Toward a Library Synthesis of the Natural Dipeptide Antibiotic TAN 1057 A,B 英文参考文献.docVIP

Molecules 2002, 7, 469-474 molecules ISSN 1420-3049 Toward a Library Synthesis of the Natural Dipeptide Antibiotic TAN 1057 A,B Nuria Aguilar and Jochen Krüger* Bayer-AG, Business Group Pharma, Research, 42096 Wuppertal, Germany, Tel. +49-202-368644, Fax +49 202/364061. * Author to whom correspondence should be addressed; e-mail: Joachim.Krueger.JK2@bayer-ag.de Received: 2 May 2002; in revised form: 10 June 2002 / Accepted: 14 June 2002/ Published: 30 June 2002 Abstract: The natural dipeptide antibiotic TAN 1057 A,B represents a promising new antibiotic entity. In this communication we report a novel approach for the synthesis of TAN 1057 A,B analogs bearing variations in the β-arginine side chain. This approach involves a combination of liquid and solid phase methods and allows for a library synthesis of analogs of the natural product. Keywords: TAN 1057 A, B, dipeptide antibiotics, combinatorial chemistry. Introduction The natural dipeptide antibiotic TAN 1057 A,B (1, Figure 1) was first isolated and characterized by Takeda [1]. To date, two independent total syntheses of this natural product have been disclosed [2]. TAN 1057 A,B displays excellent in vitro and in vivo activity against staphylococci including Methicillin Resistant Staphylococcus Aureus (MRSA) and represents a promising new antibiotic entity [3]. However, TAN 1057 A,B suffers from strong toxic side effects (LD50 = 50 mg/Kg) which are in our view prohibitive for therapeutic use in humans. Therefore, we launched a synthesis program with the goal of identifying  Molecules 2002, 7 470 analogs with significantly improved tolerance and concomitant retention of the promising antibiotic activity. In this communication we report a new strategy that allows for the parallel synthesis of novel derivatives of the natural product focusing on alteration of the β-arginine moiety. Figure 1: TAN 1057 A, B (1). H NH HN NH O