STAT3 (Signal Transducer and Activator for Transcription 3) is a latent cytosolic protein that directly relates extracellular signals(e.g. growth factors, poly-peptide, cytokines etc.) from the membrane to the nucleus [1]. STAT3 is constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of human solid and blood tumours. Since STAT3 inhibition leads to apoptosis in tumour cells but not in normal cells, it represents a promising target for cancer therapy [2]. In our research we focused on the discovery of new ureido oxadiazole derivatives related to AVS-2088 (lead compound), as potential STAT3 inhibitors, with the aim to identify the essential structure-activity requirements for the development of novel active compounds. Our previous results [3] indicated that the presence of a phenyl moiety in position 4 of the oxadiazole ring was critical for the interaction with the biological target, so we planned the synthesis of the styryl derivatives. On these basis, we analyzed the X-Ray structures of the compounds having the general formula reported in Figure 2 and structure-activity relationships were derived. The drop in activity of the derivatives with respect to the lead could be due to the presence of the common flexible benzyl chain linked to the urea that disrupted the flat conformation of the entire molecule, influencing its orientation and interaction at the receptor site. The synthetic procedures applied for the preparation of the new derivatives as well as the results of the crystallographic studies and their biological evaluation will be presented.[1] Yu, H.; Jove, R. The STATs of cancer-new molecular targets come of age. Nat. Rev. Cancer 2004, 4, 97-105. [2] D. Masciocchi, A. Gelain, S. Villa, F. Meneghetti, D. Barlocco. Signal Transducer and Activator of Transcription 3 (STAT3): a promising target for anticancer therapy. Future Med. Chem. 2011, 3, 567-597. [3] Shin, D.-S.; Masciocchi, D.; Gelain, A.; Villa, S.; Barlocco, D.; Meneghetti, F.; Pedretti, A.; Han, Y.-M.; Han, D. C.; Han, M. Y.; Kwon, B.-M.; Legnani, L.; Toma L. Synthesis, modeling, and crystallographic study of 3,4-disubstituted-1,2,5-oxadiazoles and evaluation of their ability to decrease STAT3 activity. Med. Chem. Comm. 2010, 1, 156-164.

Chemical behaviour and crystallographic characterization of ureido 1,2,5-oxadiazole derivatives, related to Stat3 inhibitors / F. Meneghetti, D. Masciocchi, A. Gelain, S. Villa - In: atti congresso[s.l] : none, 2011 Jun. (( convegno Frontiers in Medicinal Chemistry Meeting : Emerging Targets, Novel Candidates and Innovative Strategies tenutosi a Stockholm nel 2011.

Chemical behaviour and crystallographic characterization of ureido 1,2,5-oxadiazole derivatives, related to Stat3 inhibitors

F. Meneghetti
Primo
;
D. Masciocchi
Secondo
;
A. Gelain
Penultimo
;
S. Villa
Ultimo
2011-06

Abstract

STAT3 (Signal Transducer and Activator for Transcription 3) is a latent cytosolic protein that directly relates extracellular signals(e.g. growth factors, poly-peptide, cytokines etc.) from the membrane to the nucleus [1]. STAT3 is constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of human solid and blood tumours. Since STAT3 inhibition leads to apoptosis in tumour cells but not in normal cells, it represents a promising target for cancer therapy [2]. In our research we focused on the discovery of new ureido oxadiazole derivatives related to AVS-2088 (lead compound), as potential STAT3 inhibitors, with the aim to identify the essential structure-activity requirements for the development of novel active compounds. Our previous results [3] indicated that the presence of a phenyl moiety in position 4 of the oxadiazole ring was critical for the interaction with the biological target, so we planned the synthesis of the styryl derivatives. On these basis, we analyzed the X-Ray structures of the compounds having the general formula reported in Figure 2 and structure-activity relationships were derived. The drop in activity of the derivatives with respect to the lead could be due to the presence of the common flexible benzyl chain linked to the urea that disrupted the flat conformation of the entire molecule, influencing its orientation and interaction at the receptor site. The synthetic procedures applied for the preparation of the new derivatives as well as the results of the crystallographic studies and their biological evaluation will be presented.[1] Yu, H.; Jove, R. The STATs of cancer-new molecular targets come of age. Nat. Rev. Cancer 2004, 4, 97-105. [2] D. Masciocchi, A. Gelain, S. Villa, F. Meneghetti, D. Barlocco. Signal Transducer and Activator of Transcription 3 (STAT3): a promising target for anticancer therapy. Future Med. Chem. 2011, 3, 567-597. [3] Shin, D.-S.; Masciocchi, D.; Gelain, A.; Villa, S.; Barlocco, D.; Meneghetti, F.; Pedretti, A.; Han, Y.-M.; Han, D. C.; Han, M. Y.; Kwon, B.-M.; Legnani, L.; Toma L. Synthesis, modeling, and crystallographic study of 3,4-disubstituted-1,2,5-oxadiazoles and evaluation of their ability to decrease STAT3 activity. Med. Chem. Comm. 2010, 1, 156-164.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/160123
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