Diversity-oriented Synthesis Based On Chromone & Discovery And Modification Of Lead Compound

Lead compounds often arised from a variety of different compound sources by high-throughput screenings(HTS), which means that molecular diversity is important with the biological space. So there is a strong desire for a diversified molecules library to fill the demands of HTS. Diversity-oriented synthesis, which relys on the use of cascade reactions or multicomponent reactions, serves as an ideal approach for the efficient synthesis of structurally complex and functionally diverse molecules.This paper based on diversity-oriented synthesis, from functionalized 3-(1-alkynyl) chromones, through a cascade addition-cyclization-oxidation sequence, generated highly substituted furo[3, 2-c]coumarins scaffold, and then build up the diversified furo[3, 2-c] coumarins library for high throughput screening. This cascade reaction has advantages of readily accessible starting material, mild reaction condition and atom economy. Also, furo[3, 2-c]coumarins has natural product-like scaffold.By high-throughput screenings, furo[3, 2-c]coumarins in the library exhibited activity as xanthine oxidase inhibitors.The compound A11, with IC50 up to 2.6 μM, was chosen as lead compound. Co-workers in our group explored the structure-activity relationship and improved the IC50 up to 7nM.However, its activity in vivo is very low, owing to the feature that its water-solubility is too high and lipid-solubility is too low. Thus, this paper conducted structural modification in order to improve its activity in vivo. Firstly, the lipophilic group- alkoxyl group was added at 8-position, and the activity of the compound in vivo is improved. Secondly, the hydrophilic group was removed away. When phenolic hydroxyl group was removed away, the compound lost activity. Then, the 4-carbonyl group was modified, if the 4-carbonyl group was replaced by phenyl group, the compound lost activity, if the 4-carbonyl group was replaced by methyl group or was removed away, their activity was still acceptable and the vivo activity is under investigating currently.From the current finding, the structure-activity relationship of the active compounds was complemented with that the methoxy group of the compound at 8-position on phenyl ring could be replaced by larger alkoxyl group, and the phenolic hydroxyl group should be remained. On the other hand, activity in vivo was improved by adding larger alkoxyl group at 8-position on the phenyl ring. However, the activity in vivo is still not good enough, the continuous modification and further structure-activity relationship in this series compounds for 4- carbonyl group is ongoing.