FUNCTION-ORIENTED SYNTHESIS (FOS), RATIONAL DESIGN AND SERENDIPITY: THE AZA-TANSHINONE STORY

Pierfausto Seneci, Leonardo Manzoni, Luciana Marinelli, Marco Fragai, Vito d’Agostino and Alessandro Provenzani

Chemistry Dept., University of Milan, Italy

Abstract

A HTS campaign¹ identified naturally occurring tetracyclic dihydrotanshinone I² (DHTS I, 1) as a potent inhibitor of the HuR-mRNA interaction. We used FOS to structurally dissect DHTS I, and we rebuilt a biologically similar/structurally innovative bicyclic aza-tanshinone scaffold 2. We created a binding model between the HuR dimer and 1-2, using molecular modelling and NMR, and we established a preliminary SAR on rationally designed 1-, 3-, 6- and 7-substituted aza-tanshinones. We fully characterized aza-tanshinone leads 2a-c in terms of their anticancer and anti-inflammatory properties. We synthesized chemical probes 3 that were used to elucidate the cellular mechanism of action of azatanshinones 2.

REFERENCES

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[2] Zhang, Y.; Jiang, P.; Ye, M.; Kim, S. H.; Jiang, C.; Lu, J. Tanshinones: sources, pharmacokinetics and anti-cancer activities. Int. J. Mol. Sci. 2012, 13, 13621-13666.