Click Chemistry and its diverse chemical biology applications

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Click Chemistry for Drug Development and Diverse Chemical Biology Applications Mohammad Ovais Dar M.S(PHARM.) Ist SEM MEDICINAL CHEMISTRY 1

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Flow of Presentation 2

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Introduction Do what nature do so easily and what is easier to do in the lab : C-X bond ! 3 Born 28th April 1941 Institutions Massachusetts institute of technology The scripps research institute Known for Enantioselective synthesis, Click chemistry Notable awards Nobel prize in chemistry(2001) Benjamin franklin medal(2001) Barry Sharpless

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4 A 'CLICK REACTION' would : be modular be wide in scope give very high yields generate only inoffensive by-products (easily removed) be stereospecific required simple product isolation and purification required simple reaction conditions required no or benign solvent or easily removable solvent gives product that are stable in physiological conditions have a high thermodynamic driving force (more than 20 kcal mol -1 ) Angew. Chem. Int. Ed. 2001 , 40, 2004-2021

Click Reactions:

5 Click Reactions Nucleophilic substitution Cycloadditions “Non-aldol” carbonyl

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Copper Catalyzed Azide-Alkyne Cycloaddition (CuAAC) 7 Thermodynamic & kinetically favorable Regiospecific Can be carry out in both aqueous and organic solvents Minimal work up and purification Tolerance with wide range of functional groups and reaction conditions

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Proposed mechanism for the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition 8

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9 Applications Triazole as bioisosteres of aromatic rings and double bonds Click chemistry and carbohydrate drug discovery Development of enzyme inhibitors Protein tyrosine phosphate inhibitors Protein kinase inhibitors Glycosyltransferase inhibitors Development of neoglycopolymers

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10 Triazole as bioisosteres of aromatic rings and double bonds J Med Chem . 2010 ; 53 , 254–272. 1,4-Diphenyl-1,2,3-triazoles would retain strong geometrical resemblance to furamidine . A series of novel 1,2,3-triazoles were synthesized by Tidwell et al. via click chemistry.

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11 Resveratrol is a phytoalexin able to display an array of biological activities. Genazzani et al. replaced the double bond with a 1,2,3-triazole ring using archetypical click chemistry. D isplayed some, but not all, properties of the parent compound Resveratrol J Med Chem. 2006 ; 49 :467-70.

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12 Click chemistry and carbohydrate drug discovery Tetrahedron 2010 , 66 , 9475-9492 IC50 = 6.4 mM

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13 ChemBioChem 2006 , 7 , 1384–1391. Leishmania β-1,2-mannosyltransferase enzymes display a relevant role in the biosynthesis of β-1,2-mannan and/or mannosecontaining surface glycoconjugates that are essential for intracellular survival of Leishmania amastigotes in macrophages Therefore, to explore the substrate specificity of Leishmania β-1,2-mannosyltransferases for further design of potential inhibitors, Williams et al. prepared a library of modified substrates using the highly selective CuAAC reactions.

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14 Development of enzyme inhibitors

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15 Protein tyrosine phosphate inhibitors PTP1B (protein tyrosine phosphatase 1B, nonreceptor phosphortrosine PTP) has been identified as the major regulator of both insulin and leptin signaling pathways Cu(I)-catalyzed “click” cycloaddition reactions were employed to generate libraries of PTP inhibitors by Seto et al. Subsequent inhibitor screening revealed a potent inhibitor with values of 550 nM against Yersinia PTP and 710 nM against TCPTP Bioorg . Med. Chem. 2007 , 15 , 458–473.

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16 Protein kinase inhibitors Merrer and co-workers reported a library of pyrido [2,3-d] pyrimidines as inhibitors of FGFR3 tyrosine kinase Among the 27 analogues synthesized, more than one half exhibited 55 − 89% inhibition of in vitro FGFR3 kinase activity at 2 μM One of the pyrido [2,3-d] pyrimidine derivatives was able to inhibit autophosphorylation of mutant FGFR3-K650 M in transfected HEK (human embryonic kidney) cells Org. Biomol . Chem . 2010 , 1 , 2164–2173

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17 Glycosyltransferase inhibitors Wong et al. reported a nanomolar α-1,3-fucosyltransferase inhibitor was prepared by linking a GDP-derived acetylene to a library of azides, using the copper(I)-catalyzed triazole formation. Biphenyl derivative as the most potent inhibitor of human α-1,3-fucosyltransferase VI , and it was also revealed to be selective for this enzyme with K i = 62 nM J. Am. Chem. Soc . 2003 , 125 , 9588–9589.

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18 Development of neoglycopolymers

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19 ‘ Click chemistry’ reactions have been widely applied to the synthesis of biopolymers of great structural diversity by a combination of polymeric and biological materials through a triazole bridge, involving the coupling of azide and alkyne -containing molecules, such as nucleic acids, peptides, sugars, proteins or viruses and cells Development of neoglycopolymers

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20 The potential application of peptidotriazoles in studies of cellular recognition to mimic natural peptides was also investigated by the coupling of peptides containing terminal alkyne or azide groups with different amino acid sequences via copper(I)-catalysed 1,3-dipolar cycloadditions J. Org. Chem . 2002 , 67 , 3057–3064.

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21 Conclusions Stepwise, non-concerted mechanism accounts for 1,4 regiospecificity Nice concept to facilitate drug discovery Lots of applications We will continue to hear about it

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