Thymidine phosphorylase (TP) is an enzyme that is up-regulated in a wide variety of solid tumors, including breast and colorectal cancers. It is involved in tumor growth and metastasis, for this reason it is one of the key enzyme to be inhibited, in an attempt to prevent tumor proliferation. However, it also plays an active role in cancer treatment, through its contribution in the conversion of the anti-cancer drug 5-fluorouracil (5-FU) to an irreversible inhibitor of thymidylate synthase (TS), responsible of the inhibition of the DNA synthesis. In this work, the intrinsic TP fluorescence has been investigated for the first time and exploited to study TP binding affinity for the unsubstituted 5-FU and for two 5-FU derivatives, designed to expose this molecule on liposomal membranes. These molecules were obtained by functionalizing the nitrogen atom with a chain consisting of six (1) or seven (2) units of glycol, linked to an alkyl moiety of 12 carbon atoms. Derivatives (1) and (2) exhibited an affinity for TP in the micromolar range, 10 times higher than the parent compound, irrespective of the length of the polyoxyethylenic spacer. This high affinity was maintained also when the compounds were anchored in liposomal membranes. Experimental results were supported by molecular dynamics simulations and docking calculations, supporting a feasible application of the designed supramolecular lipid structure in selective targeting of TP, to be potentially used as a drug delivery system or sensor device.

Lettieri, R., D'Abramo, M., Stella, L., La Bella, A., Leonelli, F., Giansanti, L., et al. (2018). Fluorescence and computational studies of thymidine phosphorylase affinity toward lipidated 5-FU derivatives. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY, 195, 84-94 [10.1016/j.saa.2018.01.036].

Fluorescence and computational studies of thymidine phosphorylase affinity toward lipidated 5-FU derivatives

LETTIERI, RAFFAELLA;Stella L.;Venanzi M.;Gatto E.
2018-01

Abstract

Thymidine phosphorylase (TP) is an enzyme that is up-regulated in a wide variety of solid tumors, including breast and colorectal cancers. It is involved in tumor growth and metastasis, for this reason it is one of the key enzyme to be inhibited, in an attempt to prevent tumor proliferation. However, it also plays an active role in cancer treatment, through its contribution in the conversion of the anti-cancer drug 5-fluorouracil (5-FU) to an irreversible inhibitor of thymidylate synthase (TS), responsible of the inhibition of the DNA synthesis. In this work, the intrinsic TP fluorescence has been investigated for the first time and exploited to study TP binding affinity for the unsubstituted 5-FU and for two 5-FU derivatives, designed to expose this molecule on liposomal membranes. These molecules were obtained by functionalizing the nitrogen atom with a chain consisting of six (1) or seven (2) units of glycol, linked to an alkyl moiety of 12 carbon atoms. Derivatives (1) and (2) exhibited an affinity for TP in the micromolar range, 10 times higher than the parent compound, irrespective of the length of the polyoxyethylenic spacer. This high affinity was maintained also when the compounds were anchored in liposomal membranes. Experimental results were supported by molecular dynamics simulations and docking calculations, supporting a feasible application of the designed supramolecular lipid structure in selective targeting of TP, to be potentially used as a drug delivery system or sensor device.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore CHIM/02 - Chimica Fisica
English
Con Impact Factor ISI
Binding; Dissociation constants; Fluorescence; Liposomes; Spectroscopy; Thymidine phosphorylase
Lettieri, R., D'Abramo, M., Stella, L., La Bella, A., Leonelli, F., Giansanti, L., et al. (2018). Fluorescence and computational studies of thymidine phosphorylase affinity toward lipidated 5-FU derivatives. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY, 195, 84-94 [10.1016/j.saa.2018.01.036].
Lettieri, R; D'Abramo, M; Stella, L; La Bella, A; Leonelli, F; Giansanti, L; Venanzi, M; Gatto, E
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/193329
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