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The AgOAc-catalysed reaction of 3-nitro-2-phenyl-2H-chromenes with stabilized azomethine ylides generated from the imines based on methyl glycinate and arylaldehydes leads to a mixture of endo and endo' isomers of the corresponding chromeno[3,4-c]pyrrolidines in a ratio of 2.0-2.3:1 in 85-93% total yields as a result of a Michael addition/Mannich reaction sequence. In a similar reaction involving 2-trifluoromethyl-3-nitro-2H-chromenes, only endo chromeno[3,4-c]pyrrolidines are formed in 85-94% yields. 3-Nitro-2-(trichloromethyl)-2H-chromenes under the same conditions react with these azomethine ylides to give the corresponding Michael adducts as individual anti-isomers with the cis,trans-configuration of the chromane ring in 40-67% yields. Some 4-CF3-substituted chromano[3,4-c]pyrrolidines exhibited high cytotoxic activity against HeLa human cervical carcinoma cells.
The 1,3-dipolar cycloaddition of active azomethine ylide, which were generated in situ from addition reaction of α-amino acids with dialkyl acetylenedicarboxylates, with 2-arylidene-1,3-indanediones showed versatile regioselectivity and diastereoselectivity. The reaction of sarcosine and glycine afforded one kind of functionalized spiro[indene-2,3'-pyrrolidines]. The other primary α-amino acids such as alanine, phenylalanine and leucine gave another kind of regioisomeric spiro[indene-2,3'-pyrrolidines]. The cyclic α-amino acids resulted in the corresponding spiro[indene-2,2'-pyrrolizines] and [indene-2,6'-pyrrolo[1,2-c]thiazoles].
A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 μM) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-α-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an IC50 value of 3.6 mM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines.
Alkaloids are a class of natural products known to have wide pharmacological activity and have great potential for the development of new drugs to treat a wide array of pathologies. Some alkaloids have antiviral activity and/or have been used as prototypes in the development of synthetic antiviral drugs. In this study, eleven anti-coronavirus alkaloids were identified from the scientific literature and their potential therapeutic value against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is discussed. In this study, in silico studies showed an affinity of the alkaloids for binding to the receptor-binding domain of the SARS-CoV-2 spike protein, putatively preventing it from binding to the host cell. Lastly, several mechanisms for the known anti-coronavirus activity of alkaloids were discussed, showing that the alkaloids are interesting compounds with potential use as bioactive agents against SARS-CoV-2.
The design and synthesis of a small library of pyrrolidine iminocyclitol inhibitors with a structural similarity to 1,4-dideoxy-1,4-imino-D-arabitol (DAB-1) is reported. This library was specifically designed to gain a better insight into the mechanism of inhibition of glycosidases by polyhydroxylated pyrrolidines or iminocyclitols. Pyrrolidine-3,4-diol 15a and pyrrolidine-3,4-diol diacetate 15b had emerged as the most potent α-glucosidase inhibitors in the series. Docking studies performed with an homology model of α-glucosidase disclosed binding poses for compounds 15a, 15b, 16a, and 16a' occupying the same region as the NH group of the terminal ring of acarbose and suggest a closer and stronger binding of compound 15a and 15b with the enzyme active site residues. Our studies indicate that 2 or 5-hydroxyl substituents appear to be vital for high inhibitory activity.
A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal β-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.
Tropinone is the first intermediate in the biosynthesis of the pharmacologically important tropane alkaloids that possesses the 8-azabicyclo[3.2.1]octane core bicyclic structure that defines this alkaloid class. Chemical synthesis of tropinone was achieved in 1901 but the mechanism of tropinone biosynthesis has remained elusive. In this study, we identify a root-expressed type III polyketide synthase from Atropa belladonna (AbPYKS) that catalyzes the formation of 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid. This catalysis proceeds through a non-canonical mechanism that directly utilizes an unconjugated N-methyl-Δ1-pyrrolinium cation as the starter substrate for two rounds of malonyl-Coenzyme A mediated decarboxylative condensation. Subsequent formation of tropinone from 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid is achieved through cytochrome P450-mediated catalysis by AbCYP82M3. Silencing of AbPYKS and AbCYP82M3 reduces tropane levels in A. belladonna. This study reveals the mechanism of tropinone biosynthesis, explains the in planta co-occurrence of pyrrolidines and tropanes, and demonstrates the feasibility of tropane engineering in a non-tropane producing plant.
This study compared aroma compositions and sensory aroma attributes of raw and cooked Tenebrio molitor larvae (mealworms). Main sensory aroma attributes of raw mealworms were strong wet-soil-like, and less-intense oily, shrimp-like and sweet-corn-like. Quantitatively, the major aroma components of raw mealworms were hydrocarbons and aldehydes. As cooking proceeded, sweet-corn-like, roasted, and fried-oil-like sensory attributes were increasingly perceived with steaming, roasting, and frying, respectively. Some pyrazines, pyrrolidines, and carbonyls increased or appeared in roasted and fried mealworms. Partial least squares regression also showed differences in raw and cooked mealworms based on aroma components and their sensory attributes. Unlike raw mealworms, steamed mealworms had a relatively strong sweet-corn-like aroma attribute, which was related to 2,4,6-trimethyl-heptane, 2,4-dimethyl-dodecane, and 3,5-dihydroxy-6-methyl-2,3-dihydropyran-4-one. In comparison, roasted and fried mealworms exhibited roasted, shrimp-like, and fried-oil-like aroma attributes, which were associated with intermediates of the Maillard reaction and lipid oxidation, such as pyrazines, alcohols, and aldehydes. This result during thermal reactions was very similar to those of meat and/or seafood. The use of mealworms as a savory-type flavor enhancer can be expected.
Biomolecular recognition underlying drug-target interactions is determined by both binding affinity and specificity. Whilst, quantification of binding efficacy is possible, determining specificity remains a challenge, as it requires affinity data for multiple targets with the same ligand dataset. Thus, understanding the interaction space by mapping the target space to model its complementary chemical space through computational techniques are desirable. In this study, active site architecture of FabD drug target in two apicomplexan parasites viz. Plasmodium falciparum (PfFabD) and Toxoplasma gondii (TgFabD) is explored, followed by consensus docking calculations and identification of fifteen best hit compounds, most of which are found to be derivatives of natural products. Subsequently, machine learning techniques were applied on molecular descriptors of six FabD homologs and sixty ligands to induce distinct multivariate partial-least square models. The biological space of FabD mapped by the various chemical entities explain their interaction space in general. It also highlights the selective variations in FabD of apicomplexan parasites with that of the host. Furthermore, chemometric models revealed the principal chemical scaffolds in PfFabD and TgFabD as pyrrolidines and imidazoles, respectively, which render target specificity and improve binding affinity in combination with other functional descriptors conducive for the design and optimization of the leads.
Plant-specialized metabolism is complex, with frequent examples of highly branched biosynthetic pathways, and shared chemical intermediates. As such, many plant-specialized metabolic networks are poorly characterized. The N-methyl Δ1 -pyrrolinium cation is a simple pyrrolidine alkaloid and precursor of pharmacologically important tropane alkaloids. Silencing of pyrrolidine ketide synthase (AbPyKS) in the roots of Atropa belladonna (Deadly Nightshade) reduces tropane alkaloid abundance and causes high N-methyl Δ1 -pyrrolinium cation accumulation. The consequences of this metabolic shift on alkaloid metabolism are unknown. In this study, we utilized discovery metabolomics coupled with AbPyKS silencing to reveal major changes in the root alkaloid metabolome of A. belladonna. We discovered and annotated almost 40 pyrrolidine alkaloids that increase when AbPyKS activity is reduced. Suppression of phenyllactate biosynthesis, combined with metabolic engineering in planta, and chemical synthesis indicates several of these pyrrolidines share a core structure formed through the nonenzymatic Mannich-like decarboxylative condensation of the N-methyl Δ1 -pyrrolinium cation with 2-O-malonylphenyllactate. Decoration of this core scaffold through hydroxylation and glycosylation leads to mono- and dipyrrolidine alkaloid diversity. This study reveals the previously unknown complexity of the A. belladonna root metabolome and creates a foundation for future investigation into the biosynthesis, function, and potential utility of these novel alkaloids.
κ-Opioid receptors (KORs) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Two strategies were followed to introduce a F atom into the very potent class of cis,trans-configured perhydroquinoxalines. Whereas the synthesis of fluoroethyltriazole 2 has already been reported, fluoropyrrolidines 14 (1-[2-(3,4-dichlorophenyl)acetyl]-8-[(R)-3-fluoropyrrolidin-1-yl]-perhydroquinoxalines) were prepared by SN2 substitution of a cyclic sulfuric acid derivative with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F substituent. Fluoropyrrolidines 14 showed similar low-nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and β-arrestin assay, 14b (proton at the 4-position) exhibited similar KOR agonistic activity as U-50,488. The fluoro derivatives 14b and 14c (CO2CH3 at the 4-position) revealed KOR-mediated anti-inflammatory activity as CD11c and the IFN-γ production were reduced significantly in mouse and human dendritic cells. Compounds 14b and 14-c also displayed anti-inflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer [18F]-2 was prepared by 1,3-dipolar cycloaddition. In vivo, [18F]-2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [18F]-14c. Unfortunately, defluorination of [18F]-14c occurred in vivo, which was analyzed in detail by in vitro studies.
1,1-Dimethylhydrazine is used as a fuel for carrier rockets in the majority of countries implementing space exploration programs. Being highly reactive, 1,1-dimethylhydrazine easily undergoes oxidative transformation with the formation of a number of toxic, mutagenic, and teratogenic compounds. The use of high-resolution mass spectrometry for the study of the reaction of 1,1-dimethylhydrazine oxidation with hydrogen peroxide in aqueous solution allowed us to find hundreds of nitrogen-containing products of the CHN and CHNO classes, formed via radical processes. The vast majority of the compounds have not been previously considered as possible products of the transformation of rocket fuel. We have shown that the oxidation of 1,1-dimethylhydrazine proceeds in two stages, with the formation of a great number of complex unstable intermediates that contain up to ten nitrogen atoms. These intermediates are subsequently converted into final reaction products with a concomitant decrease in the average molecular weight. The intermediates and final products of the oxidative transformation of 1,1-dimethylhydrazine were characterised on the basis of their elemental composition using van Krevelen diagrams and possible compounds corresponding to the most intense peaks in the mass spectra were proposed. The data obtained are indicative of the presence of the following classes of heterocyclic nitrogen-containing compounds among the oxidation products: imines, piperidines, pyrrolidines, dihydropyrazoles, dihydroimidazoles, triazoles, aminotriazines, and tetrazines. The results obtained open up possibilities for the targeted search and identification of new toxic products of the degradation of rocket fuel and, as a result, a more adequate assessment of the ecological consequences of space-rocket activity.
The 7-nitro-2'-phenyl-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H)-dicarbonitrile (SIQPI), 2'-(4-cyanophenyl)-7-nitro-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H) dicarbonitrile (SIQPII), and 2'-(4-methoxyphenyl)-7-nitro-5',6',7',7a'-tetrahydrospiro[indeno[1,2-b]quinoxaline-11,3'-pyrrolizine]-1',1'(2'H)-dicarbonitrile (SIQPIII) were used to photocatalyze quinonoid phenolphthalein (QHIn) in aq-ACN-EtOH (mixed solvent) with NaCl and KCl electrolytes. SIQPI, II, and III spiroindenoquinoxaline pyrrolidines (SIQPs) as spiroheterocyclic photocatalysts alone could not reduce QHIn, but with the addition of electrolytes they are reduced via π cationic interactions (PCI). SIQPI, II, and III with NaCl reduced QHIn in 120, 28, and 50 min, unlike in 138, 58, and 63 min with KCl in mixed solvent. SIQPI, II, and III alone have reduced methylene blue (MB) in 120, 45, and 70 min, unlike in 110, 27, and 55 min with graphene oxide (GO), whereas with NaCl and KCl hey are reduced in 82, 36, and 44 min and 89, 43, and 50 min, respectively. SIQPs with GO had reduced MB in less time than the SIQPs alone, and SIQPs with NaCl had reduced QHIn in a shorter time than KCl. The electrolytes have cocatalyzed a reduction of dyes under sunlight (SL). The electrolytes have reduced a quinonoid structure (QS) and dyes by generating negative and positive (e - and h +) holes in a shorter time. SIQPII and magnetic nanoparticles (MNPs) of 58 nm with NaCl photocatalyzed the QHIn in 2880 min. The SIQPs also reduced methyl orange (MO) and brilliant blue R (BBR) at variable temperature (T) and pH range, whereas SIQPs have developed a molecular organic framework (MOF) with transition-metal salts (NiCl2, CrO3, KMnO4, CuSO4, and MnCl2) on photocatalysis.
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