Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Bizarro, A (Author) Other; Sousa, D (Author) Other; Lima, RT (Author) Other; Musso, L (Author) Other; Cincinelli, R (Author) Other; Zuco, V (Author) Other; De Cesare, M (Author) Other; Dallavalle, S (Author) Other; Helena Vasconcelos, MH (Author) FFUP

Journal

Title: Molecules

Serial No. 9 Vol. 23 No. 2288

Final page: 407

ISSN: 1420-3049

Publisher: MDPI

Indexing

ISI Web of Knowledge - 7 Citations

Scopus - 7 Citations

Other information

Authenticus ID: P-00N-N73

DOI: 10.3390/molecules23020407

Abstract (EN): Background: Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl-naphtho[2,3-d] isoxazole-4,9-diones as inhibitors of HSP90. Methods: In the present work, various compounds with new chromenopyridinone and thiochromenopyridinone scaffolds were synthesized as potential HSP90 inhibitors. Their binding affinity to HSP90 was studied in vitro. Selected compounds (5 and 8) were further studied in various tumor cell lines regarding their potential to cause cell growth inhibition, alter the cell cycle profile, inhibit proliferation, and induce apoptosis. Their effect on HSP90 client protein levels was also confirmed in two cell lines. Finally, the antitumor activity of compound 8 was studied in A431 squamous cell carcinoma xenografts in nude mice. Results: Our results indicated that treatment with compounds 5 and 8 decreased the proliferation of tumor cell lines and compound 8 induced apoptosis. In addition, these two compounds were able to downregulate selected proteins known as "clients" of HSP90. Finally, treatment of xenografted mice with compound 5 resulted in a considerable dose-dependent inhibition of tumor growth. Conclusions: Our results show that two new compounds with a chromenopyridinone and thiochromenopyridinone scaffold are promising putative HSP90 inhibitors causing tumor cell growth inhibition.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15