eng URI http://hdl.handle.net/10795/2678 φαρμακευτικό προϊόν ένζυμο βιοχημεία βιοτεχνολογία The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18 ± 0.02 to 1.77 ± 0.10 μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4 ± 0.4 μM and 87 ± 1.9 μM, respectively), in addition to the strong enzyme inhibition profile (IC50(6) = 1,77 ± 0.10 μM; IC50(14) = 0.33 ± 0.05 μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. 14 pp. LOMv1.0 creator LOMv1.0 publisher LOMv1.0 Project Final Beneficiary LOMv1.0 Project Executing Organisation 2014-08-01 Digital Library of the Operational Programme "Education and Lifelong Learning" abstract types Text Benzophenone Enzyme inhibition Glutathione transferase Ketoxime Multiple drug resistance N-Acyl hydrazone http://www.sciencedirect.com/science/article/pii/S0968089614004532 3667701 application/pdf http://repository.edulll.gr/edulll/bitstream/10795/2678/2/2678_Paper%209.pdf URI http://hdl.handle.net/10795/2678 LOMv1.0creator 2016-04-15T09:26:57Z LOMv1.0validator 2016-04-15T09:26:57Z LOMv1.0 gre no no Copyright EYD-EPEDBM (Operational Programme "Education and Lifelong Learning")