Total synthesis and a systematic structure-activity relationship study of WAP-8294A2 |
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| Institution: | 1. Department of Chemistry, The University of Hong Kong, Hong Kong, China;2. Department of Infectious Diseases and Public Health, The City University of Hong Kong, PR China;1. Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1, Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka 808-0135, Japan;2. University of Occupational and Environmental Health, 1-1 Isegaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan;1. School of Chinese Medicine, The University of Hong Kong, Hong Kong;2. Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong;3. Department of Chemistry, Faculty of Science, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong;4. Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hung Hom, Hong Kong;1. Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy;2. Synchrotron SOLEIL, L’Orme des Merisiers, Saint-Aubin, BP 48, 91192 Gif-sur-Yvette, France;3. Université Paris-Saclay, CNRS, BioCIS, rue Jean-Baptiste Clément 5, 92290 Châtenay-Malabry, France;4. Université Paris Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SIMoS, 91191 Gif-sur-Yvette, France;5. Research Center “E. Piaggio”, Università di Pisa, Pisa 56122, Italy;6. Department of Earth Sciences, University of Pisa, Via Santa Maria 53-55, 56100 Pisa, Italy;1. Department of Chemistry, Oakland University, Rochester, MI 48309, USA;2. Department of Chemistry, Portland State University, Portland, OR 97201, USA;3. Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA;4. Department of Forensic Science, Environmental and Life Sciences, Trent University, Peterborough, ON K9J 0G2, Canada;1. Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA;2. Rammelkamp Center for Research and Department of Medicine, MetroHealth Campus, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA;1. Graduate School of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu 514-8507, Japan;2. National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan |
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| Abstract: | WAP-8294A2 is a cyclic peptide antibiotic with novel structure and excellent activity against Gram-positive pathogens. Herein, we report the total synthesis of complex macrocyclic peptide WAP-8294A2 (W1), ent-analogue W2, deoxy analogue W3 and de-methyl analogue W4 using a solid-phase synthetic route followed by a final stage solution-phase cyclization reaction. Exploitation of this process allowed the synthesis of eleven alanine-scanning analogues and eight lysine-scanning analogues. The antimicrobial activity of these analogues was evaluated in vitro against Gram-positive bacteria. Based on the MIC results, a primary systematic structure-activity relationship has been established. |
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| Keywords: | WAP-8294A2 Total synthesis Alanine scan Lysine scan |
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