SynthesisofHydantoin,Benzodiazepine‐andPiperazinedione‐FusedTricyclicCompoundLibrary

DimasPaz,Ph.D.WipfGroupResearchTopicSeminar

15January2011

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Hydantoin,Benzodiazepine‐andPiperazinedioneBiologicallyAcAve

TetrahedronLe,.2006,47,6099

Eur.J.Org.Chem.2005,610

Org.Biomol.Chem.2004,2,2415

Angew.Chem.Int.Ed.2003,42,2379

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TheseheterocyclesarepresentinavarietyofbiologicallyacIvecompounds.

Skeletonsimilartothoseoftricyclicthrombininhibitors.

Hydantoin,Benzodiazepine‐andPiperazinedioneFusedTricyclicCompound

OverviewandBiologicalImportance

Org.Biomol.Chem.,2004,2,13393

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Hydantoin,Benzodiazepine‐andPiperazinedioneScaffolds

ThestructureofpiperazinedioneisparIallyrelatedtodiketopiperazine‐basedinhibitorsofhumanhormone‐sensiIvelipase.

J.Med.Chem.2003,46,11204

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Hydantoin,Benzodiazepine‐andPiperazinedioneScaffolds

BenzodiazepinedionecontainsaprivilegedbenzodiazepineMoietythathasawiderangeofpharmaceuIcaluIliIes.

Synthesis2003,1707Chem.Rev.2003,103,893 5

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FluorousDiversity‐OrientedSynthesisofHydantoin,Benzodiazepine‐andPiperazinedione

CompoundLibrary

Eur.J.Org.Chem.2006,2055J.Comb.Chem.2006,8,687J.Comb.Chem.2009,11,452

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D.P.Curran.;Zhangandet.al.

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FluorousSynthesisAdvantages

FluoroussynthesisishighlyefficientsoluIon‐phasesynthesistechnology.Itemploysperfluoroalkyl(RF)groupsas“phasetags”tofacilitatereacIonmixtureseparaIon.

CharacterisIcs:

1Thistechnologyhasbeenappliedtoparallelandmixturesynthesisofsmallmolecules,pepIdes,oligosaccharides,andothersbiomolecules.

2FluorousmoleculescanbeseparatedbythefluorousaswellasconvenIonalmethodssuchaschromatography,disIllaIonandrecrystallizaIon.

3CanbemonitoredbyconvenIonalanalyIcalmethodssuchasTLC,HPLC,IRandNMR.

4GoodcompaIbilitywithothersyntheIctechniquessuchasmicrowaveandmulIcomponentreacIons.

Chem.Rev.2009,109,749Chem.Rev.2004,104,2531

Arkivoc2004,101Aldrichm.Acta2006,39,3

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SynthesisoftheBicycleProlineIntermediates

PreparaIonoffluorousaminoesters.

Eur.J.Org.Chem.2006,2055J.Comb.Chem.2006,8,687J.Comb.Chem.2009,11,452 Chem.Rev.2005,105,2765 8

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Synthesisoffluorousprolinebyone‐potthreecomponent[3+2]cycloaddiIonreacIon.

Eur.J.Org.Chem.2006,20559

SynthesisoftheBicycleProlineIntermediates

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StereochemistryofBicycleProlineIntermediateSingle‐CrystalX‐rayDiffracAon

Org.Le,.2001,3,3491

Eur.J.Org.Chem.2006,2055

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FluorousSynthesisofHydantoin

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StereochemistryofHydantoin–Single‐CrystalX‐rayDiffracAon

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Eur.J.Org.Chem.2006,2055

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FluorousSynthesisofBenzodiazepinedione

Eur.J.Org.Chem.2006,205513

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FluorousSynthesisofPiperazinedione

14J.Comb.Chem.2009,11,452

D.P.Curran.;Zhangandet.al.

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15J.Comb.Chem.2009,11,452

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FluorousSynthesisof90‐CompoundLibraryofPiperazinedione

J.Comb.Chem.2009,11,452 16

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SynthesisofFluorousProlineIntermediates

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Methyl–MethylSeries

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SynthesisofFluorousProlineIntermediates

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Methyl–PhenylSeries

J.Comb.Chem.2009,11,452

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SynthesisofFluorousProlineIntermediates

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Methyl–EsterSeries

J.Comb.Chem.2009,11,452

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SynthesisofFluorousProlineIntermediates

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Phenyl–MethylSeries

J.Comb.Chem.2009,11,452

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SynthesisofFluorousProlineIntermediates

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Phenyl–PhenylSeries

J.Comb.Chem.2009,11,452

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SynthesisofFluorousProlineIntermediates

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Phenyl–EsterSeries

J.Comb.Chem.2009,11,452

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Piperazinedione‐BiologicalAcAviAes

• 63compoundshavebeensubmieedtotheNIHrepositoryandevaluatedinseveralhigh‐throughputscreeningprogams.

• 6compoundsshowedacIviIesagainstSchistosomaMansoni.

• 2compoundshowedinhibitorsofBacillussubNlisSfpphosphopantetheinyltransferase(PPTase).

• 1compoundshowedacIveagainstParkinson’sdisease(5’UTRprotein).

hep://pubchem.ncbi.nlm.nih.gov/

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Piperazinedione‐BiologicalAcAviAes

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CurrentStrategyandObjecAves

• Synthesizedofapiperazinedione–compoundlibrary• TostorethecollecIonofcompoundsUPCMLD• Futurebiologicalassay

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CurrentWork

PreparaIonofthebicycleprolinederivaIve–Furylseries

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PreparaIonofthebicycleprolinederivaIve–Cinnamylseries

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Acknowledgements

•  Dr.Wipf• Wipfgroupmembers• UniversityofPiesburghandCNPq(ConselhoNacionaldeDesenvolvimentoCienjficoeTecnológico)forFellowship

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