C60: Synthesis and Biological Activity of Water-Soluble Fullerenes

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2. Carbon Allotropes. Buckminsterfullerenes found in 1985Prepared in infinitesimal amounts by means of laser vaporization of graphiteSoccer ball structure proposed in view of MS resultsChemistry Nobel prize recompensed in 1996. DiamondGraphite Fullerene. Kroto, H.W.; Heath, J. R.; O\'Brien, S.C.; Curl, R.F.; Smalley, R.E. Nature 1985, 318, 162-163..

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C 60 : Synthesis and Biological Activity of Water-Soluble Fullerenes Matthew D. Shoulders Raines Group October 5, 2006

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Carbon Allotropes Diamond Graphite Fullerene Buckminsterfullerenes found in 1985 Prepared in minuscule amounts by means of laser vaporization of graphite Soccer ball structure proposed in view of MS results Chemistry Nobel prize granted in 1996 Kroto, H.W.; Heath, J. R.; O'Brien, S.C.; Curl, R.F.; Smalley, R.E. Nature 1985 , 318 , 162-163.

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Preparation and Purification of C 60 Production Difficulties Problem comprehended in 1990 by vanishing graphite cathodes in He(g) environment Resulted underway of >95% immaculate C 60 Prompted a blast of test results Further sanitization of C 60 by means of chromatography or calixarene complexation Kr ät schmer, W. et al. Nature 1990 , 347 , 354-358; Atwood, J.L. et al. Nature 1994 , 368, 229-231. http://www.ifw-dresden.de/iff/14/Equipment/fullerene/index.htm

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The Structure of C 60 12 pentagons encompassed by 20 hexagons (corannulene substructure) Two sorts of ring intersections (6,6 and 5,6) Isolated pentagon lead (pyracylene subunits) Wudl, F. Acc. Chem. Res. 1992 , 25 , 157-161.

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Important Properties of C 60 Structural Unique geometry High symmetry Closed, round structure 7 Ǻ breadth—can typify different iotas Electronic Small HOMO-LUMO bandgap (3 deteriorate orbitals frame LUMO) Easily lessened by up to 6 electrons Strongly electronegative Highly conjugated, however not "superaromatic" Bent p securities diminish conjugation Photosensitizer

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Highly hydrophobic particle Limited dissolvability in numerous natural solvents Completely insoluble in water Low Solubility of C 60 Sivaraman, N. et al. J. Organization. Chem. 1992 , 57 , 6077-6079.

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Outline Approaches to water-solvent C 60 Non Covalent Biological uses of C 60 subordinates HIV-1 protease (HIVP) hindrance Neuroprotective properties Antibacterial properties Gene transfection and related properties Toxicity of C 60 and subsidiaries Pristine C 60 (unmodified) Functionalized C 60 Conclusions and Outlook

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Water-Soluble C 60 Pristine C 60 can be suspended in water Biological employments of fullerenes require veritable water dissolvability and practically no accumulation Complexation with water-solvent supramolecules is one successful approach Surfactants Polyvinylpyrrolidone (PVP) Cyclodextrins

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Non-Covalent Methods: C 60 - PVP Solutions PVP is a dispersant utilized as a part of makeup and prescriptions. C 60 - toluene blended with PVP-chloroform, solvents dissipated, and deposit broke down in water Highest [C 60 ] got was 400 m g/mL, utilizing 100:0.8 PVP:C 60 w/w Yamakoshi, Y.N. et al. Chem. Comm. 1994 , 517-518; Sera, N. et al. Carcinogenesis 1996 , 17 , 2163-2169; Ungurenasu, C.; Airinei, A. J. Med. Chem. 2000 , 43 , 3186-3188.

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C 60 - Cyclodextrin Complexes Non-covalent or covalent edifices upgrade water solvency Aggregation wonders experienced with 1:1 buildings g - cyclodextrin b - cyclodextrin Andersson, T. et al. Chem. Comm. 1992 , 604-606; Filippone, S. et al. Chem Comm. 2002 , 1508-1509; Liu, Y. et al. Tetrahedron Lett. 2005 , 46 , 2507-2511; Chen, Y. et al. Tetrahedron 2006 , 62 , 2045-2049.

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Covalent Approaches: Principles of C 60 Reactivity Generally that of any electron-poor polyene C 60 can be decreased by up to 6 electrons Most responses happen at the 6,6-ring intersection framing the thermodynamically stable item Electron-poor nature of unbiased C 60 Excellent substrate for nucleophilic assault Electrophilic augmentations are less normal yet have been watched (halogenation, nitronium science) Xie, Q.; Perez-Cordero, E.; Echegoyen, L. J. Am. Chem. Soc. 1992 , 114 , 3978-3980. Diederich, F.; Thilgen, C. Science 1996 , 271 , 317-323.

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Reactivity of C 60 Cycloaddition science Diels-Alder 1,3-Dipolar cycloadditions Carbene increments Bingel cyclopropanation Radical responses C 60 is steady to: Weak corrosive/base Mild oxidizing operators Some gentle decreasing specialists Other normal response conditions including peptide coupling conditions Yamago, S. et al. J. Organization. Chem. 1993 , 58 , 4796-4798. Diederich, F.; Thilgen, C. Science 1996 , 271 , 317-323.

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Synthesis of Fullerols The primary water-dissolvable, non-conglomerating C 60 subordinates Structure stays badly characterized and number of hydroxyls included is variation Chiang, L.Y. et al. Chem. Comm. 1992 , 1791; Chiang, L.Y. et al. J. Am. Chem. Soc. 1992 , 114 , 10154-10157; Li, J. et al. Chem. Comm. 1993 , 1784-1785.

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Well-Defined, Covalent C 60 Adducts Essential for organic applications Mono-adducts can experience the ill effects of accumulation wonders in polar solvents Multi-adducts can show modified properties Covalent methodologies remain the most critical and created technique for solubilizing C 60

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First Synthesis of Fulleropyrrolidines 1,3-dipolar cycloaddition of azomethine ylides Cycloaddition is irreversible under standard response conditions Addition of up to nine pyrrolidines is conceivable Maggini, M.; Scorrano, G.; Prato, M. J. Am. Chem. Soc. 1993 , 115 , 9798-9799.

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Diversity of Prato's Reaction Starting materials monetarily accessible or effortlessly arranged Wide assortment of items can be gotten Can begin with N - substituted glycines or functionalized aldehydes Da Ros, T. et al. J. Organization. Chem. 1996 , 61 , 9070-9072.

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Diversity of Prato's Reaction Da Ros, T. et al. J. Am. Chem. Soc. 1998 , 120 , 11645; Maggini, M. et al. Chem. Comm. 1994 , 305; Cusan, C. et al. Eur. J. Organization. Chem. 2002 , 3 , 2928.

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C 60 Peptides by SPPS Synthesis of fulleropeptides by means of Fmoc conventions Tyr-Gly-Gly-Fgu-Leu Fgu-Gly-Gly-Phe-Leu Gly-Orn-Gly-Fgu-Gly-Orn-Gly Complicated by properties of the fullerene, yet great yields can be gotten DBU in DMF oblivious under Ar for deprotections Pellarini, F. et al. Organization. Lett. 2001 , 3 , 1845-1848; Pantarotto, D. et al. J. Am. Chem. Soc. 2002 , 124 , 12543-12549.

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Stucture of a Fulleropeptide The water-solvent fulleropeptide Fgu-(Gly-Orn) 6 - Gly-NH 2 Antimicrobial movement against S. aureus and E. coli Pellarini, F. et al. Organization. Lett. 2001 , 3 , 1845-1848.

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Carbene expansion solely at [6,6]-ring intersections Bingel cyclopropanation Approaches to Methanofullerenes Tsuda, M. et al. Tetrahedron Lett. 1993 , 34 , 6911-6912; Bingel, C. Chem. Ber. 1993 , 126 , 1957-1959.

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Approaches to Methanofullerenes Addition of diazo mixes Suzuki, T.; Li, Q.; Khemani, K.C.; Wudl, F.; Almarsson, Ö . Science. 1991 , 254 , 1186-1188.

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[5,6] versus [6,6] augmentations 4 conceivable adducts from single expansion of a diazo compound Prato, M. et al.. J. Am. Chem. Soc. 1993 , 115 , 8479-8480.

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[5,6] versus [6,6] augmentations [5,6]-open and [6,6]-shut are framed at first [5,6]-open believers to [6,6]-shut at direct temperatures Prato, M. et al.. J. Am. Chem. Soc. 1993 , 115 , 8479-8480.

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Diazo Additions for Fullero-Amino Acids Wide scope of diazo subsidiaries is available Isaacs, L.; Diederich, F. Helv. Chim. Acta 1993 , 76 , 2454-2464; Siebe, A.; Hirsch, A. Chem. Comm. 1994 , 335-336.

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Bis, Tris, and Higher Adducts of C 60 Complex item blends and poor yields got from non-specific unions of various adducts Hirsch, A. et al. Angew. Chem. Int. Ed. Engl. 1994 , 33 , 437-438.

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Tether-Directed Remote Functionalization Diastereoselectivity in multi-adduct arrangement is fundamental to accomplish sensible yields and immaculateness Methodology has been extended to empower specific amalgamation of about all bis-, tris-, and some higher adducts of C 60 Nieregarten, J.- F. et al. Angew. Chem. Int. Ed. Engl. 1996 , 35, 1719-1723. Thilgen, C.; Diederich, F. C. R. Chimie 2006 , 9 , 868-880.

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Fullerodendrimers Methanofullerene framed by nucleophilic cyclopropanation Most water-dissolvable C 60 mono-adducts to date (65 mg/mL of C 60 at pH = 10) Anti-HIV action Brettreich, M.; Hirsch, A. Tetrahedron Lett. 1998 , 39 , 2731-2734.

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Outline Approaches to water-solvent C 60 Non Covalent Biological utilizations of C 60 subordinates HIV-1 protease (HIVP) hindrance Neuroprotective properties Antibacterial properties Gene transfection and related properties Toxicity of C 60 and subsidiaries Pristine C 60 (unmodified) Functionalized C 60 Conclusions and Outlook

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Overview of Biological Activities of C 60 Derivatives Antioxidant DNA cleavage Membrane interruption Photodynamic treatment Drug conveyance (e.g. paclitaxel) X-beam differentiate operators Inhibition of b - amyloid collection Free radical wipe Neuroprotection Antibacterial Gene transfection Enzyme restraint (HIVP, and so on.) And more…

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Life Cycle of the HIV Retrovirus http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/HIV/AIDS_images/HIV_life_cycle.gif

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First Discovery of Biological Activity of a Fullerene Hydrophobic, 7-8 Å restricting pocket of HIV-1 protease (HIVP) is an appealing focus for fullerene hindrance Computational investigation recommended C 60 fits cozily in the dynamic site of HIVP Properties K i = 5.3 M (Best inhibitors are nanomolar or lower) Toxic even against medication safe HIV-variations Kenyon G.L. what's more, associates. J. Am. Chem. Soc. 1993 , 115 , 6506-6509 and 6510-6512.

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Improving HIVP Inhibitors Zhu, Z. et al. Organic chemistry 2003 , 42 , 1326-1333.

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Improving HIVP Inhibitors Marcorin, G.L. et al. Organization. Lett . 2000 , 2 , 3955-3958.

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Bis-Adduct, Nanomolar HIVP Inhibitors Screened 10-12 cationic fullerenes Cationic functionalities close to the fullerene spine High nanomolar hindrance of HIVP (210 nM and 350 nM) Low cytotoxicity Non-harmful to other DNA-

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