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Maurizio Ricci - One of the best experts on this subject based on the ideXlab platform.
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structurAl studies of LeucinostAtin A And its boc Aib leu leu Aib ome tetrApeptide frAgment
International Journal of Peptide and Protein Research, 2009Co-Authors: Gianni Vertuani, Maurizio Ricci, C Falcomer, M Boggian, G Pochetti, S Cerrini, C Ross, Angelo ScatturinAbstract:The conformAtionAl behAviour of the peptide Antibiotic LeucinostAtin A hAs been studied in solvents of different polArity using circulAr dichroism (CD) And infrAred (i.r.) Absorption. I.r. studies provided evidence of An intrAmoleculArly hydrogen-bonded structure in CDC3 while CD studies suggested A helicAl conformAtion in LeucinostAtin A in lipophilic solvents. The tetrApeptide Boc-Aib-Leu-Leu-Aib-OMe, A frAgment of LeucinostAtin A, wAs Also studied both in solution And in solid stAte using X-rAy diffrAction. The crystAl structure shows thAt the peptide bAckbone folds into A right-hAnded 310-helicAl conformAtion stAbilized by two intrAmoleculAr 4 1 hydrogen bonds. The spectroscopic AnAlysis in solution is consistent with the conformAtion found in solid stAte. CrystAl dAtA: orthorhombic, P212121, A= 23.583, b= 15.791, c= 9.554 A Z = 4; the finAl R And Rw Are 0.090 And 0.126, respectively.
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LeucinostAtin A loAded nAnospheres chArActerizAtion And in vivo toxicity And efficAcy evAluAtion
International Journal of Pharmaceutics, 2004Co-Authors: Maurizio Ricci, Paolo Blasi, Stefano Giovagnoli, Luana Perioli, Claudia Vescovi, Carlo RossiAbstract:LeucinostAtin A (Leu-A) is A nonApeptide exerting A remArkAble Activity especiAlly AgAinst CAndidA AlbicAns And Cryptococcus neoformAns; nevertheless, its employment is limited due its toxicity. Therefore, we recently developed liposomAl formulAtions, As suitAble delivery systems, in order to increAse its therApeutic index. However, liposomes present disAdvAntAges relAted to their long-term instAbility. For this reAson poly(lActic-co-glycolic) nAnospheres (NS) were chosen As AlternAtive colloidAl cArriers for Leu-A delivery. NS were formulAted by spontAneous emulsificAtion solvent diffusion method. This study investigAtes the effects of different pArAmeters on drug encApsulAtion efficiency And pArticle size As well. The best prepArAtion obtAined wAs Also chArActerized for its in vitro releAse, in vivo Acute toxicity (LD50), And effectiveness AgAinst C. AlbicAns in mice. In vitro releAse wAs performed over 100 h And resulted sufficiently sustAined with more thAn 93% of the peptide releAsed. Acute toxicity showed thAt the LD50 wAs increAsed more thAn 18-fold And the study on systemic cAndidiAsis models reveAled high effectiveness of the NS in reducing either the growth of fungAl colonies in infected mice liver or in the mortAlity index. In conclusion, we cAn propose thAt Leu-A loAded NS could represent A new promising therApeutic system AgAinst CAndidA infection.
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AntimicrobiAl nonApeptide LeucinostAtin A dependent effects on the physicAl properties of phospholipid model membrAnes
Journal of Colloid and Interface Science, 2000Co-Authors: Massimo Fresta, Maurizio Ricci, Carlo Rossi, Pio Maria Furneri, Giovanni PuglisiAbstract:AbstrAct The influence exerted by the AntimicrobiAl And Antimicotic nonApeptide LeucinostAtin A (Leu A) on A biologicAl membrAne model mAde up of dipAlmitoylphosphAtidylcholine (DPPC) wAs investigAted. Drug–membrAne interActions, studied by meAns of differentiAl scAnning cAlorimetry And Fourier-trAnsform infrAred spectroscopy, depend on the behAvior of the molecule which positions its hydrophilic pArt towArd the bilAyer phospholipid polAr heAds, while it inserts its hydrophobic portion into the membrAne phospholipid Acyl chAin moiety. CAlorimetric experiments showed thAt the peptide undergoes self-AggregAtion within the bilAyer structure when present At molAr frActions higher thAn 0.03. Peptide–membrAne interActions As A function of time were AnAlyzed As well. The lAtter demonstrAted thAt Leu A inserts rApidly into the outer bilAyers of DPPC membrAnes. 45 CA 2+ uptAke by DPPC vesicles gAve A reAson for the ionophoric Activity of Leu A AgAinst both mouse thymocytes And ArtificiAl membrAnes, which seems to be correlAted to the self-Assembling property of the peptide within the bilAyers.
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Liposome-bAsed formulAtions for the Antibiotic nonApeptide LeucinostAtin A: Fourier trAnsform infrAred spectroscopy chArActerizAtion And in vivo toxicologic study
AAPS PharmSciTech, 2000Co-Authors: Maurizio Ricci, Paola Sassi, Claudio Nastruzzi, Carlo RossiAbstract:LeucinostAtin-A is A nonApeptide isolAted from PAecilomyces mArquAndii PAecilomyces lilAcinus A257, And Acremonium sp. , exerting remArkAble phytotoxic, AntibActeriAl (especiAlly AgAinst GrAm-positive) And Antimycotic Activities. With the Aim to find AlternAtive formulAtion for in vivo AdministrAtion, A number of LeucinostAtin-A—loAded liposomAl formulAtions hAve been prepAred And chArActerized. Both lArge unilAmellAr vesicles And multilAmellAr vesicles consisting of synthetic And nAturAl lipids were evAluAted. In Addition, to determine the nAture of peptide-membrAne interActions And the stAbility of liposomes loAded with LeucinostAtin-A, A Fourier TrAnsform InfrAred Spectroscopy study wAs performed. The results suggest thAt the mode of interAction of the peptide is dependent on its concentrAtion, on bilAyer fluidity, And on liposome type. FinAlly, the LD_50 of both free And liposome-delivered LeucinostAtin-A wAs determined in mice. These results suggest thAt the incorporAtion of LeucinostAtin-A into liposomes mAy result in decreAsed LeucinostAtin-A toxicity, As the intrAperitoneAl AdministrAtion of LeucinostAtin-A—loAded liposomes reduced the LD_50 of LeucinostAtin-A 15-fold.
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structure Activity studies on chemicAlly modified homologues of the Antibiotic phytotoxic LeucinostAtin A
The Journal of Antibiotics, 1995Co-Authors: Gianni Vertuani, Maurizio Ricci, M Boggian, Angelo Scatturin, Meli B Balbocchino, L Tuttobello, Carlo RossiAbstract:The synthesis And A conformAtionAl study of A number of homologues of the well known Antibiotic, phytotoxic LeucinostAtin A Are reported. The circulAr dichroism of All the compounds Are discussed. Some conclusions on the SAR of these compounds Are drAwn. The influence of the AlphA-helicAl conformAtion And/or the increAsed lipophile chArActer on their interesting biologicAl Activities is emphAsized.
Masakatsu Shibasaki - One of the best experts on this subject based on the ideXlab platform.
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cAtAlytic Asymmetric totAl synthesis of LeucinostAtin A
Chemical Record, 2021Co-Authors: Takumi Watanabe, Hikaru Abe, Masakatsu ShibasakiAbstract:This review describes our efforts towArd Achieving cAtAlytic Asymmetric totAl synthesis of LeucinostAtin A, A compound thAt interferes with the tumor-stromA interAction. The synthesis utilizes four cAtAlytic Asymmetric reActions, including direct-type reActions exemplified by high Atom-economy, And three C-C bond forming reActions. Thorough AnAlysis of the NMR dAtA, HPLC profiles, And biologic Activity led us to unAmbiguously revise the Absolute configurAtion regArding the 6-position of the AHMOD residue side chAin from S (reported) to R. Other exAmples of previously reported importAnt studies on the stereoselective synthesis of HyLeu And AHMOD Are Also described.
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structure Activity relAtionship study of LeucinostAtin A A modulAtor of tumor stromA interAction
Tetrahedron, 2018Co-Authors: Hikaru Abe, Manabu Kawada, Chiharu Sakashita, Takumi Watanabe, Masakatsu ShibasakiAbstract:AbstrAct Structure-Activity relAtionship study of LeucinostAtin A, A nAturAl nonApeptide, wAs performed to gAin insight into the structurAl requirements for LeucinostAtin A to exhibit AntiproliferAtive Activity AgAinst DU-145 prostAte cAncer cells under cocultured conditions with the corresponding stromAl cells. Twenty truncAted peptide AnAlogs of LeucinostAtin A reveAled thAt the nonApeptide structure As A whole is essentiAl for the biologicAl Activity. AlAnine scAnning demonstrAted the importAnce of some of the Amino Acid components, including hydroxyleucine And the second leucine from the N-terminus. Two of the three Aminoisobutyric Acids could be substituted with one of the enAntiomers of AlAnine, cleArly demonstrAting thAt eAch methyl group in these portions hAs A distinct influence on the growth-inhibitory Activity.
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cAtAlytic Asymmetric totAl synthesis And stereochemicAl revision of LeucinostAtin A A modulAtor of tumor stromA interAction
Chemistry: A European Journal, 2017Co-Authors: Hikaru Abe, Manabu Kawada, Chiharu Sakashita, Takumi Watanabe, Hitoshi Ouchi, Masakatsu ShibasakiAbstract:TotAl synthesis of LeucinostAtin A, A modulAtor of tumor-stromA interActions, using An Asymmetric cAtAlysis, A nitroAldol reAction, thioAmide-Aldol reAction, Strecker-type reAction, And Alcoholysis of 3-methylglutAric Anhydride, is described. We demonstrAted the ApplicAbility of the estAblished cAtAlytic Asymmetric process to the synthesis of molecules with A complex structure. CAreful AnAlysis of the NMR dAtA, HPLC profiles, And biologicAl Activity reveAled thAt the correct structure of LeucinostAtin A is the epimeric form of the reported structure; the secondAry Alcohol within the AHMOD residue hAs An R-configurAtion.
Gary A Strobel - One of the best experts on this subject based on the ideXlab platform.
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Acremonium sp A LeucinostAtin A producing endophyte of europeAn yew tAxus bAccAtA
Plant Science, 1997Co-Authors: Gary A Strobel, Richard M Torczynski, Arthur P BollonAbstract:AbstrAct Acremonium sp. occurs As An endophyte in EuropeAn yew ( TAxus bAccAtA ). It produces A series of peptide AntifungAl-AnticAncer Agents known As the LeucinostAtins. LeucinostAtin A is especiAlly Active AgAinst the oomycetous—plAnt pAthogenic fungus— Pythium ultimum with An effective 1 dAy 50% inhibitory concentrAtion of μ mol. LeucinostAtin A Also possesses Activity AgAinst certAin humAn cAncer cell lines, for instAnce, its IC 50 vAlue is 2.3 nM for breAst cAncer cell line BT-20 contrAsted with 640 nM for A normAl mAmmAry cell line. LeucinostAtin A cAn be effectively prepAred rAdiolAbeled viA the AdministrAtion of [ 14 C]leucine or [ 14 C]pyruvAte to stAnding cultures of Acremonium sp. The dAtA point to A biologicAl role of AntifungAl Agents being produced by endophytic fungi As A meAns to Allow for their survivAl. Also, since AntifungAl Agents such As tAxol And LeucinostAtin A Are produced by some endophytic fungi, oomycetes such As P. ultimum mAy serve As initiAl screening tools for AnticAncer Agents.
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glucosylAtion of the peptide LeucinostAtin A produced by An endophytic fungus of europeAn yew mAy protect the host from LeucinostAtin toxicity
Chemistry & Biology, 1997Co-Authors: Gary A Strobel, W M HessAbstract:AbstrAct BAckground: Yew species ( TAxus spp. ) throughout the world Are hosts to hundreds, or perhAps thousAnds, of endophytic orgAnisms. Most commonly, these orgAnisms Are fungi, living in A commensAl or A symbiotic relAtionship with their host plAnt, so the plAnts exhibit little or no outwArd evidence thAt they Are supporting these microorgAnisms. Little is known About Any of the biochemicAl mechAnisms thAt mediAte the interActions between the yew host And its AssociAted microbes. We feel thAt such informAtion mAy not only contribute to our understAnding of endophyte-tree biology, but Also mAy provide novel phArmAceuticAl leAds, becAuse some of the compounds produced by these endophytes hAve demonstrAted phArmAcologicAl Activities. Results: , Acremonium sp. wAs isolAted As An endophytic fungus of the EuropeAn yew, TAxus bAccAtA . Entry of Acremonium sp. into the plAnt mAy proceed viA invAsion of nAturAl openings such As stomAtA. The relAtionship between Acremonium sp. And T. bAccAtA mAy be A symbiotic one, becAuse no symptoms Are seen when TAxus mediA p.v. Hicksii is inoculAted with this fungus. In culture, the fungus mAkes LeucinostAtin A, A peptide with phytotoxic, AnticAncer And AntifungAl properties. Although this peptide cAuses necrotic symptoms in mAny non-host plAnts And other cell types, it cAuses no visible symptoms in the host plAnt. T. bAccAtA And severAl other plAnts hAve A UDP glucose: LeucinostAtin A glucosyl trAnsferAse thAt cAtAlyzes the production of LeucinostAtin A β di-O-glucoside from LeucinostAtin A. This glucoside, Also mAde by the fungus, hAs A lower bioActivity AgAinst plAnts, fungi And A breAst cAncer cell line, BT-20, thAn LeucinostAtin A. Conclusions: LeucinostAtin A mAy be one of severAl potentiAlly toxic peptides produced by Acremonium sp. thAt contribute to the defense of the host, thereby preserving the fungus' own biologicAl niche. The host plAnt is relAtively immune to LeucinostAtin A becAuse it hAs An enzyme which trAnsfers two glucosyl residues to LeucinostAtin A, mArkedly reducing the peptide's bioActivity. Our results suggest thAt glucosylAtion reActions mAy plAy A more generAl role in plAnt defenses, especiAlly AgAinst toxin-mediAted diseAse development.
Manabu Kawada - One of the best experts on this subject based on the ideXlab platform.
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structure Activity relAtionship study of LeucinostAtin A A modulAtor of tumor stromA interAction
Tetrahedron, 2018Co-Authors: Hikaru Abe, Manabu Kawada, Chiharu Sakashita, Takumi Watanabe, Masakatsu ShibasakiAbstract:AbstrAct Structure-Activity relAtionship study of LeucinostAtin A, A nAturAl nonApeptide, wAs performed to gAin insight into the structurAl requirements for LeucinostAtin A to exhibit AntiproliferAtive Activity AgAinst DU-145 prostAte cAncer cells under cocultured conditions with the corresponding stromAl cells. Twenty truncAted peptide AnAlogs of LeucinostAtin A reveAled thAt the nonApeptide structure As A whole is essentiAl for the biologicAl Activity. AlAnine scAnning demonstrAted the importAnce of some of the Amino Acid components, including hydroxyleucine And the second leucine from the N-terminus. Two of the three Aminoisobutyric Acids could be substituted with one of the enAntiomers of AlAnine, cleArly demonstrAting thAt eAch methyl group in these portions hAs A distinct influence on the growth-inhibitory Activity.
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cAtAlytic Asymmetric totAl synthesis And stereochemicAl revision of LeucinostAtin A A modulAtor of tumor stromA interAction
Chemistry: A European Journal, 2017Co-Authors: Hikaru Abe, Manabu Kawada, Chiharu Sakashita, Takumi Watanabe, Hitoshi Ouchi, Masakatsu ShibasakiAbstract:TotAl synthesis of LeucinostAtin A, A modulAtor of tumor-stromA interActions, using An Asymmetric cAtAlysis, A nitroAldol reAction, thioAmide-Aldol reAction, Strecker-type reAction, And Alcoholysis of 3-methylglutAric Anhydride, is described. We demonstrAted the ApplicAbility of the estAblished cAtAlytic Asymmetric process to the synthesis of molecules with A complex structure. CAreful AnAlysis of the NMR dAtA, HPLC profiles, And biologicAl Activity reveAled thAt the correct structure of LeucinostAtin A is the epimeric form of the reported structure; the secondAry Alcohol within the AHMOD residue hAs An R-configurAtion.
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LeucinostAtin A inhibits prostAte cAncer growth through reduction of insulin like growth fActor i expression in prostAte stromAl cells
International Journal of Cancer, 2009Co-Authors: Manabu Kawada, Hiroyuki Inoue, Shunichi Ohba, Tohru Masuda, Isao Momose, Daishiro IkedaAbstract:TArgeting stromA in tumor tissues is An AttrActive new strAtegy for cAncer treAtment. We developed in vitro coculture system, in which the growth of humAn prostAte cAncer DU-145 cells is stimulAted by prostAte stromAl cells (PrSC) through insulin-like growth fActor I (IGF-I). Using this system, we hAve been seArching for smAll molecules thAt inhibit tumor growth through modulAtion of tumor-stromAl cell interActions. As A result, we hAve found thAt LeucinostAtins And Atpenins, nAturAl AntifungAl Antibiotics, inhibit the growth of DU-145 cells cocultured with PrSC more strongly thAn thAt of DU-145 cells Alone. In this study we exAmined the Antitumor effects of these smAll molecules in vitro And in vivo. When DU-145 cells were coinoculAted with PrSC subcutAneously in nude mice, LeucinostAtin A wAs found to significAntly suppress the tumor growth more thAn Atpenin B. The Antitumor effect of LeucinostAtin A in vivo wAs not obtAined AgAinst the tumors of DU-145 cells Alone. RT-PCR experiments reveAled thAt LeucinostAtin A specificAlly inhibited IGF-I expression in PrSC without effect on expressions of other IGF Axis molecules. LeucinostAtins And Atpenins Are known to AbrogAte mitochondriAl functions. However, when we used mitochondriAl DNA-depleted, pseudo-rho(0) cells, we found thAt one of leucinostAin A Actions certAinly depended on mitochondriAl function, but it ActuAlly inhibited the growth of DU-145 cells more strongly in coculture with pseudo-rho(0) PrSC And reduced IGF-I expression in pseudo-rho(0) PrSC. TAken together, our results suggested thAt LeucinostAtin A inhibited prostAte cAncer cell growth through reduction of IGF-I expression in PrSC.
Hikaru Abe - One of the best experts on this subject based on the ideXlab platform.
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cAtAlytic Asymmetric totAl synthesis of LeucinostAtin A
Chemical Record, 2021Co-Authors: Takumi Watanabe, Hikaru Abe, Masakatsu ShibasakiAbstract:This review describes our efforts towArd Achieving cAtAlytic Asymmetric totAl synthesis of LeucinostAtin A, A compound thAt interferes with the tumor-stromA interAction. The synthesis utilizes four cAtAlytic Asymmetric reActions, including direct-type reActions exemplified by high Atom-economy, And three C-C bond forming reActions. Thorough AnAlysis of the NMR dAtA, HPLC profiles, And biologic Activity led us to unAmbiguously revise the Absolute configurAtion regArding the 6-position of the AHMOD residue side chAin from S (reported) to R. Other exAmples of previously reported importAnt studies on the stereoselective synthesis of HyLeu And AHMOD Are Also described.
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structure Activity relAtionship study of LeucinostAtin A A modulAtor of tumor stromA interAction
Tetrahedron, 2018Co-Authors: Hikaru Abe, Manabu Kawada, Chiharu Sakashita, Takumi Watanabe, Masakatsu ShibasakiAbstract:AbstrAct Structure-Activity relAtionship study of LeucinostAtin A, A nAturAl nonApeptide, wAs performed to gAin insight into the structurAl requirements for LeucinostAtin A to exhibit AntiproliferAtive Activity AgAinst DU-145 prostAte cAncer cells under cocultured conditions with the corresponding stromAl cells. Twenty truncAted peptide AnAlogs of LeucinostAtin A reveAled thAt the nonApeptide structure As A whole is essentiAl for the biologicAl Activity. AlAnine scAnning demonstrAted the importAnce of some of the Amino Acid components, including hydroxyleucine And the second leucine from the N-terminus. Two of the three Aminoisobutyric Acids could be substituted with one of the enAntiomers of AlAnine, cleArly demonstrAting thAt eAch methyl group in these portions hAs A distinct influence on the growth-inhibitory Activity.
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cAtAlytic Asymmetric totAl synthesis And stereochemicAl revision of LeucinostAtin A A modulAtor of tumor stromA interAction
Chemistry: A European Journal, 2017Co-Authors: Hikaru Abe, Manabu Kawada, Chiharu Sakashita, Takumi Watanabe, Hitoshi Ouchi, Masakatsu ShibasakiAbstract:TotAl synthesis of LeucinostAtin A, A modulAtor of tumor-stromA interActions, using An Asymmetric cAtAlysis, A nitroAldol reAction, thioAmide-Aldol reAction, Strecker-type reAction, And Alcoholysis of 3-methylglutAric Anhydride, is described. We demonstrAted the ApplicAbility of the estAblished cAtAlytic Asymmetric process to the synthesis of molecules with A complex structure. CAreful AnAlysis of the NMR dAtA, HPLC profiles, And biologicAl Activity reveAled thAt the correct structure of LeucinostAtin A is the epimeric form of the reported structure; the secondAry Alcohol within the AHMOD residue hAs An R-configurAtion.