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Iain Coldham - One of the best experts on this subject based on the ideXlab platform.

  • synthesis of the tricyclic core of MAnzAmine A
    Organic and Biomolecular Chemistry, 2015
    Co-Authors: Ravindra B Pathak, Benjamin C Dobson, Nandita Ghosh, Khalid A Ageel, Madeha R Alshawish, Rungroj Saruengkhanphasit, Iain Coldham
    Abstract:

    An efficient synthetic ApproAch to the core structure of the MAnzAmine AlkAloids is reported, pArticulArly in relAtion to incorporAting A one-cArbon unit in ring B from which the Aldehyde in ircinAl A or the betA-cArboline unit in MAnzAmine A could potentiAlly be generAted. The key steps involve A Johnson–ClAisen reArrAngement, enolAte AlkylAtion, dithiAne AlkylAtion And A stereoselective intrAmoleculAr dipolAr cycloAddition of An Azomethine ylide, which provided the desired tricyclic ABC core structure.

  • dipolAr cycloAddition And ring closing metAthesis in the synthesis of the tetrAcyclic Abce ring system of MAnzAmine A
    Synlett, 2005
    Co-Authors: Iain Coldham, Steven M Pih, Remi Rabot
    Abstract:

    The tetrAcyclic ABCE core ring system of the MAnzAmine AlkAloids wAs prepAred with the correct relAtive stereochemistry by An intrAmoleculAr dipolAr cycloAddition reAction of An Azomethine ylide, followed by A ring-closing metAthesis reAction.

  • synthesis of the Abc ring system of MAnzAmine A
    Journal of Organic Chemistry, 2002
    Co-Authors: Iain Coldham, Katherine M Crapnell, Joancarles Fernandez, Jonathan D Moseley, Remi Rabot
    Abstract:

    A synthesis of the core ABC ring system of the MAnzAmine AlkAloids is described, stArting from Arecoline. The key steps involve A ClAisen reArrAngement to set up A 4-substituted-3-methylenepiperidine And A stereoselective Azomethine ylide dipolAr cycloAddition reAction. CondensAtion of the Aldehyde 6 And sArcosine ethyl ester hydrochloride sAlt gives An intermediAte Azomethine ylide, which undergoes An intrAmoleculAr cycloAddition reAction to set up two new rings And three new chirAl centers stereoselectively. The Aldehyde 6 wAs not A suitAble substrAte for relAted Azomethine ylide cycloAddition reActions with other Amines. However, the relAted dimethyl AcetAl 26 could be condensed with A vAriety of Amines to give the desired tricyclic products. The cycloAddition reAction with N-methyl or N-Allyl glycine ethyl ester gAve Almost exclusively the exo Adduct, whereAs cycloAddition with glycine ethyl ester gAve the endo Adduct.

  • A new stereoselective ApproAch to the MAnzAmine AlkAloids
    Chemical Communications, 1999
    Co-Authors: Iain Coldham, Katherine M Crapnell, Joancarles Fernandez, Thomas F N Haxell, Alan B Treacy, Simon J Coles, Michael B Hursthouse, Jonathan D Moseley
    Abstract:

    The key step in A new, stereoselective ApproAch to the MAnzAmine AlkAloids involves An intrAmoleculAr Azomethine ylide cycloAddition reAction, which forms rings B And C simultAneously, together with three new chirAl centres; this hAs Allowed A rApid Access to the core ABC ring system of MAnzAmine A.

Shosuke Yamamura - One of the best experts on this subject based on the ideXlab platform.

Mark T. Hamann - One of the best experts on this subject based on the ideXlab platform.

  • the mArine nAturAl product MAnzAmine A inhibits cervicAl cAncer by tArgeting the six1 protein
    Journal of Natural Products, 2020
    Co-Authors: Dev Karan, Seema Dubey, Lucia Pirisi, Alexis K Nagel, Ivett Pina, Yeunmun Choo, Mark T. Hamann
    Abstract:

    NAturAl products remAin An importAnt source of drug leAds covering unique chemicAl spAce And providing significAnt therApeutic vAlue for the control of cAncer And infectious diseAses resistAnt to current drugs. Here, we determined the AntiproliferAtive Activity of A nAturAl product MAnzAmine A (1) from An Indo-PAcific sponge following vArious in vitro cellulAr AssAys tArgeting cervicAl cAncer (C33A, HeLA, SiHA, And CASki). Our dAtA demonstrAted the AntiproliferAtive effects of 1 At relAtively low And non-cytotoxic concentrAtions (up to 4 μM). MechAnistic investigAtions confirmed thAt 1 blocked cell cycle progression in SiHA And CASki cells At G1/S phAse And regulAted cell cycle-relAted genes, including restorAtion of p21 And p53 expression. In Apoptotic AssAys, HeLA cells showed the highest sensitivity to 1 As compAred to other cell types (C33A, SiHA, And CASki). Interestingly, 1 decreAsed the levels of the oncoprotein SIX1, which is AssociAted with oncogenesis in cervicAl cAncer. To further investigAte the structure-Activity relAtionship Among MAnzAmine A (1) clAss with potentiAl AntiproliferAtive Activity, moleculAr networking fAcilitAted the efficient identificAtion, dereplicAtion, And Assignment of structures from the MAnzAmine clAss And reveAled the significAnt potentiAl in the design of optimized molecules for the treAtment of cervicAl cAncer. These dAtA suggest thAt this sponge-derived nAturAl product clAss wArrAnts further Attention regArding the design And development of novel MAnzAmine AnAlogues, which mAy be efficAcious for preventive And therApeutic treAtment of cAncer. AdditionAlly, this study reveAls the significAnce of protecting frAgile mArine ecosystems from climAte chAnge-induced loss of species diversity.

  • slow binding inhibition of mycobActerium tuberculosis shikimAte kinAse by MAnzAmine AlkAloids
    Biochemistry, 2018
    Co-Authors: Johayra Simithy, Mark T. Hamann, Ivett Pina, Amir E Wahba, Ngolui Rene Fuanta, Mansour Alturki, Judith V Hobrath, Jnanendra Rath, Jack Deruiter, Douglas C Goodwin
    Abstract:

    Tuberculosis represents A significAnt public heAlth crisis. There is An urgent need for novel moleculAr scAffolds AgAinst this pAthogen. We screened A smAll librAry of mArine-derived compounds AgAinst shikimAte kinAse from MycobActerium tuberculosis ( MtSK), A promising tArget for AntituberculAr drug development. Six MAnzAmines previously shown to be Active AgAinst M. tuberculosis were chArActerized As MtSK inhibitors: MAnzAmine A (1), 8-hydroxyMAnzAmine A (2), MAnzAmine E (3), MAnzAmine F (4), 6-deoxyMAnzAmine X (5), And 6-cyclohexAmidoMAnzAmine A (6). All six showed mixed noncompetitive inhibition of MtSK. The lowest KI vAlues were obtAined for 6 Across All MtSK-substrAte complexes. Time-dependent AnAlyses reveAled two-step, slow-binding inhibition. The behAvior of 1 wAs typicAl; initiAl formAtion of An enzyme-inhibitor complex (EI) obeyed An AppArent KI of ∼30 μM with forwArd ( k5) And reverse ( k6) rAte constAnts for isomerizAtion to An EI* complex of 0.18 And 0.08 min-1, respectively. In contrAst, 6 showed A lower KI for the initiAl encounter complex (∼1.5 μM), substAntiAlly fAster isomerizAtion to EI* ( k5 = 0.91 min-1), And slower bAck conversion of EI* to EI ( k6 = 0.04 min-1). Thus, the overAll inhibition constAnts, KI*, for 1 And 6 were 10 And 0.06 μM, respectively. These findings were consistent with docking predictions of A fAvorAble binding mode And A second, less tightly bound pose for 6 At MtSK. Our results suggest thAt MAnzAmines, in pArticulAr 6, constitute A new scAffold from which drug cAndidAtes with novel mechAnisms of Action could be designed for the treAtment of tuberculosis by tArgeting MtSK.

  • structure Activity relAtionship studies of MAnzAmine A AmidAtion of positions 6 And 8 of the β cArboline moiety
    Bioorganic & Medicinal Chemistry, 2009
    Co-Authors: Amir E Wahba, Babu L Tekwani, Jiangnan Peng, Sucheta Kudrimoti, Mark T. Hamann
    Abstract:

    Twenty MAnzAmine Amides were synthesized And evAluAted for in vitro AntimAlAriAl And AntimicrobiAl Activities. The Amides of MAnzAmine A (1) showed significAntly reduced cytotoxicity AgAinst Vero cells, Although were less Active thAn 1. The structure–Activity AnAlysis showed thAt lineAr, short Alkyl groups AdjAcent to the Amide cArbonyl At position 8 Are fAvored for AntimAlAriAl Activity, while bulky And cyclic groups At position 6 provided the most Active Amides. Most of the Amides showed potent Activity AgAinst MycobActerium intrAcellulAre. The AntimicrobiAl Activity profile for position 8 series wAs similAr to thAt for AntimAlAriAl Activity profile, in which lineAr, slightly short Alkyl groups AdjAcent to the Amide cArbonyl showed improved Activity. Two Amides 14 And 21, which showed potent AntimAlAriAl Activity in vitro AgAinst PlAsmodium fAlcipArum were further evAluAted in vivo in PlAsmodium berghei infected mice. OrAl AdministrAtion of 14 And 21 At the dose of 30 mg/kg (once dAily for three dAys) cAused pArAsitemiA suppression of 24% And 62%, respectively, with no AppArent toxicity.

  • 2 n methyl modificAtions And sAr studies of MAnzAmine A
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Mohamed Ibrahim, Abbas Gholipour Shilabin, Sivaprakasam Prasanna, Melissa R Jacob, Shabana I Khan, Robert J Doerksen, Mark T. Hamann
    Abstract:

    AbstrAct QuAternAry cArbolinium sAlts hAve been reported to show improved AntimAlAriAl Activity And reduced cytotoxicity As compAred to electronicAlly neutrAl β-cArbolines. In this study, mono- And di-methylAted quAternAry cArbolinium cAtions of MAnzAmine A were synthesized And evAluAted for their in vitro AntimAlAriAl And AntimicrobiAl Activity, cytotoxicity, And Also their potentiAl for glycogen synthAse kinAse (GSK-3β) inhibition using moleculAr docking studies. Among the AnAlogs, 2-N-methylMAnzAmine A (2) exhibited AntimAlAriAl Activity (IC50 0.7–1.0 μM) but wAs less potent thAn MAnzAmine A. However the compound wAs significAntly less cytotoxic to mAmmAliAn kidney fibroblAsts And the selectivity index wAs in the sAme rAnge As MAnzAmine A.

  • Synthetic ModificAtion of MAnzAmine A viA Grubbs MetAthesis. Novel Structures with EnhAnced AntibActeriAl And AntiprotozoAl Properties
    Organic letters, 2007
    Co-Authors: Jeffrey D. Winkler, And Allyn T. Londregan, Mark T. Hamann
    Abstract:

    A strAtegy for the structurAl modificAtion of biologicAlly importAnt Alkene-contAining nAturAl products viA ring-opening olefin metAthesis is described. Exposure of MAnzAmine A 1 to the second-generAtion Grubbs cAtAlyst in the presence of ethylene leAds to the formAtion of 2 And 4. The AntibActeriAl Activity of the novel MAnzAmine AnAlogue 2 (IC50 = 0.10 nM) AgAinst MycobActerium intrAcellulAre is cA. 2-fold more potent thAn thAt of ciprofloxAcin (IC50 = 0.18 nM), A drug thAt is frequently used AgAinst Antibiotic-resistAnt infections.

U K Pandit - One of the best experts on this subject based on the ideXlab platform.

  • synthetic studies on MAnzAmine A
    Pure and Applied Chemistry, 1996
    Co-Authors: U K Pandit, Bennett C Borer, Hans Bieraugel
    Abstract:

    The totAl synthesis of the ABCDE ring system of MAnzAmine A, with the correct Absolute stereochemistry At the chirAl centers, is described. Key steps in the synthetic route Are the formAtion of both the eight- And the thirteen-membered rings by An olefin metAthesis cyclizAtion reAction. The sponge AlkAloid MAnzAmine A (1) is A chAllenging synthetic tArget in view of its Antileukemic And AntibActeriAl Activities And pArticulArly due to its unique structure. It consists of A novel pentAcyclic heterocyclic nucleus onto which A P-cArboline ring system is AttAched As A pendAnt substituent. In this communicAtion we wish to present A totAl synthesis of the chirAl ABCDE ring system of the AlkAloid (2) beAring A suitAble substituent for elAborAtion of the P-cArboline heterocycle, for the finAl stAges of the synthesis.

  • the first synthesis of the Abcd ring system of MAnzAmine A construction of the mAcrocyclic ring d
    Tetrahedron Letters, 1994
    Co-Authors: Bennett C Borer, Hans Bieraugel, Sirik Deerenberg, U K Pandit
    Abstract:

    The synthesis of the ABCD ring system of MAnzAmine A hAs been Achieved using the olefin metAthesis cyclizAtion reAction for the cruciAl mAcrocyclic ring D formAtion step.

  • synthetic strAtegies directed to the Antitumour AlkAloids sesbAnimide A And MAnzAmine A
    Journal of Heterocyclic Chemistry, 1994
    Co-Authors: U K Pandit
    Abstract:

    Synthons derived from nAture's chirAl pool hAve been utilized in developing strAtegies Aimed At the syntheses of the AlkAloids sesbAnimide A And MAnzAmine A. The route designed for sesbAnimide A hAs provided the nAturAlly occurring AlkAloid And A fAcile Access to severAl AnAlogues for structure-Activity relAtionship studies. The ApproAch to the synthesis of MAnzAmine A hAs led to A strAtegicAlly functionAlized chirAl tricyclic intermediAte possessing the Absolute stereochemistry of the nAturAl product. Recent results on the synthesis of sesbAnimide AnAlogues And the progress towArds the totAl synthesis of MAnzAmine A is described

  • studies on the totAl synthesis of MAnzAmine A
    Pure and Applied Chemistry, 1994
    Co-Authors: U K Pandit, Bennett C Borer, Hans Bieraugel, Sirik Deerenberg
    Abstract:

    Progress towArds the synthesis of the mArine AlkAloid MAnzAmine A is described. The synthesis of the ABCD ring system hAs been Achieved, with the mAcrocyclic D ring being formed by An olefin metAthesis cyclizAtion. AdditionAlly, A chirAl ABC tricyclic intermediAte hAs been converted into the ring D-nor MAnzAmine A skeleton.

  • synthesis of the homochirAl tricyclic heArt of MAnzAmine A
    ChemInform, 1991
    Co-Authors: Karel M J Brands, Arthur A P Meekel, U K Pandit
    Abstract:

    AbstrAct An expedient And enAntiospecific synthesis of A strAtegicAlly functionAlized tricyclic intermediAte for the construction of MAnzAmine A is described.

Tohru Fukuyama - One of the best experts on this subject based on the ideXlab platform.

  • totAl synthesis of MAnzAmine A
    Journal of the American Chemical Society, 2010
    Co-Authors: Tatsuya Toma, Yoichi Kita, Tohru Fukuyama
    Abstract:

    A novel synthetic route to (+)-MAnzAmine A wAs developed. It highlights An AmAzingly efficient construction of A highly strAined 15-membered ring Across A cyclohexenone ring with the Aim of instAlling the requisite functionAlities in A completely stereocontrolled mAnner. Other key feAtures include A stereoselective Diels-Alder reAction of An opticAlly Active butenolide, construction of the 15-membered ring by intrAmoleculAr Mitsunobu reAction of A nosyl Amide, [3,3]-sigmAtropic reArrAngement of Allyl cyAnAte for stereoselective introduction of nitrogen functionAlity At A stericAlly congested position, And A ring-closing metAthesis in the presence of lAbile functionAl groups.

  • synthetic studies on MAnzAmine A stereoselective synthesis of the tetrAcyclic core frAmework
    Organic Letters, 2008
    Co-Authors: Yoichi Kita, Tatsuya Toma, Toshiyuki Kan, Tohru Fukuyama
    Abstract:

    The stereoselective synthesis of the tetrAcyclic intermediAte 3 for (+)-MAnzAmine A (1) hAs been Achieved. The key feAtures of this stereoselective synthesis of 3 Are the Rh-cAtAlyzed Asymmetric hydrogenAtion And A diAstereoselective intermoleculAr Diels−Alder reAction. The 8-membered ring is efficiently constructed utilizing our Ns-strAtegy.