Computer Modeling-Assisted Design And Synthesis Of Flavonols Derivatives As Proteasome Inhibitors

A total of forty four different derivatives of four flavonols; quercetin, myricetin, kaempferol and fisetin, were proposed. Out of those, 18 different ones were selected for chemical synthesis based on their superior docking scores and feasibility of chemical synthesis. These derivatives were prepared using modified methods from previously published ones, while four of them are reported here for the first time. The novel derivatives are: M1: 3-carbethoxymethylmyricetin, M3: 3-carboxymethylmyricetin, M4: 3-hydroxyethoxymyricetin and K3: 3-(2-hydroxyethoxy)-5, 7-dihydroxy-2-(4-hydroxyphenyl)-4 H-chromen-4-one.

The importance of different proteolytic sites of the proteasome in human breast, prostate and ovarian cancer cell lines-treated with quercetin and myricetin derivatives was tested. Quercetin and myricetin derivatives exhibited differential inhibitory effects on chymotrypsin-, trypsin- and caspase-like activities of proteasome.

Quercetin and myricetin derivatives showed very low anti-proliferative activity against normal human fibroblast cells CRL1554. On the other hand, quercetin and myricetin showed marked growth inhibitory effects on CRL1554. Moreover, bortezomib exhibited a very potent growth inhibitory effect on CRL1554. The efficacy of quercetin and myricetin derivatives to control the growth of tested male (prostate cancer) and female (breast and ovarian) cancers was tested. Quercetin analogues showed very low anti-proliferative effects on the tested cancers. However, myricetin analogues, in particular M1 and M4, markedly inhibited the growth of breast and ovarian cancer cell lines.

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Acknowledgements: This project was supported by Kuwait University Research Grant SL02/10. Spectral analyses were done at the General Facility, Faculty of Science, Kuwait University, supported by Grant numbers GS01/01 and GS01/03