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Molecules 2018, 23(2), 407;

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

Department of Biological Sciences, Faculty of Pharmacy of the University of Porto (FFUP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
Department of Biology, School of Sciences, University of Minho, 4710-057 Braga, Portugal
i3S—Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
Cancer Drug Resistance Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal
Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Department of Food, Environmental and Nutritional Sciences Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, 20133 Milano, Italy
Department of Experimental Oncology and Molecular Medicine, Fondazione, IRCCS—Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milano, Italy
Authors to whom correspondence should be addressed.
Received: 30 December 2017 / Revised: 3 February 2018 / Accepted: 11 February 2018 / Published: 13 February 2018
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: HSP90; naphthoquinones; (thio)chromenopyridinones; antitumor; cell proliferation; cell cycle; apoptosis; tumor xenographs HSP90; naphthoquinones; (thio)chromenopyridinones; antitumor; cell proliferation; cell cycle; apoptosis; tumor xenographs

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Bizarro, A.; Sousa, D.; Lima, R.T.; Musso, L.; Cincinelli, R.; Zuco, V.; De Cesare, M.; Dallavalle, S.; Vasconcelos, M.H. Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors. Molecules 2018, 23, 407.

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