No 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.

The synthesis of porphyrin–steroid conjugates is examined using the natural steroids oestradiol, oestrone, and lithocholic acid as precursors. Two strategies differing in the timing of formation of the steroid–porphyrin linkage leading to four different construction motifs are explored. Two approaches are based on a strategy of introduction of steroidal components in the porphyrin-forming reaction involving condensation of steroidal-alkylaldehydes and pyrrole to give 5,10,15,20-tetrakis(steroidal-alkyl)porphyrins and differ in the way in which the required aldehyde is introduced to the steroidal component. In the other strategy, a steroidal component is introduced by post-porphyrin synthesis reactions and here also two approaches were explored, one involving nucleophilic substitution and the other esterification. Of the four approaches investigated, the most efficient and most versatile one attaches the steroidal components late in the sequence to a 5,10,15,20-tetra(ω-haloalkyl)porphyrin by a nucleophilic substitution reaction. In this way, a 5,10,15,20-tetrakis[oestrone-linked-heptyl)porphyrin was obtained in 47 % yield.

The concise and step-economical total syntheses of three hydroxyaurones and one polymethoxyflavone from readily available starting materials is described. A divergent synthetic strategy was employed, which centered on a common chalcone scaffold from which both the aurone and flavone frameworks could be accessed through the use of different oxidative cyclization methods. These are the first reported total syntheses of these biologically interesting compounds.

Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly explored within drug discovery. There is considerable structural diversity possible within this compound class and large regions of potentially biologically relevant biflavonoid chemical space remain untapped or underexplored. Herein, we report the development of a modular and divergent strategy towards biflavonoid derivatives which enabled the step-economical preparation of a structurally diverse collection of novel unnatural biflavonoids. Preliminary studies established that the strategy could also be successfully extended to the preparation of very rare triflavonoids, which are also expected to be useful tools for biological intervention. Prompted by previous inhibitory studies with flavonoid libraries, amyloid anti-aggregation screening was performed, which led to the identification of several structurally novel inhibitors of the aggregation of the amyloid β peptide (Aβ). Aggregated Aβ is a pathological hallmark of Alzheimer's disease and the use of small molecules to inhibit the aggregation process has been identified as a potentially valuable therapeutic strategy for disease treatment. Methylated biaurones were associated with highest levels of potency (the most active compound had an IC value of 16 μM), establishing this scaffold as a starting point for inhibitor development.