De Novo Synthesis Of Noviose-1,2-acetonide And Synthesis Of Novobiocin Analogues

The molecular chaperone Hsp90(Heat shock protein 90) is a promising target for cacer therapy.Preclinical and clinical evaluations of a variety of Hsp90 inhibitors have shown anti-tumor effects as a single agent and in combination with other chemotheraputics.All Hsp90 inhibitors fall into two classes:the N-terminal inhibitors and the C-terminal inhibitors.The structure-activity relatioship of N-terminal inhibitors has been extensively studied,and some derivatives of these compounds are in phaseâ…¡clinic trial.Meanwhile,number of known C-terminal inhibitors,representated by Novobiocin and Coumermycin,is still very limited.This thesis was focused on discovery of potent novobiocin analogues,which are a glycoside consisting of noviose and coumarin with improved tumor inhibition activity. Research work described here includes:1.Design and de novo synthesis of noviose-1,2-acetonide(+)-Noviose is the only chiral moiety presenting in the moleculars of these antibiotics, and hence constitutes the most important building block for their syntheses.Because this unusual monosaccharide is not available from other natural soure,it has been subject for numerous synthetic studies.However,no synthetic studies achieve the region-selectivity of 3'-OH,which is the limit in expanding research range of the C-terminal inhibitors.In this work,we designed two strategies and one of them was completed successfully.Starting with L-arabinose,we successfully prepared the key intermediate 1,2-acetyl-noviose with 17 steps in 10%yield.2.Coumarin synthesisAccording to previous SAR study,six coumarins with different substitutes at the 3-and 8-position were prepared by Perkin and Pechmann condensation in 16~36%yield.3.Synthesis of novobiocin analoguesWith obtained noviose and coumarins,we prepared six novobiocin analogues with Mitsunobu reaction,and yielded a-glycoside as the predominat isomer. Totally,54 compounds have been prepared and characterized by~1 HNMR,~13 CNMR,IR, El,HRMS,among which are 31 new compounds.