Constrained cis-diol-borate bioconjugation system

Abstract

The invention pertains to bioconjugation systems comprising sterically constrained cis-diols and borates.

1 . A sterically constrained cis-diol compound, represented by:  
       
         
           
           
               
               
           
         
         wherein:  
         Ring A is an optionally substituted bicycloalkyl, heterocyclyl or fused bicycloalkyl-heterocyclyl, or Ring A is an optionally substituted cycloalkyl;  
         R 1  is an optionally substituted alkyl, alkoxy, alkyl ether, alkyl sulfide, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl ether, heterocyclylalkyl ether, aralkyl ether, heteroaralkyl ether, cycloalkylalkyl sulfide, heterocyclylalkyl sulfide, aralkyl sulfide or heteroaralkyl sulfide linking group;  
         R 2a  and R 2a′  are independently —OH or —O—PG, wherein PG is an alcohol protecting group selected from selected from optionally substituted esters, ethers, silyl ethers and carbonates, or R 2a  and R 2a′ , taken together with the portion of Ring A connecting them, are a protected cis-diol group selected from optionally substituted cyclic acetals, cyclic ketals, and cyclic ortho esters;  
         X is a bond, —O—, —S—, —C(O)—, —C(O)O—, —S(O)—, —OSO 2 —, —S(O 2 )O—, —SO 2 —, —NR 3 —, —NR 3 C(O)—, —C(O)NR 3 C—, —R 3 NNR 3 SO 2 —, —SO 2 NR 3 NR 3 —, —NR 3 SO 2 —, —SO 2 NR 3 —, —CR 3   2 C(O)NR 3 —, —NR 3 C(O)CR 3   2 , —CR 3   2 C(O)—, —C(O)CR 3   2 —, —R 3 NNR 3 —, —NR 3 NR 3 —, —R 3 NNR 3   2   + —, —NR 3   2   + NR 3 —, —CR 3   2 Ph-, -PhCR 3   2 —, —C(NR 3 )NR 3 —, —NR 3 C(NR 3 )—;  
         each R 3  is independently —H, alkyl, alkoxy, aryloxy or arylalkoxy; and  
         Y is a bioactive molecule and n is an integer from 1 to 200; or Y is a solid support or a self assembled monolayer (SAM)-inducing solid support and n is an integer from 10 to 10 10 ; or n is 1 and —Y—X together are —S—, wherein two cis-diols form a disulfide dimer represented by:  
         
           
             
             
                 
                 
             
           
         
         wherein each variable is independently as defined above; or n is 1 and —Y—X together are —OH, —SH, halogen, —OR 5 , —C(O)OR 5 , —O(O)CR 5 , —NR 5 R 6 , or —N-heterocyclyl, wherein R 5  and R 6  are independently optionally substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl,  
         provided that the constrained cis-diol is not a saccharide.  
       
     
     
         2 . The compound of  claim 1 , wherein Y is the bioactive molecule.  
     
     
         3 . The compound of  claim 2 , wherein n is 1.  
     
     
         4 . The compound of  claim 1 , wherein Y is a solid support or a self assembled monolayer (SAM)-inducing solid support and n is an integer from 10 to 10 10 .  
     
     
         5 . The compound of  claim 4 , wherein the solid support or the SAM-inducing solid support comprises gold, silver, platinum, aluminum, or copper.  
     
     
         6 . The compound of  claim 4 , wherein the solid support or the SAM-inducing solid support is in the form of a bead, a microsphere, nanoparticle, gel, membrane, surface, film, porous matrix, or interior surface of a microchannel.  
     
     
         7 . The compound of  claim 4 , wherein the solid support is a nanoparticle comprising cadmium sulfide, cadmium selenide, cadmium telluride, silicon, or gallium arsenide.  
     
     
         8 . The compound of  claim 4 , wherein the solid support comprises optionally substituted polyalkylene, polyvinylene, polystyrene, polyethylene oxide, nitrocellulose, polyvinyl acetate, polyvinyl chloride, polyvinyl dichloride, polyfluoroalkylene, polyamide, polydialkylsiloxane, glass, silica, or quartz.  
     
     
         9 . The compound of  claim 4 , wherein Y comprises a conductive layer for surface plasmon resonance.  
     
     
         10 . The compound of  claim 3 , wherein R 2a  and R 2a′  are —OH, or R 2a  and R 2a′ , taken together with the portion of Ring A connecting them, are a protected cis-diol group selected from optionally substituted cyclic acetals, cyclic ketals, and cyclic ortho esters.  
     
     
         11 . The compound of  claim 10 , wherein Y comprises one or more nucleic acids, polynucleic acids, amino acids, peptides, proteins, peptide nucleic acids, hormones, cofactors, fatty acids, carbohydrates, polysaccharides, glycopeptides, glycoproteins; peptidoglycans; glycolipids, cyclitols, prenols, terpenoids, steroids, folates, carotenoids, retinoids, tocopherols, lignans, quinines, isoprenoids, tetrapyrroles, peptide nucleic acids, lipids, prostaglandins, immunoglobulins, glycolipids, lipoproteins, neurotransmitters, biometabolites, pharmaceuticals or environmental toxins.  
     
     
         12 . The compound of  claim 10 , wherein —Y—X together are —S—, wherein two cis-diols form a disulfide dimer represented by:  
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 10 , wherein —Y—X together are —OH, —SH, halogen, —OR 5 , —C(O)OR 5 , —O(O)CR 5 , —NR 5 R 6  or —N-heterocyclyl.  
     
     
         14 . The compound of  claim 13 , wherein the cis-diol is represented by:  
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 14 , wherein R 1  is C2-C16 alkyl ether, C1-C16 alkoxy or C1-C16 alkyl.  
     
     
         16 . The compound of  claim 15 , wherein the compound is represented by:  
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 16 , wherein R′ is C6-C12 alkyl.  
     
     
         18 . The compound of  claim 16 , wherein R′ is C1-C3 alkyl.  
     
     
         19 . The compound of  claim 18 , wherein —X— is —S—.  
     
     
         20 . The compound of  claim 19 , wherein the compound is:  
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 18 , wherein the compound is:  
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 15 , wherein the cis-diol is represented by:  
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 22 , wherein the compound is: