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

Ana Bizarro, Diana Sousa, Raquel T Lima, Loana Musso, Raffaella Cincinelli, Vantina Zuco, Michelandrea De Cesare, Sabrina Dallavalle, M Helena Vasconcelos

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalMolecules
Volume23
Issue number2
DOIs
Publication statusPublished - Feb 13 2018

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HSP90 Heat-Shock Proteins
Cell growth
Tumors
Cells
Apoptosis
Isoxazoles
Scaffolds (biology)
Heterografts
Scaffolds
Proteins

Keywords

  • Animals
  • Antineoplastic Agents/chemical synthesis
  • Apoptosis/drug effects
  • Benzopyrans/chemical synthesis
  • Carcinoma, Squamous Cell/drug therapy
  • Cell Cycle/drug effects
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Cyclin-Dependent Kinase 4/antagonists & inhibitors
  • Female
  • Gene Expression Regulation, Neoplastic
  • HSP90 Heat-Shock Proteins/antagonists & inhibitors
  • Humans
  • Inhibitor of Apoptosis Proteins/antagonists & inhibitors
  • Inhibitory Concentration 50
  • Isoxazoles/chemical synthesis
  • Mice
  • Mice, Nude
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors
  • Pyridones/chemical synthesis
  • Signal Transduction
  • Skin Neoplasms/drug therapy
  • Survivin
  • Tumor Burden/drug effects
  • Xenograft Model Antitumor Assays
  • raf Kinases/antagonists & inhibitors

Cite this

Bizarro, A., Sousa, D., Lima, R. T., Musso, L., Cincinelli, R., Zuco, V., ... Vasconcelos, M. H. (2018). Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors. Molecules, 23(2). https://doi.org/10.3390/molecules23020407

Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors. / Bizarro, Ana; Sousa, Diana; Lima, Raquel T; Musso, Loana; Cincinelli, Raffaella; Zuco, Vantina; De Cesare, Michelandrea; Dallavalle, Sabrina; Vasconcelos, M Helena.

In: Molecules, Vol. 23, No. 2, 13.02.2018.

Research output: Contribution to journalArticle

Bizarro, A, Sousa, D, Lima, RT, Musso, L, Cincinelli, R, Zuco, V, De Cesare, M, Dallavalle, S & Vasconcelos, MH 2018, 'Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors', Molecules, vol. 23, no. 2. https://doi.org/10.3390/molecules23020407
Bizarro, Ana ; Sousa, Diana ; Lima, Raquel T ; Musso, Loana ; Cincinelli, Raffaella ; Zuco, Vantina ; De Cesare, Michelandrea ; Dallavalle, Sabrina ; Vasconcelos, M Helena. / Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors. In: Molecules. 2018 ; Vol. 23, No. 2.
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T1 - Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors

AU - Bizarro, Ana

AU - Sousa, Diana

AU - Lima, Raquel T

AU - Musso, Loana

AU - Cincinelli, Raffaella

AU - Zuco, Vantina

AU - De Cesare, Michelandrea

AU - Dallavalle, Sabrina

AU - Vasconcelos, M Helena

PY - 2018/2/13

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N2 - 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.

AB - 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.

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KW - Cell Proliferation/drug effects

KW - Cyclin-Dependent Kinase 4/antagonists & inhibitors

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KW - Gene Expression Regulation, Neoplastic

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KW - Inhibitor of Apoptosis Proteins/antagonists & inhibitors

KW - Inhibitory Concentration 50

KW - Isoxazoles/chemical synthesis

KW - Mice

KW - Mice, Nude

KW - Proto-Oncogene Proteins c-akt/antagonists & inhibitors

KW - Pyridones/chemical synthesis

KW - Signal Transduction

KW - Skin Neoplasms/drug therapy

KW - Survivin

KW - Tumor Burden/drug effects

KW - Xenograft Model Antitumor Assays

KW - raf Kinases/antagonists & inhibitors

U2 - 10.3390/molecules23020407

DO - 10.3390/molecules23020407

M3 - Article

VL - 23

JO - Molecules

JF - Molecules

SN - 1420-3049

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ER -