Preliminary Study On Structure Optimization Of Benzadiazem Natural Products Based On Total Synthesis

Hsp90 is molecular chaperone that facilitates the proper folding under stress conditions. It is one of factors to maintain the survival and development of tumor cell with high expression. The inhibition of Hsp90’s chaperone activity in tumor cell would lead to the ubiquitination and degeneration of a number of oncoprotein, leading to the apoptosis of tumor cellsBenzenoid ansamycin including Geldanamycin, Herbmycin A showed potent inhibiting activity toward Hsp90 by competitive binding to the ATP-binding site in the N-terminal of Hsp90. However, the hepatotoxicity caused by the benzoquinone fragments in the process of metabolism has limited the druggability. Therefore, the structure modification of the benzoquinone part is particularly important.Through the literature retrieval and the analysis of crystal structure data, we knew that there was no direct interaction between C18 oxygen with proteins. However, C21 oxygen had a huge impact on the affinity to Hsp90 on the contrary. Therefore, combined with the transformation sites of C4-C5, C11, C18-deoxy non-quinone ansamycin analogues 40-43 were designed. Depending on the existing total synthetic route of Herbimycin A, all-purposed C8-C15 synthon was synthesized based on Sharpless asymmetric dihydroxylation and Katuski asymmetric epoxidation. To introduce the aromatic fragment successfully, we improved the original coupling strategy. Then assembly of the target molecule was achieved in 5 steps including a zincate mediated coupling of the two fragments in a diastereoselective manner. Surprisingly, Friedel-Crafts phenylation took place in the last step of synthesis, universally giving undesired C15 para-methoxyphenylated final products (102a-102d). Biological study suggested that both modifications, removal of C18 oxygen and adding of bulky phenyl group at C15, are tolerated. Compound 1 exhibited retained anticancer activity and compound 2 showed a 10-fold higher anticancer activity.Based on the above total synthesis and biological activity evaluation research, we confirmed that the C18-deoxy non-quinone ansamycin analogues maintained good biological activity. At the same time, combining with the structure changes of C4-C5, C11, C15 substituents, we enriched the molecular structure activity relationship of new phenol derivatives.