Use of multivalent synthetic ligands of surface nucleolin for treating cancer or inflammation

Abstract

A method for treating disorders involving deregulation of cell proliferation and/or angiogenesis comprising the administration of an effective amount of a multivalent synthetic compound comprising a support on which at least 3 pseudopeptide units are grafted, said compound being of formula (I).

1 . A polyvalent synthetic compound comprising a support on which at least 3 pseudopeptide units are grafted, said compound being of formula (I): 
       
         
           
           
               
               
           
         
         wherein the support is a linear peptide, and wherein grafted support residues are separated by at least one amino acid; 
         each X independently represents any amino acid; 
         Y 1  and Y 2  are selected independently from arginine (R) and lysine (K); 
         Z is proline; 
         n and i are independently 0 or 1; 
         m is an integer between 0 and 1; 
         k is an integer between 3 and 8; and 
         Ψ represents a modified peptide bond selected from the group consisting of a reduced bond (—CH 2 NH—), a retro-inverso bond (—NHCO—), a methyleneoxy bond (—CH 2 —O—), a thiomethylene bond (—CH 2 —S—), a carba bond (—CH 2 CH 2 —), a ketomethylene bond (—CO—CH 2 —), a hydroxyethylene bond (—CHOH—CH 2 —), an E-alkene bond or a (—CH═CH—) bond. 
       
     
     
         2 . The polyvalent synthetic compound of  claim 1 , wherein the support comprises the amino acid sequence of KX 1 KX 4 KX 1 K, where X 1  is optional and selected from lysine (K), valine (V), alanine (A), glutamic acid (E) and isoleucine (I), and X 4  is optional and selected from valine (V), alanine (A), glutamic acid (E) and isoleucine (I). 
     
     
         3 . The polyvalent synthetic compound of  claim 1 , wherein the support is selected from a linear peptoid, or linear foldamer. 
     
     
         4 . The polyvalent synthetic compound of  claim 1 , wherein the support is a linear peptide consisting of an amino acid sequence selected from SEQ ID NO :1, SEQ ID NO :2, SEQ ID NO :3, SEQ ID NO :4, SEQ ID NO :8, SEQ ID NO :9, SEQ ID NO :13, SEQ ID NO :14, SEQ ID NO :15, SEQ ID NO :18, or SEQ ID NO :19. 
     
     
         5 . The polyvalent synthetic compound of  claim 1 , wherein the compound is selected from the following compounds: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The polyvalent synthetic compound of  claim 1 , having a support as set forth in SEQ ID NO :17. 
     
     
         7 . The polyvalent synthetic compound of  claim 1 , wherein said pseudopeptide units are grafted directly on said support. 
     
     
         8 . The polyvalent synthetic compound of  claim 1 , wherein said pseudopeptide units are grafted on said support by means of a spacer. 
     
     
         9 . A pharmaceutical composition comprising an effective amount of a polyvalent synthetic compound according to  claim 1  and an excipient. 
     
     
         10 . Method for treating inflammatory diseases comprising administering an effective amount of a polyvalent synthetic compound as defined in  claim 1  to a patient in need thereof, wherein the compound is effective in treating, alleviating, or ameliorating the inflammatory disease. 
     
     
         11 . The method according to  claim 10 , wherein said inflammatory disease is selected from autoimmune diseases, septicaemia, septic shock, cardiac inflammatory diseases, graft rejection, trauma, inflammatory diseases of the joints, inflammatory diseases of the gastrointestinal system, inflammatory diseases of the skin, inflammatory diseases of the respiratory system and allergies. 
     
     
         12 . The method according to  claim 11 , wherein said inflammatory disease is an autoimmune disease. 
     
     
         13 . The method according to  claim 12 , wherein said autoimmune disease is lupus or rheumatoid polyarthritis. 
     
     
         14 . The method according to  claim 11 , wherein said inflammatory disease is septic shock. 
     
     
         15 . The method according to  claim 11 , wherein said inflammatory disease is endocarditis.