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Quaternization of Vinyl/Alkynyl Pyridine Enables Ultrafast Cysteine

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Quaternization of Vinyl/Alkynyl Pyridine Enables Ultrafast Cysteine Angewandte Communications Chemie International Edition:DOI:10.1002/anie.201901405 Protein Modification German Edition:DOI:10.1002/ange.201901405 QuaternizationofVinyl/Alkynyl Pyridine Enables Ultrafast Cysteine- SelectiveProtein Modification and Charge Modulation Maria J. Matos+,Claudio D. Navo+,Tuuli Hakala+,Xhenti Ferhati+,Ana Guerreiro, David Hartmann, Barbara Bernardim, Kadi L. Saar,Ismael CompaÇón, Francisco Corzana,* Tuomas P. J. Knowles,* Gonzalo JimØnez-OsØs,*and GonÅalo J. L. Bernardes* Abstract: Quaternized vinyl- and alkynyl-pyridine reagents seem particularly suitable to modify native proteins in the test were shown to react in an ultrafast and selective manner with tube.Lysine,[4] methionine,[5] tryptophan,[6] and the N-[7] and several cysteine-tagged proteins at near-stoichiometric quanti- the C-terminus[8] may now be targeted by using avariety of ties.Wehave demonstrated that this method can effectively approaches.However,cysteine[9] remains perhaps the residue create ahomogenous antibody–drug conjugate that features of choice to produce functional and, in particular, clinically aprecise drug-to-antibody ratio of 2, which was stable in useful protein conjugates,namely antibody–drug conjugates human plasma and retained its specificity towards Her2 + cells. (ADCs). This choice is aresult of the high nucleophilicity of Finally,the developed warhead introduces a + 1charge to the the sulfhydryl side-chain combined with the low abundance of overall net charge of the protein, whichenabled us to show that free cysteineresidues,since many cysteines are paired as the electrophoretic mobility of the protein may be tuned structural disulfides.Thus,many research groups have through the simple attachment of aquaternized vinyl pyridi- focused on developing efficient methods to chemoselectively nium reagent at the cysteine residues.Weanticipate the modify cysteine-tagged proteins.For example,electrophiles, generalized use of quaternized vinyl- and alkynyl-pyridine such as carbonylacrylic acid reagents for Michael addition,[10] reagents not only for bioconjugation, but also as warheads for arylation reactions based on transition metals,[11] or aselective covalent inhibition and as tools to profile cysteine reactivity. amino acid sequence,[12] or conjugate additions at dehydroa- lanine[13] formed from cysteine or thiol-yne reactions using Chemical site-selective modification offers ameans to cyclooctynes[14] have been developed. Each of these methods diversify the function and properties of the protein.[1] For has relative advantages and disadvantages,but amethod example,byusing the targeting capabilities of an antibody,it based on the simple attachment of awarhead-like structure is possible to covalently attach avery potent drug to the whose utility would go beyond bioconjugation and for antibody through aprecise chemical reaction to shuttle this example be used to tune protein pharmacokinetics,through drug to aspecific tissue.[2] Thetoolbox of reactions for protein changes in the overall net charge of aprotein, or be used to modification has expanded significantly in the last decade.[3] design cysteine covalent inhibitors is missing from the current Of these,reactions that target proteinogenic amino acids toolbox. Herein, we report the computational chemistry assisted [*] Dr.M.J.Matos,[+] T. Hakala,[+] D. Hartmann,Dr. B. Bernardim, discovery of quaternization of the nitrogen of vinyl- and K. L. Saar,Prof. T. P. J. Knowles, Dr.G.J.L.Bernardes alkynyl pyridines to convert otherwise non-reactive reagents Department of Chemistry,University of Cambridge into ultrafast and chemoselective cysteine-modifying Lensfield Road, CB2 1EW Cambridge (UK) reagents.The utility of these reagents was demonstrated for E-mail:[email protected] bioconjugation and for modulation of electrophoretic mobi- [email protected] lity through charge incorporation by using microfluidics. A. Guerreiro,Dr. G. J. L. Bernardes Based on computational predictions,weidentified prom- Instituto de Medicina Molecular,Faculdade de Medicina, Universi- dade de Lisboa ising alkenes and alkynes through modelling the nucleophilic Avenida ProfessorEgas Moniz, 1649-028 Lisboa (Portugal) addition reaction between asimple thiolate or an amine with E-mail:[email protected] various electrophiles.Asaresult of the lower pKa of solvent- Dr.C.D.Navo,[+] X. Ferhati,[+] I. CompaÇón, Dr.F.Corzana, exposed thiols relative to amines,itis expected that at neutral Dr.G.JimØnez-OsØs or slightly basic pH alarger proportion of thiols would be Departamento de Química,Universidad de La Rioja, Centro de deprotonated. Activation free energies (DG°)for the corre- InvestigaciónenSíntesis Química sponding addition reactions were predicted by using quantum 26006 LogroÇo (Spain) mechanical calculations (Figure 1a and b). 2-Vinyl- and 2- E-mail:[email protected] [+] ethynyl pyridines (compounds 1 and 3)were calculated to be Dr.C.D.Navo, Dr.G.JimØnez-OsØs ° 1 poorly reactive toward thiolates (DG > 24 kcalmolÀ )and CIC bioGUNE,Bizkaia Technology Park ° 1 Building 801A, 48170 Derio (Spain) unreactive toward primary amines (DG > 31 kcalmolÀ ). E-mail:[email protected] However,when quaternized, the resulting N-methylpyridi- [+]These authors contributed equally to this work. nium derivatives were calculated to be exceedingly reactive Supportinginformation and the ORCID identification number(s) for towards nucleophilic addition, with dramatically decreased the author(s) of this article can be found under: activation free energies.For instance,2-vinyl- and 2-ethynyl- https://doi.org/10.1002/anie.201901405. pyridiniums 2 and 4 were calculated to be more than abillion 6640 2019 Wiley-VCH Verlag GmbH &Co. KGaA,Weinheim Angew.Chem.Int. Ed. 2019, 58,6640 –6644 Angewandte Communications Chemie agreement with computational predictions,the fast kinetics observed with quaternized pyridinium reagents 2 and 4 were comparable to those of N-ethylmaleimide,[15] for which the reaction with 1-propanethiol and Ac-Cys-NH2 were complete within the 4min necessary to obtain the first 1HNMR spectroscopic measurements,although the formation of an undetermined alkene by-product was observed in these reactions with maleimide (see the Supporting Information). With lysine side-chain mimic 1-propylamine (Figure 1c, Entry 7) and N-acetyllysine amide (Ac-Lys-NH2 ;Figure 1c, Entry 8) the reactions with quaternized 1-methyl-2-vinylpyr- idinium (2)were exceedingly slow (< 6% adduct formation after 24 hours with 1equivalent of electrophile). This result agrees with the computationally predicted orthogonality of these electrophiles towards cysteines,with no expected reaction on typically solvent-exposed lysines.Itisinteresting to note that the terminal alkyne hydrogen in compounds 3 and 4 quickly exchanged to deuterium in D2OatpH7.6, particularly in the case of quaternized 4,for which deutera- tion takes place within 4min. H/D exchange at the vinyl hydrogens of quaternized 2 was also observed when [D7]DMF was used as aco-solvent. Accurate reaction rate constants could not be obtained for Figure 1. Computer-assisted evaluationand experimental validation of very reactive quaternized pyridiniums 2 and 4,and N- a) vinyl- and b) alkynyl pyridinium electrophile reagents 1–4 for cys- ethylmaleimide as aresult of the ultrafast kinetics observed teine modification. c) Reaction of 1–4 with stoichiometric amounts of various nucleophiles. under the reaction conditions used (3 mm was the detection limit for 1HNMR spectroscopy in our experiments). Also,the high level of sensitivity to small reagent concentration ° 1 times more reactive with thiolates (DG = 10–12 kcalmolÀ ) changes on the observed rate for second-order reactions, than their non-quaternized analogues 1 and 3,which shows further complicates the derivation of the rate constants under predicted reactivities similar to those of maleimide[15] and stoichiometric conditions.Furthermore,although alkynyl carbonylacrylic derivatives[10] previously used for cysteine pyridinium 4 was selective towards mono-functionalization ligation. In all cases,acomplete selectivity for cysteine over under strict stoichiometric conditions,itwas found to undergo lysine addition was predicted, as reflected by the nearly double thiol addition to the external position of the triple 1 8kcalmolÀ higher activation barrier calculated for the latter. bond to give astable dithioacetal when aslight excess of the We validated our computational predictions by reacting thiol was used (see the Supporting Information). Once the stoichiometric amounts of minimal cysteine and lysine side- dramatic effect of pyridine quaternization in boosting the chain model compounds (that is 1-propanethiol and 1- electrophilicity of reagents 1 and 3 was demonstrated and propylamine,respectively) with commercially available 1–3 given the very similar and ultrafast reactivity of quaternized and synthesized reagent 4 (Figure 1c), and monitoring reagents 2 and 4 towards thiols,wedecided to use more reaction with 1HNMR spectroscopy (3 mm,phosphate convenient 1-methyl-2-vinylpyridinium 2 for cysteine-selec- buffer in D2O, pH 7.6;see the Supporting Information for tive modification on proteins (to avoid terminal alkyne additional data and adetailed discussion on the effect of using deuteration and formation of mixtures of potentially reactive aslightly more acidic pH). In agreement with theoretical alkene isomers upon nucleophilic addition). predictions,the reactions with non-quaternized reagents Having demonstrated the superior
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