publication . Article . 2016

Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors

Boris Pinchuk; Rebecca Horbert; Alexander Döbber; Lydia Kuhl; Christian Peifer;
Open Access English
  • Published: 01 Apr 2016 Journal: Molecules, volume 21, issue 5 (eissn: 1420-3049, Copyright policy)
  • Publisher: MDPI
Abstract
In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for ca...
Subjects
free text keywords: Article, photoactivatable prodrugs, caging, receptor tyrosine kinase, kinase inhibitors, VEGFR-2, 3,4-diarylmaleimides, photoremovable protecting group (PPG), QD241-441, In vitro, Organic chemistry, biology.protein, biology, Enzyme, chemistry.chemical_classification, chemistry, Prodrug, Protein kinase A, Biochemistry, Protecting group, Kinase, Signal transduction
Related Organizations
61 references, page 1 of 5

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Cella, D., Beaumont, J.L.. Pazopanib in the treatment of advanced renal cell carcinoma. Ther. Adv. Urol.. 2016; 8: 61-69 [OpenAIRE] [PubMed] [DOI]

Awasthi, N., Schwarz, R.E.. Profile of nintedanib in the treatment of solid tumors: The evidence to date. Onco. Targets Ther.. 2015; 8: 3691-3701 [OpenAIRE] [PubMed] [DOI]

Ferrara, N., Gerber, H.-P., LeCouter, J.. The biology of VEGF and its receptors. Nat. Med.. 2003; 9: 669-676 [OpenAIRE] [PubMed] [DOI]

Huang, H., Shen, J., Vinores, S.A.. Blockade of VEGFR1 and 2 suppresses pathological angiogenesis and vascular leakage in the eye. PLoS ONE. 2011; 6 [OpenAIRE] [PubMed] [DOI]

Lee, S.H., Jeong, D., Han, Y.-S., Baek, M.J.. Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis. Ann. Surg. Treat. Res.. 2015; 89: 1-8 [OpenAIRE] [PubMed] [DOI]

Shibuya, M.. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem.. 2013; 153: 13-19 [OpenAIRE] [PubMed] [DOI]

Hartsough, E.J., Meyer, R.D., Chitalia, V., Jiang, Y., Marquez, V.E., Zhdanova, I.V., Weinberg, J., Costello, C.E., Rahimi, N.. Lysine methylation promotes VEGFR-2 activation and angiogenesis. Sci. Signal.. 2013; 6: ra104 [OpenAIRE] [PubMed] [DOI]

Ferrara, N., Hillan, K.J., Novotny, W.. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem. Biophys. Res. Commun.. 2005; 333: 328-335 [OpenAIRE] [PubMed] [DOI]

Rolfo, C., Bronte, G., Sortino, G., Papadimitriou, K., Passiglia, F., Fiorentino, E., Marogy, G., Russo, A., Peeters, M.. The role of targeted therapy for gastrointestinal tumors. Expert Rev. Gastroenterol. Hepatol.. 2014; 8: 875-885 [OpenAIRE] [PubMed] [DOI]

Noonan, S., Man Wong, K., Jimeno, A.. Nintedanib, a novel triple angiokinase inhibitor for the treatment of non-small cell lung cancer. Drugs Today. 2015; 51: 357-366 [OpenAIRE] [PubMed] [DOI]

Bischoff, J., Ignatov, A.. The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer. Breast Care. 2010; 5: 134-141 [OpenAIRE] [PubMed] [DOI]

Ryan, C.W.. Dosing strategies and optimization of targeted therapy in advanced renal cell carcinoma. J. Oncol. Pharm. Pract.. 2015 [OpenAIRE] [PubMed] [DOI]

Rutkowski, P., Stępniak, J.. The safety of regorafenib for the treatment of gastrointestinal stromal tumors. Expert Opin. Drug Saf.. 2016; 15: 105-116 [OpenAIRE] [PubMed] [DOI]

Corrado, A., Ferrari, S.M., Politti, U., Mazzi, V., Miccoli, M., Materazzi, G., Antonelli, A., Ulisse, S., Fallahi, P., Miccoli, P.. Aggressive thyroid cancer: targeted therapy with sorafenib. Min. Endocrinol.. 2015

61 references, page 1 of 5
Abstract
In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for ca...
Subjects
free text keywords: Article, photoactivatable prodrugs, caging, receptor tyrosine kinase, kinase inhibitors, VEGFR-2, 3,4-diarylmaleimides, photoremovable protecting group (PPG), QD241-441, In vitro, Organic chemistry, biology.protein, biology, Enzyme, chemistry.chemical_classification, chemistry, Prodrug, Protein kinase A, Biochemistry, Protecting group, Kinase, Signal transduction
Related Organizations
61 references, page 1 of 5

Hall, R.D., Le, T.M., Haggstrom, D.E., Gentzler, R.D.. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl. Lung Cancer Res.. 2015; 4: 515-523 [OpenAIRE] [PubMed]

Cella, D., Beaumont, J.L.. Pazopanib in the treatment of advanced renal cell carcinoma. Ther. Adv. Urol.. 2016; 8: 61-69 [OpenAIRE] [PubMed] [DOI]

Awasthi, N., Schwarz, R.E.. Profile of nintedanib in the treatment of solid tumors: The evidence to date. Onco. Targets Ther.. 2015; 8: 3691-3701 [OpenAIRE] [PubMed] [DOI]

Ferrara, N., Gerber, H.-P., LeCouter, J.. The biology of VEGF and its receptors. Nat. Med.. 2003; 9: 669-676 [OpenAIRE] [PubMed] [DOI]

Huang, H., Shen, J., Vinores, S.A.. Blockade of VEGFR1 and 2 suppresses pathological angiogenesis and vascular leakage in the eye. PLoS ONE. 2011; 6 [OpenAIRE] [PubMed] [DOI]

Lee, S.H., Jeong, D., Han, Y.-S., Baek, M.J.. Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis. Ann. Surg. Treat. Res.. 2015; 89: 1-8 [OpenAIRE] [PubMed] [DOI]

Shibuya, M.. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem.. 2013; 153: 13-19 [OpenAIRE] [PubMed] [DOI]

Hartsough, E.J., Meyer, R.D., Chitalia, V., Jiang, Y., Marquez, V.E., Zhdanova, I.V., Weinberg, J., Costello, C.E., Rahimi, N.. Lysine methylation promotes VEGFR-2 activation and angiogenesis. Sci. Signal.. 2013; 6: ra104 [OpenAIRE] [PubMed] [DOI]

Ferrara, N., Hillan, K.J., Novotny, W.. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem. Biophys. Res. Commun.. 2005; 333: 328-335 [OpenAIRE] [PubMed] [DOI]

Rolfo, C., Bronte, G., Sortino, G., Papadimitriou, K., Passiglia, F., Fiorentino, E., Marogy, G., Russo, A., Peeters, M.. The role of targeted therapy for gastrointestinal tumors. Expert Rev. Gastroenterol. Hepatol.. 2014; 8: 875-885 [OpenAIRE] [PubMed] [DOI]

Noonan, S., Man Wong, K., Jimeno, A.. Nintedanib, a novel triple angiokinase inhibitor for the treatment of non-small cell lung cancer. Drugs Today. 2015; 51: 357-366 [OpenAIRE] [PubMed] [DOI]

Bischoff, J., Ignatov, A.. The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer. Breast Care. 2010; 5: 134-141 [OpenAIRE] [PubMed] [DOI]

Ryan, C.W.. Dosing strategies and optimization of targeted therapy in advanced renal cell carcinoma. J. Oncol. Pharm. Pract.. 2015 [OpenAIRE] [PubMed] [DOI]

Rutkowski, P., Stępniak, J.. The safety of regorafenib for the treatment of gastrointestinal stromal tumors. Expert Opin. Drug Saf.. 2016; 15: 105-116 [OpenAIRE] [PubMed] [DOI]

Corrado, A., Ferrari, S.M., Politti, U., Mazzi, V., Miccoli, M., Materazzi, G., Antonelli, A., Ulisse, S., Fallahi, P., Miccoli, P.. Aggressive thyroid cancer: targeted therapy with sorafenib. Min. Endocrinol.. 2015

61 references, page 1 of 5
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publication . Article . 2016

Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors

Boris Pinchuk; Rebecca Horbert; Alexander Döbber; Lydia Kuhl; Christian Peifer;