Chemically Engineered Extracts: Source of Bioactive Compounds

RAMALLO, I. A; SALAZAR, M. O.; MÉNDEZ, L.; FURLAN, R. L. E.

ACCOUNTS OF CHEMICAL RESEARCH

AMER CHEMICAL SOC

Lugar: washington; Año: 2010 vol. 44 p. 241 - 250

0001-4842

Biologicalresearchanddrugdiscoverycriticallydependonaccesstolibrariesofsmallmoleculesthathaveanaffinityforbiomacromolecules.Byvirtueoftheirsustainedsuccessassourcesofleadcompounds,naturalproductsarerecognizedas“privileged”startingpointsinstructuralspaceforlibrarydevelopment.Comparedwithsyntheticcompounds,naturalproductshavedistinguishingstructuralproperties;indeed,researchershavebeguntoquantifyandcatalogthedifferencesbetweenthetwoclassesofmolecules.Measurabledifferencesinthenumberofchiralcenters,thedegreeofsaturation,thepresenceofaromaticrings,andthenumberofthevariousheteroatomsareamongthechiefdistinctionsbetweennaturalandsyntheticcompounds.Naturalproductsalsoincludeasignificantproportionofrecurringmolecularscaffoldsthatarenotpresentincurrentlymarketeddrugs:thebioactivityofthesenaturalsubstructureshasbeenrefinedoverthelongprocessofevolution.InthisAccount,wepresentourresearchaimedatpreparinglibrariesofsemisyntheticcompounds,orchemicallyengineeredextracts(CEEs),throughchemicaldiversificationofnaturalproductsmixtures.Theapproachreliesonthepowerofnumbers,thatis,inthechemicalalterationofasizablefractionofthestartingcomplex mixture.Majorchangesincompositioncanbeachievedthroughthechemicaltransformationofreactivemolecularfragmentsthatarefoundinmostnaturalproducts.Ifsuchfragmentsarecommonenough,theirtransformationrepresentsanentrypointforchemicallyalteringahighproportionofthecomponentsofcrudenaturalextracts.WehavesearchedforcommonreactivefragmentsintheDictionaryof NaturalProducts(CRCPress)andidentifiedseveralfunctionalgroupsthatareexpectedtobepresentinalargefractionofthecomponentsofanaveragenaturalcrudeextract.Todate,wehaveusedreactionsthatincorporate(i)nitrogenatomsthroughcarbonylgroups,(ii)sulfurbytransformationof-OHandamines,and(iii)brominethroughdoublebondsandaromaticrings.TheresultingCEEshaddifferentcompositionandbiomolecularpropertiesthantheirnaturalprogenitors.Weisolatedasemisynthetic β-glucosidaseinhibitorfromaCEEpreparedbyreactionwithbenzenesulfonylchloride,anantifungalpyrazolefromaCEEpreparedbyreactionwithhydrazine,andanacetylcholinesteraseinhibitorfromaCEEpreparedthroughbromination.Ourresultsillustratehowbiologicalactivitycanbegeneratedthroughchemicaldiversificationofnaturalproductmixtures.Moreover,thelevelofcontrolthatcanbeassertedintheprocessbyjudiciousdesignandexperimentalchoicesunderscoresthepotentialforfurtherdevelopmentofCEEsinbothbasicresearchanddrugdiscovery.