Abstrakt
INTRODUCTION:
The flavone luteolin (Fig. 1) is phytochemical compound widely distributed in its glycosylated forms in celery, green pepper, camomile tea and artichoke. This polyphenolic compound has shown promising health promoting effects in human cell culture, experimental in vitro and in vivo clinical studies.1 It has been revealed to have antitumorigenic, anticancer and antioxidant effects. Due to the metal-binding pharmacophore (Fig. 2), the luteolin and its congeners have shown remarkable in vitro inhibitory potency of PA-subunit of influenza RNA-dependent RNA polymerase. This metalloenzyme can bind Mg(2+) or Mn(2+) ions which are essential for its endonuclease activity. However, low bioavailability of luteolin has been a concern as it can limit or even hinder their health effects. Therefore, attempts to improve its bioavailability in order to improve the efficacy of luteolin are being studied.
Herein, we prepared series of new compounds with different topology but same footprint. Unique synthesis approach using C-H activation (Ir-catalysis) and cross-coupling reactions (Pd-catalysis) has enabled synthesis of the aromatic core. Introduction of various metal-binding moieties has provided set of luteolin bioisosteres with submicromolar inhibitory potency of influenza RdRp and potential higher bioavailability.
GOALS:
- design and synthesis of central aromatic cores via transition-metals catalysis (scaffold hoping approach)
- introduction of various metal-binding moieties to optimized central aromatic scaffold
- determination of bioisosteres's inhibitory potency of influenza RdRp