Synthesis And Structure-Activity Relationship Of Quinazolinone Derivatives PTP1B Inhibitors;Synthesis Of Icariin Intermediates

This thesis consists of two parts.Part1. Design, synthesis and inhibitory activity on Protein tyrosine phosphatase1B (PTP1B) of quinazolinone derivatives(1) Twenty-nine compounds have been synthesized by modification of quinazolinone at2-and3-position. The inhibitory effect on PTP1B showed that2,3-disubstituted quinazolinone compounds exhibited better inhibitory activity, and2-prenylmercapto (or benzylmercapto),3-phenyl are good substituents.(2) On the basis of the previous work, fifteen compounds have been designed and prepared by modifying quinazolinone at aromatic ring. The assay showed that6-and8-position substitution is good for the inhibitory effect, and the former is better slightly than the latter. The compounds with acyl group at6-position have better inhibitory activity, especially those with aromatic acyl such as benzenesulfonamide (34) and benzamide (33). The highest value of IC50is1.5μg/mL (34).(3) In order to ameliorate physical and chemical properties, at the same time improve the selectivity of PTP1B over TCPTP (T-cell Protein Tyrosine Phosphatase), seven compounds are prepared by changing the benzyl with prenyl at2-position. Compared with those with benzyl, the compounds with prenyl are less active but more selective. The most potent inhibitors54、55have3～4-fold selectivity for PTP1B over TCPTP.Fifty compounds have been synthesized by modifying quinazolinone nucleus structure, and the structure-activity relationship (SAR) has been known preliminarily. Compared with quinazolinone nucleus, the activity has been improved for twenty times, and the position which is sensitive to the selectivity has been found. This establishes the solid bases for the further study on SAR of this kind of quinazolinone derivatives as well as the lead compound for anti-diabetes and anti-obesity.Part2. Synthesis of the intermediates for natural product IcariinThe flavonoids have a variety of bioactivities such as anti-cardiovascular disease, regulation of immune function, and its derivatives have good phosphodiesterase-5(PDE5) inhibitory activity. In this thesis, the method for synthesis of the intermediates of Icariin was explored.(1) With phloroglucinol as the starting material, the intermediate of Icariin,4’-methoxy-5,7-dihydroxyl-8-prenylflavonoid (62), was successfully prepared by seven steps including Friedel-Crafts acylation, substitution on aromatic ring with prenyl, selective protection on hydroxyl group, Aldol Condensation, formation of C-ring, dehydrogenation, and deprodection reaction. This structure of the compound was determined by NMR and HRMS spectra.(2) A new method for selective deprotection of5,7-dihydroxyl group was developed, and4’-methoxy-5-acetoxy-7-methoxymethoxy-8-prenylflavonoid (63) was synthesized.All the materials are easy to get and the conditions are moderate. This research work established bases for the following study on Icariin and its derivatives.