Abstract
Flavonoids are a large family of compounds associated with a broad range of biologically useful properties. In recent years, synthetic compounds that contain two flavonoid units linked together have attracted attention in drug discovery and development projects. Numerous flavonoid dimer systems, incorporating a range of monomers attached via different linkers, have been reported to exhibit interesting bioactivities. From a medicinal chemistry perspective, the 1,2,3-triazole ring system has been identified as a particularly attractive linker moiety in dimeric derivatives (owing to several favourable attributes including proven biological relevance and metabolic stability) and triazole-bridged flavonoid dimers possessing anticancer and antimalarial activities have recently been reported. However, there are relatively few examples of libraries of triazole-bridged flavonoid dimers and the diversity of flavonoid subunits present within these is typically limited. Thus, this compound type arguably remains underexplored within drug discovery. Herein, we report a modular strategy for the synthesis of novel and biologically interesting triazole-bridged flavonoid heterodimers and also very rare heterotrimers from readily available starting materials. Application of this strategy has enabled step-efficient and systematic access to a library of structurally diverse compounds of this sort, with a variety of monomer units belonging to six different structural subclasses of flavonoid successfully incorporated.
Highlights
Flavonoids are a large family of polyphenolic compounds that represent dietary constituents of importance to good health as well as a potentially important new class of pharmaceutical lead substrates [1,2,3]
The crude residue was purified by flash column chromatography over silica to afford the corresponding propynyloxy biflavonoid triazole hybrid
Each library member features structural motifs that are associated with biological activity and many incorporate additional potential biomolecular-interacting elements
Summary
Flavonoids are a large family of polyphenolic compounds that represent dietary constituents of importance to good health as well as a potentially important new class of pharmaceutical lead substrates [1,2,3]. OutlineenovfistahgeedSyanbtrhanetcihcinSgt-rtyapteegsytrategy to access triazole-bridged flavonoid dimers and trimers, based Inspira(Sercodhuenbmdyetph1)er[eu2v1se]i.ooIutf switaserstauatidnvtieiecicspoaoptpnedertt-hhcaeattasflylyasnveotdhno“ecisdliicsmko”o-nftyotpmreiearazlukonylients-el-bianezaikdreiendg1,3fla-adtevirpmoonlianorailcdyalckllioybanrdeadgritriioeousnps[10,11] we envisaged(“aalbkryanne-cflhaivnogno-tidy”pbeusiltdriantgegbyloctkos)accocuelsdsbteriraezaoctleed-bwriitdhgaerdanflgaevoof nfloavidondoiidmmerosnoamnedr turnimitsers, based around thbeeaurisneg oafteitrmeriantailvaezidceopgrpoeurp-c(“aatzaildyos-feladvo“ncoliidc”k”b-utiyldpinegabllkocykns)e-toazfuidrneis1h,3d-ivdeirpseolaanrd cnyocvleol additions (Scheme 1tr)ia[z2o1le]-.bridItgewd aflsavoannotiidcihpoamteo-danthd ahtetfleraov-doimnoerisd(omf tohenogmeneerralustnruitcstubreeAar, iSncghema ete1)r.mThine al alkyne group (“alpinkrteyrsonedneuc-cefltioaofvnaooffnraeoetiedhrm”ydibnroauxliyallldkfyiunnngectgiboronlouapcliktiyns)itnhceeodituihmledrermsb,oetnhrouemsapecrrtouevndiditiwnwgiottuhhledanaerlclaeosnwsgafreoyrsopyfonsfltht-aecvtyiccolhinsaaontiidodlnemonomer units bearfionrga faurttheerrmcyinclaoaldadzitiidonewgirthouvaprie(d“aalzkiydnoe--ffllaavvonoonidosidto”fubruniislhdsitnrugctbulroalclykds)ivteorsefutrrifnlaivsohnodidiverse and novel triazdoerliev-abtirviedsgoef dtheflgaevneornalofiodrmhsoBmanod- Can(Sdchhemetee1r)o. It was anticipated that this modular strategy would enable step-efficient and facile access to a structurally diverse library of triazole-bridged flavonoid dimers and trimers through the use of a variety of different flavonoid building blocks belonging to different flavonoid structural subclasses. Hydroxyl-substituted alkyne-chalcone 4 was accessed from phenol 1 via a two-step sequence: alkylation with propargyl bromide proceeded smoothly to yield aldehyde 2 and subsequent Claisen-Schmidt aldol reaction with acetophenone 3 yielded the target compound 4 (Scheme 2) [22].
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