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Alberto Brandi - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of New Indolizidine Derivatives from 1‑(2-Quinolyl)-2-propen-1-ol
2018Co-Authors: Donatella Giomi, Jacopo Ceccarelli, Alberto BrandiAbstract:The four-step procedure involving bromination, reduction, and nucleophilic substitution via elimination/addition previously applied to 1-(2-pyridyl)-2-propen-1-ol for the synthesis of indolizidine systems has now been extended to 1-(2-quinolyl)-2-propen-1-ol allowing a general access to benzo-fused derivatives. For instance, (±)-benzo[e]Lentiginosine has been easily synthesized in an 18% overall yield
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a stereoselective synthesis of Lentiginosine
Journal of Organic Chemistry, 2016Co-Authors: Franca M Cordero, Carolina Vurchio, Alberto BrandiAbstract:A concise stereoselective synthesis of (−)-Lentiginosine, an iminosugar endowed with an interesting proapoptotic activity, has been accomplished using an enantiopure pyrroline N-oxide building block derived from d-tartaric acid. Key steps are a totally diastereoselective nucleophilic addition to the cyclic nitrone followed by a combination of two simultaneous and two tandem reactions occurring under the same conditions in a single laboratory operation. Natural (+)-Lentiginosine can be synthesized by the same method but starting from l-tartaric acid.
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A Stereoselective Synthesis of Lentiginosine
2016Co-Authors: Franca M Cordero, Carolina Vurchio, Alberto BrandiAbstract:A concise stereoselective synthesis of (−)-Lentiginosine, an iminosugar endowed with an interesting proapoptotic activity, has been accomplished using an enantiopure pyrroline N-oxide building block derived from d-tartaric acid. Key steps are a totally diastereoselective nucleophilic addition to the cyclic nitrone followed by a combination of two simultaneous and two tandem reactions occurring under the same conditions in a single laboratory operation. Natural (+)-Lentiginosine can be synthesized by the same method but starting from l-tartaric acid
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recent syntheses and biological activity of Lentiginosine and its analogues
Current Topics in Medicinal Chemistry, 2014Co-Authors: Franca M Cordero, Donatella Giomi, Alberto BrandiAbstract:(+)-Lentiginosine, a natural trans-1,2-dihydroxyindolizidine belonging to the class of iminosugars, is a potent inhibitor of amyloglucosidase, and a good inhibitor of Hsp90. The non-natural enantiomer, (-)-Lentiginosine, induces apoptosis on tumor cells of different origin and is poorly cytotoxic towards non-transformed cells. The significant biological activity of these compounds has resulted in the development of many synthetic approaches for their preparation. This review is an update of a previous survey and summarizes the most recent achievements on biological studies as well as total syntheses of Lentiginosine and trans-1,2-dihydroxyindolizidine analogues.
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synthesis of biotin and fluorescein labeled Lentiginosine
Arkivoc, 2014Co-Authors: Franca M Cordero, Antonella Minutolo, Beatrice Macchi, Carolina Vurchio, Alberto BrandiAbstract:The important proapoptotic activity of (–)-Lentiginosine, the enantiomer of a natural glycosidase inhibitor, associated with its low cytotoxicity, suggests the study of the unknown receptor responsible for the triggering of the proapoptotic cascade. To this purpose derivatives of (–)Lentiginosine 7 and 8, which contain the biotin moiety as an affinity label and fluorescein as fluorophore, have been synthesized. Significantly, the compounds maintain a good activity as the hydroxyLentiginosine precursor.
Francesca Cardona - One of the best experts on this subject based on the ideXlab platform.
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Docking calculation results.
2013Co-Authors: Fabrizio Dal Piaz, Franca M Cordero, Antonio Vassallo, Maria Giovanna Chini, Francesca Cardona, Claudio Pisano, Giuseppe Bifulco, Nunziatina De Tommasi, Alberto BrandiAbstract:Three dimensional models (A and B) of (+)-Lentiginosine (1, yellow) and (−)-Lentiginosine (2, green) with HSP90. The target molecule is depicted by sky blue ribbon and the crucial amino acids by cpk (by atom type: C, purple; O, red; N, dark blue, H, white).
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natural iminosugar Lentiginosine inhibits atpase and chaperone activity of hsp90
PLOS ONE, 2012Co-Authors: Fabrizio Dal Piaz, Franca M Cordero, Antonio Vassallo, Maria Giovanna Chini, Francesca Cardona, Claudio Pisano, Giuseppe Bifulco, Nunziatina De Tommasi, Alberto BrandiAbstract:Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and cell viability. The relevance of Hsp90 as a therapeutic target for numerous diseases states has prompted the identification and optimization of novel Hsp90 inhibitors as an emerging therapeutic strategy. We performed a screening aimed to identify novel Hsp90 inhibitors among several natural compounds and we focused on the iminosugar (+)-Lentiginosine, a natural amyloglucosidases inhibitor, for its peculiar bioactivity profile. Characterization of Hsp90 inhibition was performed using a panel of chemical and biological approaches, including limited proteolysis, biochemical and cellular assays. Our result suggested that the middle domain of Hsp90, as opposed to its ATP-binding pocket, is a promising binding site for new classes of Hsp90 inhibitors with multi-target anti-cancer potential.
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1r 2r 7s 8ar 1 2 7 trihydroxyindolizidine 7s oh Lentiginosine synthesis and proapoptotic activity
ChemPlusChem, 2012Co-Authors: Franca M Cordero, Antonella Minutolo, Sandro Grelli, Alberto Brandi, Beatrice Macchi, Francesca Cardona, Paola Bonanno, Bhushan B Khairnar, Antonio MastinoAbstract:An improved approach for the preparation of enantiopure 3,4- bis-tert-butoxypyrroline N-oxides is presented. Etherification of 1-benzylpyrrolidine-3,4-diol with tBuOAc/HClO4 and subsequent N-debenzylation and pyrrolidine oxidation with oxone affords the cyclic nitrone reliably and in superior yield. The enantiomer derived from d-tartaric acid was exploited in a modified synthesis of ( )-7S-OH-Lentiginosine. The activity of this trihydroxy indolizidine in inducing the apoptosis of tumour cell lines of lymphoid and epithelial origin is examined.
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the novel proapoptotic activity of nonnatural enantiomer of Lentiginosine
Glycobiology, 2010Co-Authors: Beatrice Macchi, Antonella Minutolo, Sandro Grelli, Franca M Cordero, Antonio Mastino, Francesca Cardona, Alberto BrandiAbstract:D-(−)-Lentiginosine [(−)-4], the nonnatural enantiomer ofthe iminosugar indolizidine alkaloid L-(+)-Lentiginosine,acts as apoptosis inducer on tumor cells of different origin,in contrast to its natural enantiomer. Although D-(−)-4 ex-hibited a proapoptotic activity towards tumor cells at levellower than the chemotherapeutic agent, SN38, it was lessproapoptotic towards normal cells and less cytotoxic. Ap-optosis induced by D-(−)-4 was caspase-dependent, asshown by the increased expression and activity of cas-pase-3 and -8 in treated cells, and by inhibition followingtreatment with the pan caspase inhibitor, ZVAD-FMK.This study highlighted how a natural iminosugar alkaloidand its synthetic enantiomer, which were simply known fortheir inhibition against a fungal glucoamylase, could be-have in a complete different way when tested towards cellgrowth and death of cells of different origin.Keywords: apoptosis/cytotoxicity/iminosugars/indolizidinealkaloids/LentiginosineIntroductionIminosugars are sugar mimics characterized by a polyhydroxy-lated structure containing a nitrogen in the ring, namelypolyhydroxylated piperidine, pyrrolidine, pyrrolizidine, indoli-zidine and nortropane alkaloids (Asano et al. 2000). More thanone hundred of these compounds have been isolated fromplants and microorganisms and have been extensively studiedas glycosidase inhibitors (Watson et al. 2001), (Figure 1).The inhibition of glycosidases, key enzymes in the biosyn-thesis of glycoproteins, can have a profound effect on qualitycontrol, maturation, transport and secretion of glycoproteinsand can alter cell–cell or cell–virus/bacteria recognition pro-cesses (Asano 2003). Aberrant glycosylation of glycoproteinsand glycolipids, in which glycosidases are involved, was re-ported to be one of the molecular changes that accompanymalignant transformation and growth of tumor cells (Hakomori1985). Swainsonine (2), a natural inhibitor of Golgi α-manno-sidase II, has shown the ability to inhibit tumor cell growth andmetastasis (Mohla et al. 1990), and it was assayed also in phaseI clinical trials (Goss et al. 1997). Castanospermine (3) and itsester and salt derivatives have also shown to exhibit inhibitionof tumor growth and of tumor metastasis (Pili et al. 1995; Yeeet al. 1997). The possible application of iminosugars as carbo-hydrate processing enzyme inhibitors for cancer therapy hasbeen recently reviewed (Wrodnigg et al. 2008; Nishimura2007; Vogel et al. 2007).Our interest focused in particular on Lentiginosine (4), iso-lated in 1990 from the leaves ofAstragalus lentiginosus(Pastuszak et al. 1990), which was found to inhibit amyloglu-cosidase at levels comparable to those of castanospermine.There has been a long dispute around the absolute configura-tion of natural Lentiginosine (Cardona et al. 2007), that wascleared up with the synthesis of both enantiomers togetherwith the study of their inhibitory activity (Brandi et al.1995; Goti et al. 1996). Natural Lentiginosine was assignedas dextrorotatory. In fact, the synthetic L-(+)-Lentiginosine(4) showed an inhibition activity of (Ki = 2 μM) that was fivetimes stronger than that reported for the sample isolated fromnatural source and 35 times higher than that of D-(−)lentigino-sine. As a consequence, the synthetic L-(+)-Lentiginosine (4)was twice as potent as castanospermine in its inhibition ofamyloglucosidase.In order to give a rationale for the high activity of lenti-ginosine in spite of its simple structure (only two hydroxylgroups instead of the four hydroxyl groups of its deoxyno-jirimycin and castanospermine analogues), a computationalstudy was also performed by molecular dynamic simulationof the complex of 1-deoxynojirimycin (1) with the enzyme(for which the X-ray structure was available) with respect tothe complex with (+)-Lentiginosine-enzyme. This study re-vealed the ability of the two hydroxyl groups ofLentiginosine, (+)-4, to establish key interactions within theenzyme cavity (Cardona et al. 1997).Due to the activity of swainsonine and castanospermine to-wards cell growth and inhibition of tumor metastasis, weenvisaged that also the biological properties of (+)-4 couldgo far beyond its fungal amyloglucosidase inhibition activity.A test of (+)-4 and (−)-4 on human mixed lymphocytes wasinitially carried out. Both enantiomers slightly increased cellproliferation at low concentration (5 μM), but at higher con-500
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Lentiginosine a potent and selective inhibitor of amyloglucosidase synthetic efforts and disputes on its absolute configuration
ChemInform, 2007Co-Authors: Francesca Cardona, Andrea Goti, Alberto BrandiAbstract:(+)-Lentiginosine is a powerful and selective inhibitor of amyloglucosidases and has become a reference compound in the field among derivatives related to imino sugars. The present review focuses on the several total syntheses of this alkaloid, which rely on either a chiral pool or on enantioselective approaches that have appeared since its isolation in 1990. A summary of biological assays and molecular dynamic studies which allowed the assignment of the correct absolute configuration of natural (+)-Lentiginosine is reported.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Andrea Goti - One of the best experts on this subject based on the ideXlab platform.
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Lentiginosine a potent and selective inhibitor of amyloglucosidase synthetic efforts and disputes on its absolute configuration
ChemInform, 2007Co-Authors: Francesca Cardona, Andrea Goti, Alberto BrandiAbstract:(+)-Lentiginosine is a powerful and selective inhibitor of amyloglucosidases and has become a reference compound in the field among derivatives related to imino sugars. The present review focuses on the several total syntheses of this alkaloid, which rely on either a chiral pool or on enantioselective approaches that have appeared since its isolation in 1990. A summary of biological assays and molecular dynamic studies which allowed the assignment of the correct absolute configuration of natural (+)-Lentiginosine is reported.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
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new concise total synthesis of Lentiginosine and some structural analogues
Journal of Organic Chemistry, 2005Co-Authors: Francesca Cardona, Pierre Vogel, Guillermo Moreno, Francesco Guarna, Catherine Schuetz, Pedro Merino, Andrea GotiAbstract:An efficient and concise total synthesis of (+)-Lentiginosine (1) starting from an L-tartaric acid-derived nitrone using organometallic addition, indium-catalyzed reduction, and ring-closing metathesis reaction as the key steps is reported. Structural analogues of (+)-1 have been also synthesized, and their inhibitory activity toward 22 commercially available glycosidases has been evaluated.
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polyhydroxypyrrolidine glycosidase inhibitors related to Lentiginosine
Journal of Carbohydrate Chemistry, 2000Co-Authors: Francesca Cardona, Andrea Goti, Sylviane Picasso, Pierre Vogel, Alberto BrandiAbstract:(+)-Lentiginosine (14) and (7R)-7-hydroxyLentiginosine (26), powerful inhibitors of amyloglucosidases, and their enantiomers were obtained in high overall yields by a multistep synthesis involving 1,3-dipolar cycloaddition of enantiopure tartaric acid derived pyrroline N-oxides. Structurally related (S,S)-3,4-dihydroxypyrrolidines 29-33 were synthesized as simpler models and tested towards 24 glycosidases.
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A Straightforward Route to Enantiopure Pyrrolizidines and Indolizidines by Cycloaddition to Pyrroline N-Oxides Derived from the Chiral Pool*
1999Co-Authors: Andrea Goti, Franca M Cordero, Stefano Cicchi, Valentina FediAbstract:Abstract: Enantiomerically pure, five membered cyclic nitrones, easily obtained in large amounts from protected hydroxyacids and aminoacids such as D- and L-tartaric, L-malic, and L-aspartic acids, give cycloaddition reactions with a good diastereocontrol. The adducts of L-malic and L-aspartic acids derived from addition of nitrones to dimethyl maleate and γ-crotonolactone were easily converted into enantiopure pyrrolizidinones, which can be transformed into polyhydroxypyrrolidines or polyhydroxypyrrolizidines, both interesting compounds as potential glycosidase inhibitors. The method is suitable for natural products synthesis as exemplified by a straightforward and convenient access to the pyrrolizidine alkaloid necine base (–)-hastanecine, as well as to indolizidine alkaloids, i.e. (+)Lentiginosine
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molecular dynamics simulations on the complexes of glucoamylase ii 471 from aspergillus awamori var x100 with 1 deoxynojirimycin and Lentiginosine
Journal of Molecular Modeling, 1997Co-Authors: Francesca Cardona, Alberto Brandi, Andrea Goti, Maria Scarselli, Neri Niccolai, Stefano ManganiAbstract:Molecular dynamics (MD) simulations on the complexes of glucoamylase II (471) from Aspergillus awamori var. X100 with two powerful inhibitors, 1-deoxynojirimycin and (+)-Lentiginosine, have been performed, in order to build a model for these complexes in solution and to clarify the structure-activity relationship. MD calculations were carried out for 105 ps, over a 15 A sphere centered on the inhibitors. A 8 A residue-based cut-off was used, and the calculations were performed with explicit inclusion of solvent molecules. The MD structure of the complex 1-deoxynojirimycin-glucoamylase shows only minor deviations from the available X-ray structure. The MD structure of the complex of (+)-Lentiginosine-glucoamylase, obtained by docking the inhibitor into the active site, suggests us a suitable orientation for the molecule into the enzyme cavity, which can rationalize the high inhibition activity found for (+)-Lentiginosine towards amyloglucosidase from A. niger.
Dilip D Dhavale - One of the best experts on this subject based on the ideXlab platform.
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efficient synthesis of 1 8 8a tri epi swainsonine 1 2 di epi Lentiginosine 9a epi homocastanospermine and 9 deoxy 9a epi homocastanospermine from a d glucose derived aziridine carboxylate and study of their glycosidase inhibitory activities
Organic and Biomolecular Chemistry, 2008Co-Authors: K Ajish S Kumar, Vinod D Chaudhari, Dilip D DhavaleAbstract:The utility of a D-glucose-derived aziridine carboxylate was demonstrated for the synthesis of polyhydroxylated quinolizidine and indolizidine alkaloids. The chemoselective reduction of 1 followed by two-carbon homologation by the Wittig reaction afforded γ,δ-aziridino-α,β-unsaturated ester9, which on regioselective nucleophilic aziridine ring opening either by using water as a nucleophile or hydrogenation afforded δ-lactams 11/16—true synthons for the synthesis of four structurally different iminosugars, namely quinolizidine alkaloids5b/5c, swainsonine 6b and Lentiginosine 7b analogues. Glycosidase inhibitory activities of these iminosugars were investigated.
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synthesis of Lentiginosine its 8a epimer and dihydroxylated pyrrolizidine alkaloid from d glucose
Tetrahedron, 2006Co-Authors: Vinod D Chaudhari, K Ajish S Kumar, Dilip D DhavaleAbstract:Abstract The d -glucose derived α,β-unsaturated ester 5 on 1,2-acetonide deprotection, oxidative diol cleavage followed by treatment with N-benzylamine in the presence of NaBH3CN undergoes reductive amination and a concomitant intramolecular conjugate addition reaction leading to the formation of dihydroxypyrrolidine-ester 6a and monohydroxypyrrolidine-γ-lactone 6b . Intermediates 6a and 6b were efficiently converted to (−)-Lentiginosine 3a , its 8a-epimer 3b , and pyrrolizidine azasugar 4 in good overall yield.
Yashwant D Vankar - One of the best experts on this subject based on the ideXlab platform.
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synthesis of pyrrolidine iminosugars Lentiginosine swainsonine and their 8a epimers from d glycals
RSC Advances, 2014Co-Authors: Alafia A Ansari, Yashwant D VankarAbstract:Synthesis of pyrrolidine iminosugars has been described from D-glycals via dihydroxylation, oxidative cleavage and double nucleophilic displacement as the key steps. The pyrrolidines obtained have been utilized for the synthesis of important bicyclic iminosugars, viz. (−)-Lentiginosine and (−)-swainsonine and their 8a-epimers, which are known to be glycosidase inhibitors.
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an improved method of ring closing metathesis in the presence of basic amines application to the formal synthesis of Lentiginosine and other piperidines and carbamino sugar analogs
Tetrahedron Letters, 2011Co-Authors: Rima Lahiri, Hari Prasad Kokatla, Yashwant D VankarAbstract:A generalized method for performing ring closing metathesis in the presence of basic amines has been established and successfully used in the formal synthesis of (+)-Lentiginosine as well as some valuable intermediates for the synthesis of several other azasugars and aminocyclitols.
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total synthesis of Lentiginosine from d glucose
Tetrahedron Letters, 2008Co-Authors: Mohammad A Alam, Yashwant D VankarAbstract:Abstract A total synthesis of (+)-Lentiginosine, a potent and selective amyloglucosidase inhibitor, is reported from a d -glucose-derived epoxide in 38% overall yield. In this synthesis, ambient conditions and readily available starting materials and reagents are used.