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Structure–Activity Relationship and Rational Design of 3,4-Dephostatin Derivatives as Protein Tyrosine Phosphatase Inhibitors

✍ Scribed by Takumi Watanabe; Takayuki Suzuki; Yoji Umezawa; Tomio Takeuchi; Masami Otsuka; Kazuo Umezawa

Publisher
Elsevier Science
Year
2000
Tongue
French
Weight
429 KB
Volume
56
Category
Article
ISSN
0040-4020

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✦ Synopsis

Several alkyl-and O-methylated-3,4

-dephostatin were synthesized and evaluated for their inhibitory activity toward protein tyrosine phosphatase. Alkyl chains with a length up to that of the pentyl group gave tolerable inhibition, whereas methylation of hydroxyl groups resulted in a decrease in the activity. Based on the structure-activity relationship and X-ray crystallographic analysis of C215S PTP1B-phosphotyrosine containing peptide complex, the mode of binding of 3,4-dephostatins to the active site was speculated with the aid of calculation. Several hydrogen bonds and CH/p interactions were suggested to be important for inhibition of PTPase. A novel nitroso-free methoxime compound was designed so that all the attractive interactions were maintained. The methoxime compound was synthesized and shown to inhibit PTP1B.

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