dynamic combinatorial chemistry

File:Oligosaccharide self-assembly.pdf

By modern definition, dynamic combinatorial chemistry is generally considered to be a method of facilitating the generation of new chemical species by the reversible linkage of simple building blocks, under thermodynamic control. This principle is known to select the most thermodynamically stable product from an equilibrating mixture of a number of components, a concept commonly utilised in synthetic chemistry to direct the control of reaction selectivity.{{Cite journal|title = Dynamic Covalent Chemistry|journal = Angewandte Chemie International Edition|date = 2002-03-15|issn = 1521-3773|pages = 898–952|volume = 41|issue = 6|doi = 10.1002/1521-3773(20020315)41:6<898::AID-ANIE898>3.0.CO;2-E |first1 = Stuart J.|last1 = Rowan|author1-link=Stuart Rowan|first2 = Stuart J.|last2 = Cantrill|first3 = Graham R. L.|last3 = Cousins|first4 = Jeremy K. M.|last4 = Sanders|first5 = J. Fraser|last5 = Stoddart|pmid = 12491278 }} Although this approach was arguably utilised in the work of Fischer{{Cite journal|title = Emil Fischer—Unequalled Classicist, Master of Organic Chemistry Research, and Inspired Trailblazer of Biological Chemistry|journal = Angewandte Chemie International Edition|date = 2002-12-02|issn = 1521-3773|pages = 4439–4451|volume = 41|issue = 23|doi = 10.1002/1521-3773(20021202)41:23<4439::AID-ANIE4439>3.0.CO;2-6 |first = Horst|last = Kunz|pmid = 12458504 }} and Werner{{Cite journal|title = Coordination chemistry: the scientific legacy of Alfred Werner|journal = Chem. Soc. Rev.|pages = 1429–1439|volume = 42|issue = 4|doi = 10.1039/c2cs35428d|pmid = 23223794|first1 = Edwin C.|last1 = Constable|first2 = Catherine E.|last2 = Housecroft|date = 2013-01-28}} as early as the 19th century, their respective studies of carbohydrate and coordination chemistry were restricted to rudimentary speculation, requiring the rationale of modern thermodynamics.{{Cite journal|title = Expanding roles for templates in synthesis|journal = Accounts of Chemical Research|date = 1993-09-01|issn = 0001-4842|pages = 469–475|volume = 26|issue = 9|doi = 10.1021/ar00033a003|first1 = Sally|last1 = Anderson|first2 = Harry L.|last2 = Anderson|first3 = Jeremy K. M.|last3 = Sanders}}{{Cite journal|title = Template Syntheses|journal = Angewandte Chemie International Edition in English|date = 1994-03-03|issn = 1521-3773|pages = 375–384|volume = 33|issue = 4|doi = 10.1002/anie.199403751|first1 = Ralf|last1 = Hoss|first2 = Fritz|last2 = Vögtle}} It was not until supramolecular chemistry revealed early concepts of molecular recognition, complementarity and self-organisation that chemists could begin to employ strategies for the rational design and synthesis of macromolecular targets.{{Cite journal|title = From supramolecular chemistry towards constitutional dynamic chemistry and adaptive chemistry|journal = Chem. Soc. Rev.|pages = 151–160|volume = 36|issue = 2|doi = 10.1039/b616752g|pmid = 17264919|first = Jean-Marie|last = Lehn|date = 2007-01-30}} The concept of template synthesis was further developed and rationalised through the pioneering work of Busch in the 1960s, which clearly defined the role of a metal ion template in stabilising the desired ‘thermodynamic’ product, allowing for its isolation from the complex equilibrating mixture.{{Cite journal|title = Reactions of Coordinated Ligands. VI. Metal Ion Control in the Synthesis of Planar Nickel(II) Complexes of α-Diketo-bis-mercaptoimines|journal = Journal of the American Chemical Society|date = 1964-01-01|issn = 0002-7863|pages = 213–217|volume = 86|issue = 2|doi = 10.1021/ja01056a021|first1 = Major C.|last1 = Thompson|first2 = Daryle H.|last2 = Busch}}{{Cite journal|title = Reactions of Coördinated Ligands. II. Nickel(II) Complexes of Some Novel Tetradentate Ligands|journal = Journal of the American Chemical Society|date = 1962-05-01|issn = 0002-7863|pages = 1762–1763|volume = 84|issue = 9|doi = 10.1021/ja00868a073|first1 = Major C.|last1 = Thompson|first2 = Daryle H.|last2 = Busch}} Although the work of Busch helped to establish the template method as a powerful synthetic route to stable macrocyclic structures, this approach remained exclusively within the domain of inorganic chemistry until the early 1990s, when Sanders et al. first proposed the concept of dynamic combinatorial chemistry. Their work combined thermodynamic templation in tandem with combinatorial chemistry, to generate a mixture complex porphyrin and imine macrocycles using a modest selection of simple building blocks.

Sanders then developed this early manifestation of dynamic combinatorial chemistry as a strategy for organic synthesis; the first example being the thermodynamically-controlled macrolactonisation of oligocholates to assemble cyclic steroid-derived macrocycles capable of interconversion via component exchange.{{Cite journal|title = ?Living? macrolactonisation: thermodynamically-controlled cyclisation and interconversion of oligocholates|journal = Chemical Communications|issue = 3|doi = 10.1039/cc9960000319|first1 = Paul A.|last1 = Brady|first2 = Richard P.|last2 = Bonar-Law|first3 = Stuart J.|last3 = Rowan|first4 = Christopher J.|last4 = Suckling|first5 = Jeremy K. M.|last5 = Sanders|pages=319–320|date = January 1996}} Early work by Sanders et al. employed transesterification to generate dynamic combinatorial libraries. In retrospect, it was unfortunate that esters were selected for mediating component exchange, as transesterification processes are inherently slow and require vigorous anhydrous conditions. However, their subsequent investigations identified that both the disulfide and hydrazone covalent bonds exhibit effective component exchange processes and so present a reliable means of generating dynamic combinatorial libraries capable of thermodynamic templation. This chemistry now forms the basis of much research in the developing field of dynamic covalent chemistry, and has in recent years emerged as a powerful tool for the discovery of molecular receptors.

One of the key developments within the field of DCC is the use of proteins (or other biological macromolecules, such as nucleic acids) to influence the evolution and generation of components within a DCL.Greaney, M. F.; Bhat, V. T. Protein-directed dynamic combinatorial chemistry. In Dynamic combinatorial chemistry: in drug discovery, bioinorganic chemistry, and materials sciences; Miller, B. L., Ed.; John Wiley & Sons: New Jersey, 2010; Chapter 2, pp 43–82.{{cite journal |author1=Huang, R. |author2=Leung, I. K. H. | title = Protein-directed dynamic combinatorial chemistry: a guide to protein ligand and inhibitor discovery | journal = Molecules | volume = 21 | issue = 7 | pages = 910 |date=Jul 2016 | pmid = 27438816 | pmc = 6273345| doi = 10.3390/molecules21070910 |doi-access=free }}{{cite journal |author1=Frei, P. |author2=Hevey, R. | author3=Ernst, B. | title = Dynamic Combinatorial Chemistry: A New Methodology Comes of Age | journal = Chem. Eur. J. | volume = 25| issue = 1| pages = 60–73|date=Sep 2018 | pmid = 30204930 | doi = 10.1002/chem.201803365 |s2cid=52188992 }}{{cite journal |author1=Jaegle, M. |author2= Wong, E. L. |author3= Tauber, C. |author4= Nawrotzky, E. |author5= Arkona, C. |author6= Rademann, J. | title = Protein-templated fragment ligations - from molecular recognition to drug discovery | journal = Angew. Chem. Int. Ed. | volume = 56| issue = 26| pages = 7358–7378|date=Jan 2017 | pmid = 28117936 | pmc = 7159684| doi = 10.1002/anie.201610372 }}{{cite journal |author1=Mondal, M. |author2=Hirsch, A. K. | title = Dynamic combinatorial chemistry: a tool to facilitate the identification of inhibitors for protein targets | journal = Chem. Soc. Rev. | volume = 44 | issue = 8 | pages = 2455–2488 |date=Apr 2015 | pmid = 25706945 | doi = 10.1039/c4cs00493k | doi-access = free }}{{cite journal |author1=Herrmann, A. | title = Dynamic combinatorial/covalent chemistry: a tool to read, generate and modulate the bioactivity of compounds and compound mixtures | journal = Chem. Soc. Rev. | volume = 43 | issue = 6 | pages = 1899–1933 |date=Mar 2014 | pmid = 24296754 | doi = 10.1039/c3cs60336a }} Protein-directed DCC provides a way to generate, identify and rank novel protein ligands, and therefore have huge potential in the areas of enzyme inhibition and drug discovery.Hochgürtel, M.; Lehn, J.-M. Dynamic combinatorial diversity in drug discovery. In Fragment-based approaches in drug discovery; Jahnke, W., Erlanson, D. A., Ed.; Wiley-VCH: Weinheim, 2006; Chapter 16, pp 341–364.

File:Protein DCC.PNG

File:Types of DCC reactions.PNG

The development of Protein-directed DCC has not been straightforward because the reversible reactions employed must occur in aqueous solution at biological pH and temperature, and the components of the DCL must be compatible with proteins.

Several reversible reactions have been proposed and/or applied in Protein-directed DCC. These included boronate ester formation,{{cite journal |author1=Demetriades, M. |author2=Leung, I. K. H. |author3=Chowdhury, R. |author4=Chan, M. C. |author5=Yeoh, K. K. |author6=Tian, Y.-M. |author7=Claridge, T. D. W. |author8=Ratcliffe, P. J. |author9=Woon, E. C. Y. |author10=Schofield, C. J. | title = Dynamic combinatorial chemistry employing boronic acids/boronate esters leads to potent oxygenase inhibitors | journal = Angew. Chem. Int. Ed. | volume = 51 | issue = 27 | pages = 6672–6675 |date=Jul 2012 | pmid = 22639232 | doi = 10.1002/anie.201202000 }}{{cite journal |author1=Leung, I. K. H. |author2=Brown Jr, T. |author3=Schofield, C. J. |author4=Claridge, T. D. W. | title = An approach to enzyme inhibition employing reversible boronate ester formation | journal = Med. Chem. Commun. | volume = 2 | issue = 5 | pages = 390–395 |date=May 2011 | doi = 10.1039/C1MD00011J }} diselenides-disulfides exchange,{{cite journal |author1=Rasmussen, B. |author2=Sørensen, A. |author3=Gotfredsen, H. |author4=Pittelkow, M. |s2cid=8774608 | title = Dynamic combinatorial chemistry with diselenides and disulfides in water | journal = Chem. Commun. | volume = 50 | issue = 28 | pages = 3716–3718 |date=Feb 2014 | pmid = 24577496| doi = 10.1039/C4CC00523F }} disulphide formation,{{cite journal |author1=Ramström, O. |author2=Lehn, J.-M. | title = In situ generation and screening of a dynamic combinatorial carbohydrate library against concanavalin A | journal = ChemBioChem | volume = 1 | issue = 1 | pages = 41–48 |date=Jul 2000 | pmid = 11828397 | doi = 10.1002/1439-7633(20000703)1:1<41::AID-CBIC41>3.0.CO;2-L |s2cid=24024198 }}{{cite journal |author1=Liénard, B. M. R. |author2=Selevsek, N. |author3=Oldham, N. J. |author4=Schofield, C. J. | title = Combined mass spectrometry and dynamic chemistry approach to identify metalloenzyme inhibitors | journal = ChemMedChem | volume = 2 | issue = 2 | pages = 175–179 |date=Feb 2007 | pmid = 17206734 | doi = 10.1002/cmdc.200600250 |s2cid=36592352 }}{{cite journal |author1=Liénard, B. M. R. |author2=Hüting, R. |author3=Lassaux, P. |author4=Galleni, M. |author5=Frére, J.-M. |author6=Schofield, C. J. | title = Dynamic combinatorial mass spectrometry leads to metallo-β-lactamase inhibitors | journal = J. Med. Chem. | volume = 51 | issue = 3 | pages = 684–688 |date=Feb 2008 | pmid = 18205296 | doi = 10.1021/jm070866g }} hemithiolacetal formation,{{cite journal |author1=Caraballo, R. |author2=Dong, H. |author3=Ribeiro, J. P. |author4=Jiménez-Barbero, J. |author5=Ramström, O. | title = Direct STD NMR identification of β-galactosidase inhibitors from a virtual dynamic hemithioacetal system | journal = Angew. Chem. Int. Ed. | volume = 49 | issue = 3 | pages = 589–593 |date=Jan 2010 | pmid = 20013972 | doi = 10.1002/anie.200903920 }}{{cite journal |author1=Clipson, A. J. |author2=Bhat, V. T. |author3=McNae, I. |author4=Caniard, A. M. |author5=Campopiano, D. J. |author6=Greaney, M. F. | title = Bivalent enzyme inhibitors discovered using dynamic covalent chemistry | journal = Chem. Eur. J. | volume = 18 | issue = 34 | pages = 10562–10570 |date=Aug 2012 | pmid = 22782854 | doi = 10.1002/chem.201201507 |url=https://www.pure.ed.ac.uk/ws/files/11097675/Bivalent_Enzyme_Inhibitors_Discovered_Using_Dynamic_Covalent_Chemistry.pdf |hdl=20.500.11820/a3e3e607-6152-44b2-b74c-c9c6bd90946e |s2cid=28796078 |hdl-access=free }} hydrazone formation,{{cite journal |author1=Hochgürtel, M. |author2=Niesinger, R. |author3=Kroth, H. |author4=Piecha, D. |author5=Hofmann, M. W. |author6=Krause, S. |author7=Schaaf, O. |author8=Nicolau, C. |author9=Eliseev, A. V. | title = Ketones as building blocks for dynamic combinatorial libraries: highly active neuraminidase inhibitors generated via selective pressure of the biological target | journal = J. Med. Chem. | volume = 46 | issue = 3 | pages = 356–358 |date=Jan 2003 | pmid = 12540234 | doi = 10.1021/jm025589m }}{{cite journal |author1=Sindelar, M. |author2=Lutz, T. A. |author3=Petrera, M. |author4=Wanner, K. T. | title = Focused pseudostatic hydrazone libraries screened by mass spectrometry binding assay: optimizing affinities toward γ-aminobutyric acid transporter 1 | journal = J. Med. Chem. | volume = 56 | issue = 3 | pages = 1323–1340 |date=Feb 2013 | pmid = 23336362 | doi = 10.1021/jm301800j }} imine formation{{cite journal |author1=Yang, Z. |author2=Fang, Z. |author3=He, W. |author4=Wang, Z. |author5=Gang, H. |author6=Tian, Q. |author7=Guo, K. | title = Identification of inhibitors for vascular endothelial growth factor receptor by using dynamic combinatorial chemistry | journal = Bioorg. Med. Chem. Lett. | volume = 26 | issue = 7 | pages = 1671–1674 |date=Apr 2016 | pmid = 26920800 | doi = 10.1016/j.bmcl.2016.02.063 }}{{cite journal |author1=Zameo, S. |author2=Vauzeilles, B. |author3=Beau, J.-M. | title = Direct composition analysis of a dynamic library of imines in an aqueous medium | journal = Eur. J. Org. Chem. | volume = 2006 | issue = 24 | pages = 5441–5444 |date=Dec 2006 | doi = 10.1002/ejoc.200600859 }}{{cite journal | author = Herrmann, A. | title = Dynamic mixtures and combinatorial libraries: imines as probes for molecular evolution at the interface between chemistry and biology | journal = Org. Biomol. Chem. | volume = 7 | issue = 16 | pages = 3195–3204 |date=Aug 2009 | pmid = 19641772 | doi = 10.1039/B908098H }} and thiol-enone exchange.{{cite journal |author1=Shi, B. |author2=Stevenson, R. |author3=Campopiano, D. J. |author4=Greaney, M. F. | title = Discovery of glutathione S-transferase inhibitors using dynamic combinatorial chemistry | journal = J. Am. Chem. Soc. | volume = 128 | issue = 26 | pages = 8459–8467 |date=Jul 2006 | pmid = 16802811 | doi = 10.1021/ja058049y }}

For reversible reactions that do not occur in aqueous buffers, the pre-equilibrated DCC approach can be used. The DCL was initially generated (or pre-equilibrated) in organic solvent, and then diluted into aqueous buffer containing the protein target for selection. Organic based reversible reactions, including Diels-Alder{{cite journal |author1=Boul, P. J. |author2=Reutenauer, P. |author3=Lehn, J.-M. | title = Reversible Diels-Alder reactions for the generation of dynamic combinatorial libraries | journal = Org. Lett. | volume = 7 | issue = 1 | pages = 15–18 |date=Jan 2005 | pmid = 15624966 | doi = 10.1021/ol048065k }} and alkene cross metathesis reactions,{{cite journal|last1=Poulsen|first1=S.-A.|author-link=Sally-Ann Poulsen|last2=Bornaghi|first2=L. F.|date=May 2006|title=Fragment-based drug discovery of carbonic anhydrase II inhibitors by dynamic combinatorial chemistry utilizing alkene cross metathesis|journal=Bioorg. Med. Chem.|volume=14|issue=10|pages=3275–3284|doi=10.1016/j.bmc.2005.12.054|pmid=16431113|hdl-access=free|hdl=10072/14469}} have been proposed or applied to Protein-directed DCC using this method.

Reversible non-covalent reactions, such as metal-ligand coordination,{{cite journal |author1=Sakai, S. |author2=Shigemasa, Y. |author3=Sasaki, T. | title = A self-adjusting carbohydrate ligand for GalNAc specific lectins | journal = Tetrahedron Lett. | volume = 38 | issue = 47 | pages = 8145–8148 |date=Nov 1997 | doi = 10.1016/S0040-4039(97)10187-3 }}{{cite journal |author1=Sakai, S. |author2=Shigemasa, Y. |author3=Sasaki, T. | title = Iron(II)-assisted assembly of trivalent GalNAc clusters and their interactions with GalNAc-specific lectins | journal = Bull. Chem. Soc. Jpn. | volume = 72 | issue = 6| pages = 1313–1319 | year = 1999 | doi = 10.1246/bcsj.72.1313 | url = http://ci.nii.ac.jp/naid/130004150385 | url-access = subscription }} has also been applied in Protein-directed DCC. This strategy is useful for the investigation of the optimal ligand stereochemistry at the binding site of the target protein.{{cite journal |author1=Kilpin, K. J. |author2=Dyson, P. J. | title = Enzyme inhibition by metal complexes: concepts, strategies and applications | journal = Chem. Sci. | volume = 4 | issue = 4| pages = 1410–1419 |date=Feb 2013 | doi = 10.1039/C3SC22349C | doi-access = free }}

Enzyme-catalysed reversible reactions, such as protease-catalysed amide bond formation/hydrolysis reactions{{cite journal |author1=Swann, P. G. |author2=Casanova, R. A. |author3=Desai, A. |author4=Frauenhoff, M. M. |author5=Urbancic, M. |author6=Slomczynska, U. |author7=Hopfinger, A. J. |author8=Le Breton, G. C. |author9=Venton, D. L. | title = Nonspecific protease-catalyzed hydrolysis/synthesis of a mixture of peptides: product diversity and ligand amplification by a molecular trap | journal = Biopolymers | volume = 40 | issue = 6 | pages = 617–625 | year = 1996 | pmid = 9140201 | doi = 10.1002/(sici)1097-0282(1996)40:6<617::aid-bip3>3.0.co;2-z|s2cid=24603197 }} and the aldolase-catalysed aldol reactions,{{cite journal |author1=Lins, R. J. |author2=Flitsch, S. L. |author3=Turner, N. J. |author4=Irving, E. |author5=Brown, S. A. | title = Enzymatic generation and in situ screening of a dynamic combinatorial library of sialic acid analogues | journal = Angew. Chem. Int. Ed. | volume = 41 | issue = 18 | pages = 3405–3407 |date=Sep 2002 | pmid = 12298046 | doi = 10.1002/1521-3773(20020916)41:18<3405::AID-ANIE3405>3.0.CO;2-P }}{{cite journal |author1=Lins, R. J. |author2=Flitsch, S. L. |author3=Turner, N. J. |author4=Irving, E. |author5=Brown, S. A. | title = Generation of a dynamic combinatorial library using sialic acid aldolase and in situ screening against wheat germ agglutinin | journal = Tetrahedron | volume = 60 | issue = 3 | pages = 771–780 |date=Jan 2004 | doi = 10.1016/j.tet.2003.11.062 }} have also been applied to Protein-directed DCC.

Protein-directed DCC system must be amenable to efficient screening. Several analytical techniques have been applied to the analysis of Protein-directed DCL. These include HPLC, mass spectrometry, NMR spectroscopy, and X-ray crystallography.{{cite journal |author1=Valade, A. |author2=Urban, D. |author3=Beau, J.-M. | title = Two galatosyltransferases' selection of different binders from the same uridine-based dynamic combinatorial library | journal = J. Comb. Chem. | volume = 9 | issue = 1 | pages = 1–4 |date=Jan–Feb 2007 | pmid = 17206823 | doi = 10.1021/cc060033w }}

Although most applications of Protein-directed DCC to date involved the use of single protein in the DCL, it is possible to identify protein ligands by using multiple proteins simultaneously, as long as a suitable analytical technique is available to detect the protein species that interact with the DCL components.{{cite journal |author1=Das, M. |author2=Tianming, Y. |author3=Jinghua, D. |author4=Prasetya, F. |author5=Yiming, X. |author6= Wong, K. |author7= Cheong, A. |author8= Woon, E. C. Y. | title = Multi-Protein Dynamic Combinatorial Chemistry: A Novel Strategy that Leads to Simultaneous Discovery of Subfamily-Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3 | journal = Chem. Asian J. | volume = 13| issue = 19| pages = 2854–2867|date=Jun 2018 | pmid = 29917331 | doi = 10.1002/asia.201800729 |s2cid=49291870 |url=https://discovery.ucl.ac.uk/id/eprint/10107020/ }} This approach may be used to identify specific inhibitors or broad-spectrum enzyme inhibitors.

DCC is useful in identifying molecules with unusual binding properties, and provides synthetic routes to complex molecules that aren't easily accessible by other means. These include smart materials, foldamers, self-assembling molecules with interlocking architectures and new soft materials. The application of DCC to detect volatile bioactive compounds, i.e. the amplification and sensing of scent, was proposed in a concept paper.{{cite journal | author = Herrmann, A. | title = Dynamic Mixtures: Challenges and Opportunities for the Amplification and Sensing of Scents | journal = Chem. Eur. J. | volume = 18 | issue = 28 | pages = 8568–8577 |date=Jul 2012 | pmid = 22588709 | doi = 10.1002/chem.201200668 }} Recently, DCC was also used to study the abiotic origins of life.{{cite journal |last1=Chandru |first1=Kuhan |last2=Guttenberg |first2=Nicholas |last3=Giri |first3=Chaitanya |last4=Hongo |first4=Yayoi |last5=Butch |first5=Christopher |last6=Mamajanov |first6=Irena |last7=Cleaves |first7=H. James |title=Simple prebiotic synthesis of high diversity dynamic combinatorial polyester libraries |journal=Communications Chemistry |date=31 May 2018 |volume=1 |issue=1 |doi=10.1038/s42004-018-0031-1 |language=En |issn=2399-3669|doi-access=free }}

• Combinatorial biology
• Combinatorial chemistry
• Drug discovery
• Fragment-based lead discovery
• High-throughput screening

{{Reflist}}

• [https://archive.today/20121215105653/http://www.chem.unc.edu/cdcc University of North Carolina at Chapel Hill: Center for Dynamic Combinatorial Chemistry] {{Citation needed|reason=Page does not exist|date=October 2017}}
• [http://www-sanders.ch.cam.ac.uk/DCL.htm University of Cambridge: Dynamic Combinatorial Chemistry]

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Category:Cheminformatics

Category:Drug discovery

Category:Combinatorial chemistry