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5'-TATA Sequence Through Bisintercalation from the Minor Groove (04/02/05) Jayati Roy Choudhury and Uli Bierbach In a search for synthetic molecules that can be targeted to the sites of transcription initiation (TATA box sequences), we identified a platinum-bis(acridine) agent that targets alternating TA sequences in a groove-specific manner (2-D NMR spectroscopy). Stereoview of an AMBER model of d(GCTATAGC)2 x PT-BIS(ACRAMTU): |
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NMR Solution Structure Determined (08/20/2004) Hemanta Baruah, Marcus W. Wright, Uli BierbachThe structure of a model duplex containing the most abundant DNA adduct induced by PT-ACRAMTU, a potent novel anticancer agent, has been determined by a combination of high-resolution NMR spectroscopy and restrained molecular dynamics/mechanics calculations and refined using the NOE-based full-relaxation matrix approach. Important structural features: (1) Platinum is bound to N7 of guanine in the major groove. (2) Acridine intercalates into the 5'-CG/CG base-pair step on the 5' face of the platinated guanine base. (3) The modified duplex is unwound at the intercalation site but not bent. (4) Overall, the adduct causes DNA conformational changes different from those induced by the 1,2 intrastrand cross-link formed by cisplatin (details to appear soon in the literature). STEREOVIEW OF THE STRUCTURE
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Platinum Targets Adenine-N3 in the Minor Groove of DNA (08/14/2004) Colin Barry, Cynthia Day, and Uli Bierbach For the first time in the history of platinum antitumor chemistry, a platinum agent (PT-ACRAMTU) has been identified that binds to endocyclic N3 of adenine. The adduct was isolated from mixtures of acidically digested drug-treated DNA and crystallized at pH 6.2 by slow evaporation of sitting drops. Minor-groove adducts of this hybrid agent are potentially cytotoxic lesions, which may have profound consequences for the proper transcription of genetic information. THERMAL ELLIPSOID PLOT OF [{Pt(en)(adenine-N3)ACRAMTU}2]6+
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