Aminocoumarin Class Hsp90 Inhibitor Optimization And Explore Synthetic Methods

Aminocoumarin antibiotics are natural coumarin7-O-L-noviosides composed of3-amino-4,7-dihydroxylcoumarin central pieces and3-O-acylated-L-noviose. These compounds and their analogues exhibit excellent antibacterial and antineoplastic activities by unique mechanism of action. The research on the structural modification and structure activity relationship (SAR) of these compounds shows that L-noviose is the key fragment. The construction of a-noviosides still exist some deficiencies in stereoselectivity, separation and yield, which blockes the research on structure activity relationship of these compounds.The thesis was focused on discovery of Hsp90C-terminal inhibitors with improved tumor inhibition activity, for the preliminary discussion of the relationships of3-amino-L-noviose bioisostere and the antiproliferation activities against cancer cells of these compouds. We designed and synthesied a series of aminocoumarin antibiotics, which introduced a basic amino group and keeped the active lipophilic motif comprising the gem-dimethyl and the methoxy groups, and evaluated their antiproliferation activities. On the other hand, we preliminarily discussed the construction of a-noviosides on the basis of Tsuji-Trost allylation reaction.1、Synthesis of N-Cbz-3-amino-3-deoxy-L-novioseAccording to the synthesis of3-N-benzoyl-L-noviose, we successfully designed and synthesied3-N-Cbz-L-noviose, and optimized the key steps.2、Synthesis of7-OH coumarinAccording to previous SAR study, six coumarins with different substitutes at the3-and8-position were prepared by Perkin and Pechmann condensation, and we optimized the key steps.3、Construction of a-noviosides and evaluation of their antiproliferation activitiesWe prepared six aminocoumarin antibiotics analogues with Mitsunobu reaction in30～50%yield, and evaluated their antiproliferation activities.4、De nove synthesis of a-noviosides on the basis of Tsuji-Trost allylation reactionIn this work, we took o-methyl phenol as the template of coumarin,1-O-Boc-pyrone as the precursor of noviose, by Tsuji-Trost allylation reaction, diastereoselective reduction, O-methylation and substrate-controlled stereoselective dihydroxylation four-step reactions, rapidly constructed the racemic a-noviosides. On the other hand, we successfully achieved the stereoselective aminohydroxylation.