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Title: Investigations on aurones as modulators of ABCG2
Keywords: Aurones,ABCG2,ABCB1,modulators, structure-activity relationships,pharmacophore
Issue Date: 19-Aug-2010
Citation: SIM HONG MAY (2010-08-19). Investigations on aurones as modulators of ABCG2. ScholarBank@NUS Repository.
Abstract: Aurones were hypothesized to interact with the ATP-Binding Cassette (ABC) protein ABCG2 to modulate its efflux activity. ABCG2 is associated with multi-drug resistance to cancer chemotherapy and modulation of ABCG2 by aurones would underscore the potential of this template for the design of multi-drug reversal agents. Twelve series of compounds comprising 112 functionalized aurones and related analogs were synthesized and screened for inhibition of Pheophorbide a (PhA) efflux in MDA-MB-231/R cells. Several dimethoxyaurones, benzylideneindanones, dimethoxyflavones were found to have micromolar modulatory potencies that were comparable to an established ABCG2 inhibitor, Fumitremorgin C (FTC). A qualitative assessment of the structural features required for modulatory activity highlighted important roles for (i) a methoxylated ring A but not a hydroxylated or unsubstituted ring A; (ii) an intact exocyclic double bond attached to a 5-membered ring C (iii) the location of the double bond on ring C. Activity is retained when O in aurone is replaced by a methylene CH2 but not by a NH. A dimethoxylated ring A together with a disubstituted ring B, particularly with dimethoxy groups at 3',4' or 3',5'-positions yielded the most potent inhibitors among the aurones, indanones and flavones (EC50: 0.91 to 2.45uM). QSAR approach based on the modified Free-Wilson method identified methoxy groups on ring A as significant contributors to activity, functioning as hydrogen bond acceptors and hydrophobic features in a pharmacophore model. Mitoxantrone (MX) sensitization assay showed that potent analogs completely restored sensitivity to MX in MDA-MB-231/R cells at 0.5uM which can be attributed to the increase in the accumulation of intracellular MX. Direct interaction between ABCG2 and selected flavonoidic compounds were investigated with the ABCG2 ATPase assay which showed the most potent inhibitors stimulating ATPase activity at nanomolar Km values. Photoaffinity-labeling of ABCG2 by [125 I]-IAAP was reduced in the presence of several potent members, pointing to competition for IAAP binding site on ABCG2. Likelihood of the compounds interfering with upstream cellular processes involved in the synthesis of the ABCG2 protein was excluded by Western blot analysis. The in vivo efficacy of a representative dimethoxyaurone (1-26) in sensitizing a MDA-MB-231/R xenograft induced in Balb/c mice to the cytotoxic effects of MX was also demonstrated. The combination of 1-26 and MX significantly increased the life span of the treated mice, illustrating the translation of in vitro results to xenograft-bearing animals. In conclusion, the findings of this thesis supported the hypothesis that aurones was a promising template with modulatory properties on the ABCG2. Well-defined structural requirements were needed for interaction with ABCG2. Aurone 1-26 was identified as a promising lead for further advancement to preclinical evaluation as a non-toxic and potent modulator of ABCG2.
Appears in Collections:Ph.D Theses (Open)

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