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molecules Review Review AmideAmide BondBond ActivationActivation of Biological Molecules Molecules Sriram Mahesh, Kuei-Chien Tang and Monika Raj * Sriram Mahesh, Kuei-Chien Tang and Monika Raj * Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, USA; [email protected] of Chemistry (S.M.); and kzt0026@ti Biochemistry,germail.auburn.edu Auburn University, (K.-C.T.) Auburn, AL 36849, USA; [email protected]* Correspondence: [email protected]; (S.M.); [email protected] Tel.: +1-334-844-6986 (K.-C.T.) * Correspondence: [email protected]; Tel.: +1-334-844-6986 Academic Editor: Michal Szostak AcademicReceived: Editor:7 September Michal 2018; Szostak Accepted: 9 October 2018; Published: date Received: 7 September 2018; Accepted: 9 October 2018; Published: 12 October 2018 Abstract: Amide bonds are the most prevalent structures found in organic molecules and various Abstract: Amide bonds are the most prevalent structures found in organic molecules and various biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide bonds is their biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide bonds ability to form resonating structures, thus, they are highly stable and adopt particular three- is their ability to form resonating structures, thus, they are highly stable and adopt particular dimensional structures, which, in turn, are responsible for their functions. The main focus of this three-dimensionalreview article is to structures, report the which, methodologies in turn, are for responsible the activation for their of functions.the unactivated The main amide focus bonds of this reviewpresent article in biomolecules, is to report thewhich methodologies includes the for enzy thematic activation approach, of the metal unactivated complexes, amide and bonds non-metal present inbased biomolecules, methods. whichThis article includes also the discusses enzymatic some approach, of the applications metal complexes, of amide and bond non-metal activation based methods.approaches This in articlethe sequencing also discusses of proteins some of and the th applicationse synthesis ofof amide peptide bond acids, activation esters, approachesamides, and in thethioesters. sequencing of proteins and the synthesis of peptide acids, esters, amides, and thioesters. Keywords:Keywords: peptide bond cleavage; amide amide bond bond reso resonance;nance; twisted twisted amides; amides; enzymes; enzymes; metal metal complexes;complexes; catalystscatalysts 1.1. IntroductionIntroduction TheThe amideamide bondbond is one of the most abundant abundant ch chemicalemical bonds bonds and and widely widely exists exists in in many many organic organic moleculesmolecules andand biomolecules biomolecules [1– 6[1–6].]. Nature Nature has usedhas amideused bondsamide tobonds make theseto make important these biomoleculesimportant becausebiomolecules of the because high stability of the high of amide stability bonds of amide towards bonds various towards reaction various conditions reaction conditions (acidic and (acidic basic conditions),and basic conditions), high temperature, high temperature, and the presence and the ofpresence other chemicalsof other chemicals [7]. The high[7]. The stability high stability of amide bondsof amide is attributedbonds is attributed to its tendency to its tendency to form to a fo resonatingrm a resonating structure, structure, which which provides provides a double a double bond characterbond character to the to amide the amide CO-N CO-N bond bond (Figure (Figure1)[ 1)8– [8–10].10]. The The resonance resonance ofof thesethese amide bonds bonds forms forms aa planarplanar structure and and hinders hinders the the free free rotation rotation arou aroundnd the the CO-N CO-N bond, bond, thus, thus, it is itresponsible is responsible for 3D for 3Dstructures structures adopted adopted by byproteins proteins and and other other biomolec biomolecules.ules. These These 3D 3D structures structures of of biomolecules biomolecules are are responsibleresponsible forfor variousvarious importantimportant biological functions. O O O R C O R' R' R' R N R N R N R' N R'' R'' R'' R'' = 0 o; N = 0 o Figure 1. ClassicalClassical amide amide bo bondnd resonance. resonance. HansenHansen etet al.al. carried carried out out the the rate rate studies studies on on the the hydrolysis hydrolysis of of amide amide bonds bonds at at various various pH pH conditionsconditions [[11].11]. The The study study concluded concluded that that at atpH pH 7, 7,the the rate rate of ofhydrolysis hydrolysis is due is due to the to thedirect direct attack attack of ofwater water on on peptide peptide and and measured measured as as kH kH2O.2O. The The rate rate constant constant showed showed th thatat the the half-life half-life of of the the amide amide bondsbonds isis 267267 years,years, similar to the value determined determined by by Radzicka Radzicka and and Wolfenden Wolfenden [12]. [12]. This This study study also also + − showedshowed thatthat thethe ratesrates ofof acidacid (kH(kH33O+)) and and base base hydrolysis hydrolysis (kOH (kOH−) are) are identical, identical, therefore, therefore, the the rate rate of of thethe hydrolysishydrolysis ofof thethe peptidepeptide bondbond is dominated by by kH kH22OO throughout throughout the the pH pH range range from from pH pH 5–9. 5–9. Molecules 2018, 23, x; doi: www.mdpi.com/journal/molecules Molecules 2018, 23, 2615; doi:10.3390/molecules23102615 www.mdpi.com/journal/molecules Molecules 2018, 23, 2615 2 of 43 Molecules 2018, 23, x 2 of 43 Recently,Recently, variousvarious methods methods have have been been reported reported in thein literaturethe literature to activate to activate the amide the amide bonds towardsbonds atowards variety a of variety nucleophiles of nucleophiles or electrophiles or electrophiles for the synthesis for the synthesis of other of organic other organic compounds. compounds. This includes This theincludes use of the enzymes, use of enzymes, metal complexes, metal complexes, and non-metal and non-metal based methods based methods [13–15]. [13–15]. One widely One reportedwidely approachreported approach for the activation for the activation of amide of bonds amide involves bonds involves the distortion the distortion of amide of amide bonds, bonds, thus, thethus, amide the bondamide is bond no longer is no ablelonger to formable to a resonatingform a resonating structure, structure, loses its loses double its bonddouble character, bond character, and becomes and morebecomes susceptible more susceptible to nucleophilic to nucleophilic or electrophilic or electr attack.ophilic A attack. higher A distortion higher distortion of the amide of the bond amide from thebond planar from structurethe planar makes structure it more makes reactive, it more as reac evidencedtive, as evidenced by various by twisted various amide twisted bonds amide present bonds in cyclicpresent nonplanar in cyclic bridgednonplanar lactams, bridged as demonstratedlactams, as demonstrated by Stoltz [16 by,17 ],Stoltz Kirby [16,17], [18–20 Kirby], and others[18–20], [21 and–23 ] (Figureothers 2[21–23]). One of(Figure the special 2). One cases of the to achieve special maximumcases to achieve rotational maximum inversion rotational of the amide inversion bond of so the that itamide remains bond in so the that twisted it remains conformation in the twisted is the useconformation of N-acyl-glutarimides is the use of N [24-acyl-glutarimides–29] and N,N-substituted [24–29] amideand N, bondsN-substituted [30,31] (Figureamide 2bonds). It is [30,31] this strong (Figure distortion 2). It is ofthis amide strong bonds distortion that provides of amide amide bonds bonds that withprovides a high amide reactivity bonds toward with a ahigh variety reactivity of nucleophiles toward a variety and electrophiles. of nucleophiles and electrophiles. H H H R N N O S Me N N O N Me BF4 N O H O O CO2H Lukes (1938) Woodward (1941) Kirby (1998) Stoltz (2006) Aube (2005) -lactam perpendicularly twisted medium bridged ( = 90 , N = 60o) ( = 50 ; N = 35o) O O O O R' n O [M] n+2 N R-Y R' R'' R R N or N R [M] R R + R R'' acyl aryl O Ln N-acyl-glutarimide N-C(O) rotation electronic activation N-C amide activation by distortion = 88.6 ; N = 6.6o (twist tuneable reactivity) FigureFigure 2. 2. TwistedTwisted amides amides for for activation activation of of amide amide bonds. bonds. ThereThere are already some excellent review review articles articles in in the the literature literature covering covering the the reactivity reactivity of of twisted/activatedtwisted/activated amide amide bonds bonds for for the the synthesis synthesis of of th thee variety variety of of different different organic organic molecules molecules such such as as ketones,ketones, esters, esters, acids, acids, and and alcohols, alcohols, by cross-coupli by cross-couplingng reactions reactions [24–31]. [24 The–31]. main The focus main of focusthis review of this reviewis to summarize is to summarize the methods the for methods the activation for the of activation less reactive of lessamide reactive bonds present amide bondsin biomolecules present in biomoleculessuch as peptides, such proteins, as peptides, glycopeptides, proteins, glycopeptides,nucleotides in DNA nucleotides and RNA in DNA and various and RNA other and peptide various otherbioconjugates, peptide bioconjugates,toward attack towardby various attack nucleophiles. by various nucleophiles.This task was This accomplished task was accomplished
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