Abstract
Mycobacterium tuberculosis (Mtb) is a bacterial pathogen that causes a potentially serious infectious disease called tuberculosis (TB). Cyclohexapeptide wollamides A and B were recently isolated from Streptomyces nov. sp. (MST-115088) and subsequently reported to show excellent in vitro antituberculosis activity with minimum inhibitory concentration (MIC) of 1.56 μg/mL against Mtb (H37Rv) and favorable selectivity profile. This chapter describes the detailed synthesis of antitubercular wollamide analogs using solid-phase synthesis of linear hexapeptide precursors, followed by solution-phase HBTU-mediated macrocyclization and global side chain deprotection.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Smith I (2003) Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev 16:463–496
Hoagland DT, Liu J, Lee RB, Lee RE (2016) New agents for the treatment of drug-resistant Mycobacterium tuberculosis. Adv Drug Deliv Rev 102:55–72
Koch A, Cox H, Mizrahi V (2018) Drug-resistant tuberculosis: challenges and opportunities for diagnosis and treatment. Curr Opin Pharmacol 42:7–15
Prior AM, Sun D (2018) Scope and optimization of the double Knorr cyclization: Synthesis of novel symmetrical and unsymmetrical tricyclic 1,8-diazaanthraquinones. Synthesis 50:859–871
Khalil ZG, Salim AA, Lacey E, Blumenthal A, Capon RJ (2014) Wollamides: antimycobacterial cyclic hexapeptides from an Australian soil Streptomyces. Org Lett 16:5120–5123
Tsutsumi LS, Elmore JM, Dang UT, Wallace MJ, Marreddy R, Lee RB et al (2018) Solid-phase synthesis and antibacterial activity of cyclohexapeptide wollamide B analogs. ACS Comb Sci 20:172–185
Asfaw H, Laqua K, Walkowska AM, Cunningham F, Martinez-Martinez MS, Cuevas-Zurita JC et al (2017) Design, synthesis and structure-activity relationship study of wollamide B; a new potential anti TB agent. PLoS One 12:e0176088
Tsutsumi LS, Tan GT, Sun D (2017) Solid-phase synthesis of cyclic hexapeptides wollamides A, B and desotamide B. Tetrahedron Lett 58:2675–2680
Chen Y-X, Liu C, Liu N, Wu Y, Zhao Q-J, Hu H-G et al (2018) Total synthesis and antibacterial study of cyclohexapeptides Desotamide B, Wollamide B and their analogs. Chem Biodivers 15:e1700414
Asfaw H, Wetzlar T, Martinez-Martinez MS, Imming P (2018) An efficient synthetic route for preparation of antimycobacterial wollamides and evaluation of their in vitro and in vivo efficacy. Bioorg Med Chem Lett 28:2899–2905
Khalil ZG, Hill TA, De Leon Rodriguez LM, Lohman R-J, Hoang HN, Reiling N et al (2019) Structure-activity relationships of wollamide cyclic hexapeptides with activity against drug-resistant and intracellular Mycobacterium tuberculosis. Antimicrob Agents Chemother 63:e01773–18. https://doi.org/10.1128/AAC.01773-18
Prior A, Hori T, Fishman A, Sun D (2018) Recent reports of solid-phase cyclohexapeptide synthesis and applications. Molecules 23:1475
Sun D, Lee RE (2007) Solid-phase synthesis of a thymidinyl dipeptide urea library. J Comb Chem 9:370–385
Acknowledgments
This work was, in part, supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM103466 and the DKICP RTRF fund.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Prior, A.M., Sun, D. (2020). Solid-Phase Synthesis of Wollamide Cyclohexapeptide Analogs. In: Hussein, W., Skwarczynski, M., Toth, I. (eds) Peptide Synthesis. Methods in Molecular Biology, vol 2103. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0227-0_11
Download citation
DOI: https://doi.org/10.1007/978-1-0716-0227-0_11
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-0226-3
Online ISBN: 978-1-0716-0227-0
eBook Packages: Springer Protocols