:Molecular tweezers

The term "molecular tweezers" was first used by Whitlock.Chen C.-W.; Whitlock H. W. "Molecular Tweezers – A Simple-Model of Bifunctional Intercalation", J. Am. Chem. Soc. 1978, 100, 4921 The class of hosts was developed and popularized by Zimmerman in the mid-1980s to early 1990sZimmerman, S. C.; VanZyl, C. M. "Rigid molecular tweezers: synthesis, characterization, and complexation chemistry of a diacridine", J. Am. Chem. Soc. 1987, 109, 7894.Zimmerman, S. C.; Wu, W. "A rigid molecular tweezers with an active site carboxylic acid: exceptionally efficient receptor for adenine in an organic solvent", J. Am. Chem. Soc. 1989, 111, 8054.Zimmerman, S. C. "Rigid molecular tweezers as hosts for the complexation of neutral guests", Top. Curr. Chem. 1993, 165, 71. and later by Klärner.{{cite journal | title = Molecular Tweezers and Clips as Synthetic Receptors. Molecular Recognition and Dynamics in Receptor-Substrate Complexes |author1=F.-G. Klärner |author2=B. Kahlert |name-list-style=amp | journal = Acc. Chem. Res. | volume = 36 | issue = 12 | pages = 919–932 | year = 2003 | doi = 10.1021/ar0200448 | pmid = 14674783|s2cid=29313731 }}

Some molecular tweezers bind aromatic guests.{{cite journal |author1=A. Petitjean |author2=R. G. Khoury |author3=N. Kyritsakas |author4=J. M. Lehn | title = Dynamic Devices. Shape Switching and Substrate Binding in Ion-Controlled Nanomechanical Molecular Tweezers | year = 2004 | journal = J. Am. Chem. Soc. | volume = 126 | issue = 21 | pages = 6637–6647 | doi = 10.1021/ja031915r | pmid = 15161291|bibcode=2004JAChS.126.6637P }} These molecular tweezers consist of a pair of anthracene arms held at a distance that allows aromatic guests to gain π–π interactions from both (see Figure). Other molecular tweezers feature a pair of tethered porphyrins.{{cite journal |author1=X. Huang |author2=N. Fujioka |author3=G. Pescitelli |author4=F. Koehn |author5=R. T. Williamson |author6=K. Nakanishi |author7=N. Berova | title =Absolute Configurational Assignments of Secondary Amines by CD-sensitive Dimeric Zinc Porphyrin Host | year = 2002 | journal = J. Am. Chem. Soc. | volume = 124 | issue = 17 | pages = 10320–10335 | doi = 10.1021/ja020520p |pmid=12197735 |bibcode=2002JAChS.12410320H |s2cid=33852448 }}

Yet another type of molecular tweezers binds fullerenes.{{cite journal |author1=A. Sygula |author2=F. R. Fronczek |author3=R. Sygula |author4=P. W. Rabideau |author5=M. M. Olmstead | title = A Double Concave Hydrocarbon Buckycatcher | year = 2007 | journal = J. Am. Chem. Soc. | volume = 129 | issue = 13 | pages = 3842–3843 | doi = 10.1021/ja070616p | pmid = 17348661|bibcode=2007JAChS.129.3842S |s2cid=25154754 }} These "buckycatchers" are composed of two corannulene pincers that complement the surface of the convex fullerene guest (Figure 2). An association constant (K_a) of 8,600 M⁻¹ was calculated using ¹H NMR spectroscopy.

Stoermer and co-workers described clefts capable of capturing cyclohexane or chloroform molecules. Intriguingly, pi interactions played key roles in guest capture as well as cleft formation rate.{{Cite journal|last1=Stoermer|first1=Martin J.|last2=Wickramasinghe|first2=Wasantha A.|last3=Byriel|first3=Karl A.|last4=Hockless|first4=David C. R.|last5=Skelton|first5=Brian W.|last6=Sobolev|first6=Alexandre N.|last7=White|first7=Allan H.|last8=Mak|first8=Jeffrey Y. W.|last9=Fairlie|first9=David P.|date=2017-12-08|title=Stereoelectronic Effects on Dienophile Separation Influence the Diels–Alder Synthesis of Molecular Clefts|journal=European Journal of Organic Chemistry|language=en|volume=2017|issue=45|pages=6793–6796|doi=10.1002/ejoc.201701319|issn=1099-0690|url=http://espace.library.uq.edu.au/view/UQ:709407/UQ709407_OA.pdf|doi-access=free}}

[[File:Lysine+tweezer.jpg|thumb|

Figure 3. The aliphatic sidechain of lysine bound inside the cavity of the phosphate-substituted molecular benzene tweezer by electrostatic, CH-p and hydrophobic interactions reported by Klärner, Schrader, and coworkers.^[9,10]

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Water-soluble phosphate-substituted molecular tweezers made of alternating phenyl and norbornenyl substituents bind to positively charged aliphatic side chains of basic amino acids, such as lysine and arginine (Figure 3).M Fokkens, T Schrader, and F-G Klärner. A molecular tweezer for lysine and arginine. J. Am. Chem. Soc. 2005; 127: 14415–14421.{{cite journal |author1=P. Talbiersky |author2=F. Bastkowski |author3=F.-G. Klärner |author4=T. Schrader | title = Molecular Clip and Tweezer Introduce New Mechanisms of Enzyme Inhibition | year = 2008 | journal = J. Am. Chem. Soc. | volume = 130 | issue = 30 | pages = 9824–9828| doi = 10.1021/ja801441j|pmid=18605724 |bibcode=2008JAChS.130.9824T }} Similar compounds called "molecular clips", whose side walls are flat rather than convex, prefer to enclose flat pyridinium rings (for example the nicotinamide ring of NAD(P)+) between their plane naphthalene sidewalls (Figure 4).{{cite journal |author1=J. Polkowska |author2=F. Bastkowski |author3=T. Schrader |author4=F.-G. Klärner |author5=J. Zienau |author6=F. Koziol |author7=C. Ochsenfeld | title = A combined experimental and theoretical study of the pH-dependent binding mode of NAD+ by water-soluble molecular clips | year = 2009 | journal = J. Phys. Org. Chem. | volume = 22 | issue = 30 | pages = 779–790| doi = 10.1002/poc.1519}} These mutually exclusive binding modes make these compounds valuable tools for probing critical biological interactions of basic amino acid side chains in peptides and proteins as well as of NAD(P)⁺ and similar cofactors. For example, both types of compounds inhibit the oxidation reactions of ethanol by alcohol dehydrogenase or of glucose-6-phosphate by glucose-6-phosphate dehydrogenase,{{cite journal |author1=M. Kirsch |author2=P. Talbiersky |author3=J. Polkowska |author4=F. Bastkowski |author5=T. Schaller |author6=H. de Groot |author7=F.-G. Klärner |author8=T. Schrader | title = A Mechanism of Efficient G6PD Inhibition by a Molecular Clip | year = 2009 | journal = Angew. Chem. Int. Ed. | volume = 48 |issue=16 | pages = 2886–2890 | doi = 10.1002/anie.200806175|pmid=19283805 }} respectively.

[[File:NAD+clip.jpg|thumb|

Figure 4. The double-sandwich host–guest complex of the phosphate-substituted molecular clip and nicotinamide adenine dinucleotide (NAD⁺, the cofactor of many redox enzymes). The nicotinamide ring (the active site of NAD⁺) is bound between the clip naphthalene sidewalls, as reported by Klärner, Schrader, Ochsenfeld, and coworkers.^[11]

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The molecular tweezers, but not the clips, efficiently inhibit the formation of toxic oligomers and aggregates by amyloidogenic proteins associated with different diseases. Examples include the proteins involved in Alzheimer's disease – amyloid β-protein (Aβ) and tau;S Sinha, DHJ Lopes, Z Du, ES Pang, A Shanmugam, A Lomakin, P Talbiersky, A Tennstaedt, K McDaniel, R Bakshi, P-Y Kuo, M Ehrmann, GB Benedek, JA Loo, F-G Klärner, T Schrader, C Wang, and G Bitan. Lysine-specific molecular tweezers are broad-spectrum inhibitor of aggregation and toxicity of amyloid proteins. [http://pubs.acs.org/doi/abs/10.1021/ja206279b J. Am. Chem. Soc. 2011; 133(42): 16958–16969].S Sinha, Z Du, P Maiti, F-G Klärner, T Schrader, C Wang, and G Bitan. Comparison of Three Amyloid Assembly Inhibitors: The Sugar scyllo-Inositol, the Polyphenol Epigallocatechin Gallate, and the Molecular Tweezer CLR01. [http://pubs.acs.org/doi/abs/10.1021/cn200133x ACS Chem. Neurosci. 2012; 3(6): 451–458].X Zheng, D-Y Liu, F-G Klärner, T Schrader, G Bitan, and MT Bowers. Amyloid β-protein Assembly: The Effect of Molecular Tweezer CLR01 and CLR03. [http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.5b00692?src=recsys J. Phys. Chem. B, 2015; 119: 4831–4841]. α-synuclein, which is thought to cause Parkinson's disease and other synucleinopathiesS Prabhudesai*, S Sinha*, A Attar, A Kotagiri, AG Fitzmaurice, R Lakshmanan, MI Ivanova, JA Loo, F-G Klärner, T Schrader, M Stahl, G Bitan#, and JM Bronstein#. A Novel "Molecular Tweezer" Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo. [https://link.springer.com/article/10.1007%2Fs13311-012-0105-1 Neurotherapeutics. 2012; 9(2): 464–476].S Acharya, BM Safaie, P Wongkongkathep, MI Ivanova, A Attar, F-G Klärner, T Schrader, JA Loo, G Bitan, and LJ Lapidus. Molecular Basis for Preventing α-Synuclein Aggregation by a Molecular Tweezer. [http://www.jbc.org/content/early/2014/02/24/jbc.M113.524520.abstract J. Biol. Chem. 2014; 289(15): 10727–10737].A Lulla, L Barnhill, G Bitan, MI Ivanova, B Nguyen, K O'Donnell, MC Stahl, C Yamashiro, F-G Klärner, T Schrader, A Sagasti, and JM Bronstein, [http://ehp.niehs.nih.gov/ehp141/ Environ. Health Perspect. 2016; 124: 1766–1775.] {{Webarchive|url=https://web.archive.org/web/20170705083708/https://ehp.niehs.nih.gov/ehp141/ |date=2017-07-05 }}{{Cite journal|last1=Richter|first1=Franziska|last2=Subramaniam|first2=Sudhakar R.|last3=Magen|first3=Iddo|last4=Lee|first4=Patrick|last5=Hayes|first5=Jane|last6=Attar|first6=Aida|last7=Zhu|first7=Chunni|last8=Franich|first8=Nicholas R.|last9=Bove|first9=Nicholas|date=2017-06-05|title=A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing α-Synuclein|journal=Neurotherapeutics|volume=14|issue=4|language=en|pages=1107–1119|doi=10.1007/s13311-017-0544-9|pmid=28585223|pmc=5722755|issn=1933-7213}} and is involved in spinal-cord injury;SM Fogerson, AJ van Brummen, DJ Busch, SR Allen, R Roychaudhuri, S Banks, F-G Klärner, T Schrader, G Bitan, and JR Morgan, Reducing synuclein accumulation improves neuronal survival after spinal cord injury, [https://www.ncbi.nlm.nih.gov/pubmed/26854933 Exp. Neurol. 2016; 278: 105–115]. mutant huntingtin, which causes Huntington's disease;{{Cite journal|last1=Vöpel|first1=Tobias|last2=Bravo-Rodriguez|first2=Kenny|last3=Mittal|first3=Sumit|last4=Vachharajani|first4=Shivang|last5=Gnutt|first5=David|last6=Sharma|first6=Abhishek|last7=Steinhof|first7=Anne|last8=Fatoba|first8=Oluwaseun|last9=Ellrichmann|first9=Gisa|date=2017-04-26|title=Inhibition of Huntingtin Exon-1 Aggregation by the Molecular Tweezer CLR01|journal=Journal of the American Chemical Society|volume=139|issue=16|pages=5640–5643|doi=10.1021/jacs.6b11039|issn=0002-7863|pmc=5506490|pmid=28406616|bibcode=2017JAChS.139.5640V }} islet amyloid polypeptide (amylin), which kills pancreatic β-cells in type-2 diabetes;DHJ Lopes, A Attar, G Nair, EY Hayden, Z Du, K McDaniel, S Dutt, K Bravo-Rodriguez, S Mittal, F-G Klärner, C Wang, E Sanchez-Garcia, T Schrader, and G Bitan (2015) Molecular tweezers inhibit islet amyloid polypeptide assembly and toxicity by a new mechanism, [http://pubs.acs.org/doi/pdf/10.1021/acschembio.5b00146 ACS Chem. Biol. 2015; 10: 1555–1569]. transthyretin (TTR), which causes familial amyloid polyneuropathy, familial amyloid cardiomyopathy, and senile systemic amyloidosis;N Ferreira, A Pereira-Henriques, A Attar, F-G Klärner, T Schrader, G Bitan, L Gales, MJ Saraiva, and MR Almeida. Molecular Tweezers Targeting Transthyretin Amyloidosis. [https://link.springer.com/article/10.1007/s13311-013-0256-8 Neurotherapeutics. 2014; 11: 450–461]. aggregation-prone mutants of the tumor-suppressor protein p53;G Herzog, MD Shmueli, L Levi, L Engel, E Gazit, F-G Klärner, T Schrader, G Bitan, and D Segal. The Lys-specific molecular tweezer, CLR01, modulates aggregation of mutant p53 DNA binding domain and inhibits its toxicity, [http://pubs.acs.org/doi/abs/10.1021/bi501092p Biochemistry, 2015; 54: 3729–3738]. and semen proteins whose aggregation enhances HIV infection.E Lump, LM Castellano, C Meier, J Seeliger, N Erwin, B Sperlich, CM Stürzel, S Usmani, RM Hammond, J von Einem, G Gerold, F Kreppel, K Bravo-Rodriguez, T Pietschmann, VM Holmes, D Palesch, O Zirafi, D Weissman, A Sowislok, B Wettig, C Heid, F Kirchhoff, T Weil, F-G Klärner, T Schrader, G Bitan, E Sanchez-Garcia, R Winter, J Shorter, and Jan Münch, A molecular tweezer antagonizes seminal amyloids and HIV infection, [https://elifesciences.org/content/4/e05397 eLife, 2015; 4:e05397]. Importantly, the molecular tweezers have been found to be effective and safe not only in the test tube but also in animal models of different diseases,A Attar, C Ripoli, E Riccardi, P Maiti, DD Li Puma, T Liu, J Hayes, MR Jones, K Lichti-Kaiser, F Yang, GD Gale, C-h Tseng, M Tan, C-W Xie, JL Straudinger, F-G Klärner, T Schrader, SA Frautschy, C Grassi and G Bitan. Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers. [https://web.archive.org/web/20160731213823/http://brain.oxfordjournals.org/content/brain/135/12/3735.full.pdf?ijkey=ol7puZ6taUB9mpy&keytype=ref Brain. 2012; 135(Pt 12): 3735–3748].A Attar, W-TC Chan, F-G Klärner, T Schrader, and G Bitan. Safety and pharmacological characterization of the molecular tweezer CLR01 – a broad-spectrum inhibitor of amyloid proteins' toxicity. [http://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/2050-6511-15-23 BMC Pharm. Tox. 2014; 15(23): doi:10.1186/2050-6511-15-23]. suggesting that they may be developed as drugs against diseases caused by abnormal protein aggregation, all of which currently have no cure. They were also shown to destroy the membranes of enveloped viruses, such as HIV, herpes, and hepatitis C, which makes them good candidates for development of microbicides.

The above examples show the potential reactivity and specificity of these molecules. The binding cavity between the side arms of the tweezer can evolve to bind to an appropriate guest with high specificity, depending on the configuration of the tweezer. That makes this overall class of macromolecule truly synthetic molecular receptors with important application to biology and medicine.F-G Klärner and T Schrader. Aromatic Interactions by Molecular Tweezers and Clips in Chemical and Biological Systems. [http://pubs.acs.org/doi/abs/10.1021/ar300061c Acc. Chem. Res. 2013; 46: 967–978].A Attar and G Bitan. Disrupting self-assembly and toxicity of amyloidogenic protein oligomers by "molecular tweezers" – from the test tube to animal models, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261945/ Curr. Pharm. Des. 2014; 20: 2469–2483].T Schrader, G Bitan, and F-G Klärner, Molecular Tweezers for Lysine and Arginine – Powerful Inhibitors of Pathologic Protein Aggregation, [http://pubs.rsc.org/en/content/articlelanding/2014/cc/c6cc04640a#!divAbstract Chem. Commun. 2016: 52: 11318–11334.]

• Clathrate compound
• Host–guest chemistry

{{reflist}}

• Journal of Chemical Education Featured Molecules December 2004: [http://jchemed.chem.wisc.edu/JCEWWW/Features/MonthlyMolecules/2004/Dec/index.html Nanoscale Molecular Tweezers] and [http://144.92.39.64/HS/Journal/Issues/2004/Dec/clicSubscriber/V81N12/p1818.pdf article]{{dead link|date=February 2018 |bot=InternetArchiveBot |fix-attempted=yes }}
• [https://web.archive.org/web/20050404171858/http://www.crystalmaker.com/news/tweezer_mol.html Crystalmaker molecular tweezers]

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Category:Supramolecular chemistry

Category:Molecular machines