A Strategy for the Diversity-oriented Synthesis of Macrocyclic Scaffolds Using Multidimensional Coupling

Overview

Journal Nat Chem

Specialty Chemistry

Date 2013 Sep 24

PMID 24056343

Citations 33

Authors

Henning S G Beckmann

Feilin Nie

Caroline E Hagerman

Henrik Johansson

Yaw Sing Tan

David Wilcke

David R Spring

Affiliations

Soon will be listed here.

Abstract

A prerequisite for successful screening campaigns in drug discovery or chemical genetics is the availability of structurally and thus functionally diverse compound libraries. Diversity-oriented synthesis (DOS) provides strategies for the generation of such libraries, of which the build/couple/pair (B/C/P) algorithm is the most frequently used. We have developed an advanced B/C/P strategy that incorporates multidimensional coupling. In this approach, structural diversity is not only defined by the nature of the building blocks employed, but also by the linking motif installed during the coupling reaction. We applied this step-efficient approach in a DOS of a library that consisted of 73 macrocyclic compounds based around 59 discrete scaffolds. The macrocycles prepared cover a broad range of different molecular shapes, as illustrated by principal moment-of-inertia analysis. This demonstrates the capability of the advanced B/C/P strategy using multidimensional coupling for the preparation of structurally diverse compound collections.

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References

Brown L, Cheng K, Wei W, Yuan P, Dai P, Trilles R . Discovery of new antimalarial chemotypes through chemical methodology and library development. Proc Natl Acad Sci U S A. 2011; 108(17):6775-80. PMC: 3084078. DOI: 10.1073/pnas.1017666108. View

Frearson J, Collie I . HTS and hit finding in academia--from chemical genomics to drug discovery. Drug Discov Today. 2009; 14(23-24):1150-8. PMC: 2814004. DOI: 10.1016/j.drudis.2009.09.004. View

Clemons P, Bodycombe N, Carrinski H, Wilson J, Shamji A, Wagner B . Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles. Proc Natl Acad Sci U S A. 2010; 107(44):18787-92. PMC: 2973913. DOI: 10.1073/pnas.1012741107. View

. Methods for the synthesis of macrocycle libraries for drug discovery. Drug Discov Today Technol. 2013; 7(2):e95-e146. DOI: 10.1016/j.ddtec.2010.06.002. View

Kelly A, Wei J, Kesavan S, Marie J, Windmon N, Young D . Accessing skeletal diversity using catalyst control: formation of n and n + 1 macrocyclic triazole rings. Org Lett. 2009; 11(11):2257-60. PMC: 2702139. DOI: 10.1021/ol900562u. View

Marsault E, Peterson M . Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J Med Chem. 2011; 54(7):1961-2004. DOI: 10.1021/jm1012374. View

Macarron R, Banks M, Bojanic D, Burns D, Cirovic D, Garyantes T . Impact of high-throughput screening in biomedical research. Nat Rev Drug Discov. 2011; 10(3):188-95. DOI: 10.1038/nrd3368. View

White C, Yudin A . Contemporary strategies for peptide macrocyclization. Nat Chem. 2011; 3(7):509-24. DOI: 10.1038/nchem.1062. View

Burke M, Schreiber S . A planning strategy for diversity-oriented synthesis. Angew Chem Int Ed Engl. 2003; 43(1):46-58. DOI: 10.1002/anie.200300626. View

10.

Comer E, Liu H, Joliton A, Clabaut A, Johnson C, Akella L . Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles. Proc Natl Acad Sci U S A. 2011; 108(17):6751-6. PMC: 3084052. DOI: 10.1073/pnas.1015255108. View

11.

Yoo B, Shin S, Huang M, Kirshenbaum K . Peptoid macrocycles: making the rounds with peptidomimetic oligomers. Chemistry. 2010; 16(19):5528-37. DOI: 10.1002/chem.200903549. View

12.

Sauer W, Schwarz M . Molecular shape diversity of combinatorial libraries: a prerequisite for broad bioactivity. J Chem Inf Comput Sci. 2003; 43(3):987-1003. DOI: 10.1021/ci025599w. View

13.

Tornoe C, Christensen C, Meldal M . Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J Org Chem. 2002; 67(9):3057-64. DOI: 10.1021/jo011148j. View

14.

Burke M, Berger E, Schreiber S . Generating diverse skeletons of small molecules combinatorially. Science. 2003; 302(5645):613-8. DOI: 10.1126/science.1089946. View

15.

O Connor C, Beckmann H, Spring D . Diversity-oriented synthesis: producing chemical tools for dissecting biology. Chem Soc Rev. 2012; 41(12):4444-56. DOI: 10.1039/c2cs35023h. View

16.

Spring D . Diversity-oriented synthesis; a challenge for synthetic chemists. Org Biomol Chem. 2003; 1(22):3867-70. DOI: 10.1039/b310752n. View

17.

Oh S, Park S . A design strategy for drug-like polyheterocycles with privileged substructures for discovery of specific small-molecule modulators. Chem Commun (Camb). 2011; 47(48):12754-61. DOI: 10.1039/c1cc14042f. View

18.

Dandapani S, Marcaurelle L . Grand challenge commentary: Accessing new chemical space for 'undruggable' targets. Nat Chem Biol. 2010; 6(12):861-3. DOI: 10.1038/nchembio.479. View

19.

Galloway W, Isidro-Llobet A, Spring D . Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun. 2010; 1:80. DOI: 10.1038/ncomms1081. View

20.

Menand M, Jabin I . Synthesis of the first calix[6]crypturea via a versatile tris-azide precursor. Org Lett. 2009; 11(3):673-6. DOI: 10.1021/ol8027384. View