting materials, featuring an aza-Claisen rearrangement to simultaneously set both stereocentres of the dimethyl moiety with complete atom economy, and a highly exo-selective Diels-Alder cycloaddition to construct the challenging contiguous tertiary and quaternary stereocentres of the spirocyclic core of 13-desmethyl spirolide C. A comprehensive study of the key Diels-Alder reaction was also performed to evaluate the stereoselectivity and reactivity of various functionalised dienes and protected lactam dienophiles, wherein the first successful exo-selective Diels-Alder cycloaddition to construct spirocyclic structures using a bromodiene and α-exo-methylene dienophiles is reported. This strategy not only establishes a more efficient stereoselective access to the spirocyclic core that can be used for the total synthesis of 13-desmethyl spirolide C, but also serves as a sound platform for convenient preparations of a range of spirocyclic analogues required for a comprehensive biological evaluation of this desirable pharmacophore.

1,3-Dipolar cycloaddition reactions of isatin-derived azomethine ylides for the synthesis of spirooxindole and indole-derived scaffolds: recent developments.

The unique therapeutic and biological characteristics of spirooxindole have led to the presentation of numerous reactions for the synthesis of spirooxindoles through 1,3-Dipolar cycloaddition of highly reactive isatin-derived azomethine ylides with activated olefins as the main tool for the formation of spirocyclic oxindoles during the last 4 years. Therefore, there is a need to highlight the recent developments in this area, along with the representative synthetic methods and relevant reaction mechanisms from 2018 to 2021. The representative synthetic methodologies were listed in four sections based on the procedure to form the azomethine ylide species including isatins and amino acids, isatin-derived α-(trifluoromethyl)imine, isatins and benzylamines, and from isatin-derived cyclic imine 1,3-dipoles.

Asymmetric Synthesis of Spiro-3,3'-cyclopropyl Oxindoles via Vinylogous Michael Initiated Ring Closure Reaction.

A novel organocatalytic cascade approach for the synthesis of spiro-cyclopropyl oxindole derivatives has been developed. The methodology is based on asymmetric vinylogous Michael addition of 4-nitroisoxazole derivatives to N-Boc isatylidene malonates followed by intramolecular alkylation. Its remarkable stereocontrol, wide substrate scope, and scalability highlight this new developed strategy. Moreover, this work represents the first example of vinylogous Michael initiated ring closure (MIRC) reaction for the synthesis of chiral 3,3'-cyclopropyl oxindole.

Green Synthesis of Spiro Compounds with Potential Anticancer Activity through Knoevenagel/Michael/Cyclization Multicomponent Domino Reactions Organocatalyzed by Ionic Liquid and Microwave-Assisted.

In this work a microwave-assisted Knoevenagel/Michael/cyclization multicomponent domino methodology, using ethanol as solvent and the ionic liquid 1-methylimidazolium chloride as catalyst was developed for the synthesis of spiro compounds. The reaction conditions considered ideal were determined from a methodological study varying solvent, catalyst, amount of catalyst, temperature, and heating mode. Finally, the generality of the methodology was evaluated by exploring the scope of the reaction, varying the starting materials (isatin, malononitrile, and barbituric acid). Overall, the twelve spiro compounds were synthesized in good yields (43-98%) and the X-ray structure of compound 1b was obtained. In addition, the in vitro antiproliferative activities of the spirocycles against four types of human cancer cell lines including HCT116 (human colon carcinoma), PC3 (prostate carcinoma), HL60 (promyelocytic leukemia), and SNB19 (astrocytoma) were screened by MTT-based assay. It is noteworthy that spiro compound 1c inhibited the four cell lines tested with the lowest IC50 values: 52.81 µM for HCT116, 74.40 µM for PC3, 101 µM for SNB19, and 49.72 µM for HL60.

Synthesis, Structure and Stereochemistry of Dispirocompounds Based on Imidazothiazolotriazine and Pyrrolidineoxindole.

Methods for the synthesis of two types of isomeric dispirocompounds based on imidazothiazolotriazine and pyrrolidineoxindole, differing in the structure of imidazothiazolotriazine fragment, namely, linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3'-pyrrolidine- 4',3″-indolines] and angular dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3'-pyrrolidine-4',3″-indolines] were proposed. The first method relies on a 1,3-dipolar cycloaddition of azomethine ylides generated in situ from paraformaldehyde and N-alkylglycine derivatives to the corresponding oxindolylidene derivatives of imidazothiazolotriazine. The cycloaddition leads to a mixture of two diastereomers resulted from anti- and syn-approaches of azomethine ylide in approximately a 1:1 ratio, which were separated by column chromatography. Another method consists in rearrangement of linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3'-pyrrolidine-4',3″-indolines] into hitherto unavailable angular dispiro[imidazo[4,5-e]thiazolo[2,3-c]-[1,2,4]triazine-7,3'-pyrrolidine-4',3″-indolines] upon treatment with KOH. It was found that the anti-diastereomer of linear type underwent rearrangement into the isomeric angular syn-diastereomer, while the rearrangement of the linear syn-diastereomer gave the angular anti-diastereomer.

Synthesis of Spiro[5.5]trienones- and Spiro[4.5]trienones-Fused Selenocyanates via Electrophilic Selenocyanogen Cyclization and Dearomative Spirocyclization.

A practical strategy for the synthesis of spiro[5.5]trienones-fused selenocyanates and spiro[4.5]trienones-fused selenocyanates through electrophilic selenocyanogen cyclization and dearomative spirocyclization is reported. This approach was conducted under mild conditions with broad substrate scope and good functional group tolerance. The utility of this procedure is exhibited in the late-stage functionalization of nature product and drug molecules.

Organo/Silver Dual Catalytic (3 + 2)/Conia-Ene Type Cyclization: Asymmetric Synthesis of Indane-Fused Spirocyclopenteneoxindoles.

Developing efficient strategies to synthesize spirocyclopenteneoxindoles is an attractive target due to their potential biological activity. This work described the thiourea/silver dual catalytic (3 + 2)/Conia-ene type reaction of 2-(2-oxoindolin-3-yl)malononitrile with ortho-ethynyl substituted nitrostyrene. The reaction features mild conditions and good atom- and step-economy. Three new C-C bonds were formed within one synthetic step, providing the indane-fused spirocyclopenteneoxindoles in good yields, with excellent chemo-, regio-, and stereoselectivity.

Spiro Derivatives in the Discovery of New Pesticides: A Research Review.

Spiro compounds are biologically active organic compounds with unique structures, found in a wide variety of natural products and drugs. They do not readily lead to drug resistance due to their unique mechanisms of action and have, therefore, attracted considerable attention regarding pesticide development. Analyzing structure-activity relationships (SARs) and summarizing the characteristics of spiro compounds with high activity are crucial steps in the design and development of new pesticides. This review mainly summarizes spiro compounds with insecticidal, bactericidal, fungicidal, herbicidal, antiviral, and plant growth regulating functions to provide insight for the creation of new spiro compound pesticides.

Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties.

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

Efficient construction of diverse spiro[indoline-3,4'-pyrrolo[3,4-b]pyridines] via [3 + 3] cycloaddition of MBH carbonates of isatins with ß-enamino maleimides.

An efficient method to construct unique spiro[indoline-3,4'-pyrrolo[3,4-b]pyridines] was successfully developed via a DABCO promoted formal [3 + 3] cycloaddition reaction of MBH carbonates of isatins with ß-enamino maleimides in acetonitrile at room temperature. This reaction afforded multifunctionalized spiro[indoline-3,4'-pyrrolo[3,4-b]pyridines] and spiro[dipyrrolo[3,4-b:3',4'-e]pyridine-8,3'-indolines] in good yields and with lower diastereoselectivity. The relative configuration of the two diasteromers of the spiro compounds was clearly elucidated by the determination of eight single crystal structures.

A triple cascade approach towards the diastereoselective synthesis of spiro trans-decalinol scaffolds.

A [2+2+2] annulation reaction between cyclohexanone, ß-nitrostyrene and 2-arylidene-1,3-indanedione afforded multisubstituted spiro trans-decalinol derivatives in high chemical yields (up to 75%) and excellent diastereoselectivity (up to >20 : 1) at room temperature. This one-pot three-component system follows a triple cascade sequence via the Michael/nitro-Michael/Aldol process, resulting in the formation of three C-C bonds, five contiguous stereocenters as well as a spiro quaternary carbon center.

Preparation and characterization of an immunoaffinity column for the selective extraction of azaspiracids.

The presence of azaspiracids (AZAs) in shellfish may cause food poisoning in humans. AZAs can accumulate in shellfish filtering seawater that contains marine dinoflagellates such as Azadinium and Amphidoma spp. More than 60 AZA analogues have been identified, of which AZA1, AZA2 and AZA3 are regulated in Europe. Shellfish matrices may complicate quantitation by ELISA and LC-MS methods. Polyclonal antibodies have been developed that bind specifically to the C-26-C-40 domain of the AZA structure and could potentially be used for selectively extracting compounds containing this substructure. This includes almost all known analogues of AZAs, including AZA1, AZA2 and AZA3. Here we report preparation of immunoaffinity chromatography (IAC) columns for clean-up and concentration of AZAs. The IAC columns were prepared by coupling polyclonal anti-AZA IgG to CNBr-activated sepharose. The columns were evaluated using shellfish extracts, and the resulting fractions were analyzed by ELISA and LC-MS. The columns selectively bound over 300 ng AZAs per mL of gel without significant leakage, and did not retain the okadaic acid, cyclic imine, pectenotoxin and yessotoxin analogues that were present in the applied samples. Furthermore, 90-92% of the AZAs were recovered by elution with 90% MeOH, and the columns could be re-used without significant loss of performance.

Visible light-induced selenylative spirocyclization of biaryl ynones toward the formation of selenated spiro[5.5]trienones.

A visible-light induced dearomative cascade cyclization of biaryl ynones with diselenides under photocatalyst and external additive-free conditions has been explored, giving a series of selenated spiro[5.5]trienones in moderate to good yields. The Se-Se bond in diselenides could be cleaved to generate arylselenyl radicals under visible light irradiation in the absence of a photocatalyst. This protocol provides a facile and green method for the synthesis of spiro[5.5]trienones.