title: Combinatorial Synthesis of Structurally Diverse Triazole-Bridged Flavonoid Dimers and Trimers.
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. ths29@cam.ac.uk.
authors.forename: Tze Han
authors.initials: TH
authors.lastname: Sum
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. tjs76@cam.ac.uk.
authors.forename: Tze Jing
authors.initials: TJ
authors.lastname: Sum
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. wrjdg2@cam.ac.uk.
authors.forename: Warren R J D
authors.initials: WR
authors.lastname: Galloway
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. sc806@cam.ac.uk.|Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK. sc806@cam.ac.uk.
authors.forename: Súil
authors.initials: S
authors.lastname: Collins
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. dgt24@cam.ac.uk.
authors.forename: David G
authors.initials: DG
authors.lastname: Twigg
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK. fh111@cam.ac.uk.
authors.forename: Florian
authors.initials: F
authors.lastname: Hollfelder
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. spring@ch.cam.ac.uk.
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D005419:Flavonoids; D014230:Triazoles
keywords: dimer; flavonoid; hybridization; structural diversity; triazole; trimer