Vinylsulfonamides For Chemoselective Reaction And Their Application

Antibody-Drug Conjugates?ADC?are a unique kind of therapeutic agents that have less side reactions to cancer patients because of the specific binding of antibody and antigen on target cells.ADCs cantain three main components:a monoclonal antibody,a linker and a cytotoxic chemotherapetutic agent.The linker plays a significant role in ADC,which can chemoselectively reacts with specific amino acids.Herein,a new class of N-phenyl-divinylsulfonamides which is easy to prepare,have been successfully developed and utilized as the efficient linkers in the field of disulfide bond modification.Under the optimal reaction conditions,the peptides oxytocin and salmon calcitonin?sCT?were shown to readily form a selective disulfide bond conjugation.Moreover,we make it possible to specifically introduce functional divinylsulfonamides of various functionalities,including affinity probes,fluorescent tags and drugs,into the target peptides or proteins.Moreover we have successfully inserted alkyne at the disulfide of polypeptide,this provides a useful tool to efficiently modify polypeptide with diverse molecular tags by“click chemistry”.Since antiboties contain four disulfide bonds,site-selective bioconjugation in ADC using disulfide bond attracts more and more attentions in the ADC field.Our current studies in site-selective disulfide re-bridging of the new linker,provide a new strategy to disulfide re-bridging in ADC drug development.The second part of my research concerns vinylsulfonamides saving as chemoselective handles to nuclephiles via Michael addition.It is a challenge to chemoselectively react with amines and alcohols with no protecting groups.The current approaches include enzyme catalyzed reactions or mental catalysts with strong bases such as LiHMDS.These strategies greatly limit the application of this reaction due to high cost and the“water free”strict condition.We report a metal free chemoselective alkylation of hydroxy group or amino group using N-methyl-N-phenyl-vinylsulfonamide.We demonstrated that the O-alkylation products can be obtained in the regular THF solvent without additional water supplemented with saturated solid KOH.On the other hand,the N-alkylation products would be formed when reaction were performed in mixed solvent of THF/H₂O?4:1?under 0.5 equvalent KOH.The selective Michael addition between N-methyl-N-bensylvinylsulfonates and amines/alcohols under different reactions is applicable to both inter-molecular and intra-molecular reactions.