ABSTRACT
Among all the malaria parasites, P. falciparum is the most predominant species which has developed drug resistance against most of the commercial anti-malarial drugs. Thus, finding a new molecule for the inhibition of enzymes of P. falciparum is the pharmacological challenge in present era. Herein, ten novel molecules have been designed with an amalgamation of cinchonidine, carbohydrate moiety and triazole ring by utilizing copper-catalyzed click reaction of cinchonidine-derived azide and clickable glycosyl alkynes. The molecular docking of developed molecules showed promising results for plasmepsin inhibition in the form of effective binding with target proteins.
Subject(s)
Antimalarials/chemical synthesis , Aspartic Acid Endopeptidases/antagonists & inhibitors , Cinchona Alkaloids/chemistry , Plasmodium falciparum/drug effects , Protease Inhibitors/chemical synthesis , Protozoan Proteins/antagonists & inhibitors , Antimalarials/chemistry , Antimalarials/pharmacology , Aspartic Acid Endopeptidases/chemistry , Catalysis , Cinchona Alkaloids/chemical synthesis , Cinchona Alkaloids/pharmacology , Click Chemistry , Copper/chemistry , Drug Design , Humans , Malaria, Falciparum/parasitology , Molecular Docking Simulation , Molecular Structure , Plasmodium falciparum/enzymology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protozoan Proteins/chemistry , Triazoles/chemistryABSTRACT
The development of efficient syntheses of complex natural products has long been a major challenge in synthetic chemistry. Designing cascade reactions and employing bioinspired transformations are an important and reliable means of achieving this goal. Presented here is a combination of these two strategies, which allow efficient asymmetric synthesis of the cinchona alkaloid (+)-cinchonidine. The key steps of this synthesis are a controllable, visible-light-induced photoredox radical cascade reaction to efficiently access the tetracyclic monoterpenoid indole alkaloid core, as well as a practical biomimetic cascade rearrangement for the indole to quinoline transformation. The use of stereoselective chemical transformations in this work makes it an efficient synthesis of (+)-cinchonidine.
Subject(s)
Cinchona Alkaloids/chemical synthesis , Cinchona Alkaloids/chemistry , Free Radicals/chemistry , Indoles/chemistry , Light , Oxidation-Reduction , Quinolines/chemistry , StereoisomerismABSTRACT
Novel cinchona alkaloid derived chiral phase-transfer catalysts enabled the highly chemo-, regio-, diastereo-, and enantioselective umpolung addition of trifluoromethyl imines to α,ß-unsaturated N-acyl pyrroles. With a catalyst loading ranging from 0.2 to 5.0â mol %, this new catalytic asymmetric transformation provides facile and high-yielding access to highly enantiomerically enriched chiral trifluoromethylated γ-amino acids and γ-lactams.
Subject(s)
Amino Acids/chemistry , Carboxylic Acids/chemistry , Imines/chemistry , Amino Acids/chemical synthesis , Catalysis , Cinchona Alkaloids/chemical synthesis , Cinchona Alkaloids/chemistry , Crystallography, X-Ray , Lactams/chemical synthesis , Lactams/chemistry , Molecular Conformation , Pyrroles/chemistry , StereoisomerismABSTRACT
The cinchona alkaloids are a privileged class of natural products and are endowed with diverse bioactivities. However, for compounds with the closely-related oxazatricyclo[4.4.0.0]decane ("oxazatwistane") scaffold, which are accessible from cinchonidine and quinidine by means of ring distortion and modification, biological activity has not been identified. We report the synthesis of an oxazatwistane compound collection through employing state-of-the-art C-H functionalization, and metal-catalyzed cross-coupling reactions as key late diversity-generating steps. Exploration of oxazatwistane bioactivity in phenotypic assays monitoring different cellular processes revealed a novel class of autophagy inhibitors termed oxautins, which, in contrast to the guiding natural products, selectively inhibit autophagy by inhibiting both autophagosome biogenesis and autophagosome maturation.
Subject(s)
Autophagy/drug effects , Cinchona Alkaloids/chemistry , Cinchona Alkaloids/pharmacology , Biological Products/chemical synthesis , Biological Products/chemistry , Biological Products/pharmacology , Cinchona/chemistry , Cinchona Alkaloids/chemical synthesis , HEK293 Cells , Humans , MCF-7 CellsABSTRACT
Fluorescent derivatives of the archetypal antimalarial quinine and its diastereomer, quinidine, suitable for cellular imaging have been synthesised by attaching the small extrinsic fluorophore, NBD. Interactions of these derivatives with ferriprotoporphyrin IX were evaluated to verify that insights generated by live-cell imaging were relevant to the parent molecules. These analogues are shown by confocal and super-resolution microscopy to accumulate selectively in Plasmodium falciparum. Localisation to the region corresponding to the digestive vacuole supports the putative primary role of these alkaloids as haemozoin inhibitors. Quantitative analysis revealed minimal accumulation within the nucleus, rejecting the disruption of DNA replication as a possible mode of action. While extensive localisation to phospholipid structures and associated organelles was observed, the analogues did not show evidence of association with neutral lipid bodies.
Subject(s)
Antimalarials/pharmacology , Cinchona Alkaloids/pharmacology , Erythrocytes/drug effects , Fluorescent Dyes/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Antimalarials/chemistry , Cinchona Alkaloids/chemical synthesis , Cinchona Alkaloids/chemistry , Erythrocytes/parasitology , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Hemeproteins/antagonists & inhibitors , Humans , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
A direct enantioselective vinylogous Mannich reaction of ketimines with γ-butenolide has been developed. Good yields and enantioselectivities were observed for the reaction of various ketimines by using a cinchona alkaloid amide/Zn(OTf)2 catalyst and Et3N. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts.
Subject(s)
4-Butyrolactone/analogs & derivatives , Cinchona Alkaloids/chemical synthesis , Imines/chemistry , Nitriles/chemistry , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , Amides , Cinchona Alkaloids/chemistry , Mesylates/chemistry , Molecular Structure , StereoisomerismABSTRACT
Nature is full of dimeric alkaloids of various types from many plant families, some of them with interesting biological properties. However, dimeric Cinchona alkaloids were not isolated from any species but were products of designed partial chemical synthesis. Although the Cinchona bark is amongst the sources of oldest efficient medicines, the synthetic dimers found most use in the field of asymmetric synthesis. Prominent examples include the Sharpless dihydroxylation and aminohydroxylation ligands, and dimeric phase transfer catalysts. In this article the syntheses of Cinchona alkaloid dimers and oligomers are reviewed, and their structure and applications are outlined. Various synthetic routes exploit reactivity of the alkaloids at the central 9-hydroxyl group, quinuclidine, and quinoline rings, as well as 3-vinyl group. This availability of reactive sites, in combination with a plethora of linker molecules, contributes to the diversity of the products obtained.
Subject(s)
Cinchona Alkaloids/chemistry , Molecular Structure , Cinchona Alkaloids/chemical synthesisABSTRACT
The straightforward synthesis of polystyrene-supported Chinchona alkaloids and their application in the asymmetric dimerization of ketenes is reported. Six different immobilized derivatives, consisting of three dimeric and two monomeric 9-O ethers, were prepared by "click" anchoring of soluble alkaloid precursors on to azidomethyl resins. The resulting insoluble polymer-bound (IPB) organocatalysts were employed for promoting the dimerization of in-situ generated ketenes. After opening of the ketene dimer intermediates with N,O-dimethylhydroxylamine, valuable Weinreb amides were eventually obtained in good yield (up to 81 %) and excellent enantiomeric purity (up to 96 % ee). All of the IPB catalysts could be recycled effectively without significant loss of activity and enantioselectivity. The extension to other asymmetric transformations (meso-anhydride desymmetrization and α-amination of 2-oxindoles) is also briefly discussed.
Subject(s)
Cinchona Alkaloids/chemistry , Polymers/chemistry , Alkynes/chemistry , Catalysis , Cinchona Alkaloids/chemical synthesis , Click Chemistry , Copper/chemistry , Cycloaddition Reaction , Dimerization , Ethylenes/chemistry , Ketones/chemistry , Polystyrenes/chemistry , StereoisomerismABSTRACT
A new class of 9-amino-(9-deoxy)cinchona alkaloid-derived chiral phase-transfer catalysts bearing amino groups was developed by using known cinchona alkaloids as the starting materials. Due to the transformation of the 9-hydroxyl group into a 9-amino functional group, the catalytic performances were significantly improved in comparison with the corresponding first generation phase-transfer catalysts, and excellent yields (92-99%) and high enantioselectivities (87-96% ee) were achieved in the benchmark asymmetric α-alkylation of glycine Schiff base. Based on the special contribution of the amino group to the high yield and enantioselectivity, the possible catalytic mechanism was conjectured.
Subject(s)
Cinchona Alkaloids/chemistry , Indole Alkaloids/chemistry , Quinuclidines/chemistry , Catalysis , Cinchona Alkaloids/chemical synthesis , Indole Alkaloids/chemical synthesis , Molecular Structure , Phase Transition , Quinuclidines/chemical synthesis , StereoisomerismABSTRACT
We report the discovery of novel N,N'-disubstituted cinchona alkaloids as efficient phase-transfer catalysts for the assembly of stereogenic quaternary centers. In comparison to traditional cinchona-alkaloid-based phase-transfer catalysts, these new catalysts afford substantial improvements in enantioselectivity and reaction rate for intramolecular spirocyclization reactions with catalyst loadings as low as 0.3â mol% under mild conditions.
Subject(s)
Cinchona Alkaloids/chemistry , Cinchona Alkaloids/chemical synthesis , Catalysis , Molecular Structure , Spiro Compounds , StereoisomerismABSTRACT
We describe two procedures for the synthesis of primary amines derived from 9-amino(9-deoxy)epi cinchona alkaloids, valuable catalysts used in the asymmetric functionalization of carbonyl compounds. The first approach allows the one-pot 5-g-scale syntheses of four cinchona-based analogs (1, 3, 5 and 7) from the alkaloids quinine (QN), quinidine (QD), dihydroquinine (DHQN) and dihydroquinidine (DHQD), respectively, performed by means of a Mitsunobu reaction to introduce an azide group, followed by reduction and hydrolysis. Demethylation of 1, 3, 5 and 7 with BBr(3) provided direct access to the bifunctional aminocatalysts 2, 4, 6 and 8. A second approach, more convenient for scale-up (tested to a 20-g scale), is also provided. In this second procedure, the azides, formed from the O-mesylated derivatives of QN and QD, are selectively reduced with LiAlH(4) to afford catalysts 1 and 3, whereas hydrogenation (Pd/C) provides 5 and 7. Demethylation of 1, 3, 5 and 7 using an alkylthiolate affords 2, 4, 6 and 8 in a process in which the less-expensive QN and QD are the only starting materials used.
Subject(s)
Chemistry Techniques, Synthetic/methods , Cinchona Alkaloids/chemical synthesis , Aluminum Compounds , Catalysis , Hydrogenation , Hydrolysis , Lithium Compounds , Molecular Structure , Oxidation-Reduction , Quinidine/analogs & derivatives , Quinidine/chemistry , Quinine/chemistryABSTRACT
Main-chain chiral quaternary ammonium polymers were successfully synthesized by the quaternization polymerization of cinchonidine dimer with dihalides. The polymerization occurred smoothly under optimized conditions to give novel type of main-chain chiral quaternary ammonium polymers. The catalytic activity of the polymeric chiral organocatalysts was investigated on the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester.
Subject(s)
Polymers/chemical synthesis , Quaternary Ammonium Compounds/chemical synthesis , Catalysis , Cinchona Alkaloids/chemical synthesis , Polymerization , Quaternary Ammonium Compounds/chemistry , Stereoisomerism , Sulfhydryl Compounds/chemical synthesisABSTRACT
We report the design and evaluation of a library of chiral bifunctional organocatalysts in which the distance between the catalytically active units can be systematically varied.
Subject(s)
Cinchona Alkaloids/chemistry , Catalysis , Cinchona Alkaloids/chemical synthesis , Models, Molecular , Molecular StructureABSTRACT
The study showed that a combination of an achiral silicon-based Lewis acid and chiral Lewis base, such as iodotrimethylsilane (TMSI) and cinchonine, generated a highly enantioselective catalyst system under solvent-free conditions which gave aromatic ß-amino ketones with up to >99% ee. Mechanistic studies demonstrate the enhanced asymmetric induction may be due to the combined and competitive activation of a carbonyl moiety of chalcone with cinchonine and the silicon-based Lewis acid in the aza-Michael reaction.
Subject(s)
Chalcones/chemistry , Cinchona Alkaloids/chemical synthesis , Silanes/chemistry , Silanes/chemical synthesis , Catalysis , Cinchona Alkaloids/chemistry , Ketones/chemical synthesis , Ketones/chemistry , Lewis Acids/chemistry , Molecular Structure , StereoisomerismSubject(s)
Anti-HIV Agents/chemical synthesis , Cinchona Alkaloids/chemistry , Imines/chemical synthesis , Nitriles/chemical synthesis , Thiourea/chemistry , Anti-HIV Agents/chemistry , Catalysis , Chemistry Techniques, Synthetic , Cinchona/chemistry , Cinchona Alkaloids/chemical synthesis , Halogenation , Imines/chemistry , Nitriles/chemistry , Stereoisomerism , Thiourea/chemical synthesisABSTRACT
Multifunctionalized tetrahydroindan derivatives with four stereocenters were constructed via two sequential Michael reactions between cyclic γ,δ-unsaturated-ß-ketoester and nitroalkenes initiated with 0.5-2 mol % of cinchona alkaloid based bifunctional organocatalysts and then with 1 equiv of tetramethylguanidine for cyclization. The desired products could be obtained in high yields (up to 99% yield) with excellent enantioselectivities (95-99% ee) as well as diastereoselectivities (up to >99:1 dr) even on a gram scale.
Subject(s)
Alkenes/chemistry , Cinchona Alkaloids/chemical synthesis , Cyclopentanes/chemistry , Indans/chemical synthesis , Nitro Compounds/chemistry , Catalysis , Cinchona Alkaloids/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Cyclization , Indans/chemistry , Molecular Structure , StereoisomerismABSTRACT
Immobilization strategy based on Huisgen 1,3-dipolar cycloaddition (click chemistry) of 10,11-didehydrocinchona tert-butylcarbamates to azido-grafted silica gels has been evaluated for preparation of novel chiral stationary phases (CSP 1-3). The resultant 1,2,3-triazole-linked CSPs were tested under various mobile phase conditions (polar organic and reversed phase mode) with a representative set of structurally diverse racemic acids including N-protected aminoacids, aromatic and aryloxycarboxylic acids as well as binaphthol phosphate. The chiral recognition performance of the C3-triazole-linked CSPs was found to mirror largely that of the known C3-thioether-linked CSP in terms of elution order, enantioselectivity and retention behavior. In an effort to assess the non-specific binding expressed as retention increment of these triazole-linked CSPs, the parent azidopropyl- and triazole-modified silica materials (thus not containing the chiral head ligand) were studied independently. Compared with the corresponding CSPs, the analyte retention on the azidopropyl control column was very low, and practically negligible on the corresponding triazole-modified reference column. Only minor losses in analyte retention behavior (<5%) were observed with triazole-linked CSPs after two month of continuous use with polar-organic and reversed-phase-type mobile phases, highlighting the excellent stability of the 1,2,3-triazole linker.
Subject(s)
Carbamates/chemistry , Cinchona Alkaloids/chemistry , Cinchona Alkaloids/chemical synthesis , Click Chemistry/methods , Chromatography , StereoisomerismABSTRACT
An easily prepared cinchona alkaloid derivative was found to be an effective organocatalyst in a direct, enantioselective aza-Mannich addition. By establishing a quaternary carbon stereocenter, a series of modified chiral 2-(ethylthio)-thiazolone derivatives have been obtained with excellent diastereo- and enantioselectivities. And these derivatives have been found to show anticancer activities against five different cancer cell lines using the MTT assay.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Cinchona Alkaloids/chemical synthesis , Thiazoles/chemical synthesis , Amino Acids/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Carbon , Catalysis , Cinchona Alkaloids/chemistry , Cinchona Alkaloids/pharmacology , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Molecular Structure , Stereoisomerism , Thiazoles/chemistry , Thiazoles/pharmacology , Tumor Cells, CulturedABSTRACT
Novel nucleoside-Cinchona alkaloid conjugates were synthesized using 'click' chemistry approach based on the copper(I) catalyzed Huisgen azide-alkyne cycloaddition. Two series of conjugates were prepared employing 3'-azido-3'-deoxythymidine (AZT) as the azide component and the four 10,11-didehydro Cinchona alkaloids as well as their 9-O-propargyl ethers as the alkyne components. All obtained conjugates showed strong fluorescence emission and some of them exhibited marked cytotoxic activity in vitro.