Therapeutic quassinoid preparations with antineoplastic, antiviral, and herbistatic activity

Abstract

The present invention includes purified and isolated quassinoids and synthetically derived quassinoid analogs based on a picrasane carbon skeleton. Novel sidechains at C-15 incorporating water solubilizing agents such as glycine are discussed. Therapeutic methods taking advantage of anticancer, antiviral, and herbistatic properties of these quassinoids are disclosed, including use against solid tumors and human immunodeficiency virus infected cells.

What is claimed is:  
     
         1 . A compound characterized by the formula  
       
         
           
           
               
               
           
         
       
       wherein R represent hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y is a sidechain comprising hydrogen, oxygen, halogen, hydroxyl, ester, carbonyl, alkyl, hydroxyalkyl, aryl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, and protein, wherein any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage.  
     
     
         2 . The compound of  claim 1 , wherein Y comprises an ester sidechain represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R 5 , R 6 , and R 7  represent hydrogen, halogen, methyl, ethyl, alkyl, aryl, hydroxyl, carboxyl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, protein, and any of the foregoing attached to the central carbon by an ether, ester, carbonyl, or glycosidic linkage.  
     
     
         3 . The compound of  claim 2 , wherein R 5  represents a methyl group, R 6  represents hydrogen, and R 7  represents an ethyl group.  
     
     
         4 . The compound of  claim 1 , wherein Y includes a water soluble sidechain selected from the group consisting of dextrans, dextrins, cyclodextrins, polyethyleneglycols, polymers of ethyleneglycol, polymers of propyleneglycol, carbohydrate polymers, carboxymethylcellulose, polyamines, polyglutamine, N-(2-hydroxypropyl)methacrylamide copolymers, polyoxamines, polyoxyethylene block polymers, and polyoxypropylene block polymers.  
     
     
         5 . The compound of  claim 4 , wherein Y includes a protein selected from the group consisting of antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease.  
     
     
         6 . A therapeutic preparation comprising a pharmaceutically effective carrier and a compound represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R represent hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y is a sidechain comprising hydrogen, oxygen, halogen, hydroxyl, ester, carbonyl, alkyl, hydroxyalkyl, aryl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, and protein, wherein any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage.  
     
     
         7 . The compound of  claim 6 , wherein Y comprises an ester sidechain represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R 5 , R 6 , and R 7  represent hydrogen, halogen, methyl, ethyl, alkyl, aryl, hydroxyl, carboxyl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, protein, and any of the foregoing attached to the central carbon by an ether, ester, carbonyl, or glycosidic linkage.  
     
     
         8 . The compound of  claim 7 , wherein R 5  represents a methyl group, R 6  represents hydrogen, and R 7  represents an ethyl group.  
     
     
         9 . The compound of  claim 6 , wherein Y includes a water soluble sidechain selected from the group consisting of dextrans, dextrins, cyclodextrins, polyethyleneglycols, polymers of ethyleneglycol, polymers of propyleneglycol, carbohydrate polymers, carboxymethylcellulose, polyamines, polyglutamine, N-(2-hydroxypropyl)methacrylamide copolymers, polyoxamines, polyoxyethylene block polymers, and polyoxypropylene block polymers.  
     
     
         10 . The compound of  claim 9 , wherein Y includes a protein selected from the group consisting of antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease.  
     
     
         11 . A method of treating solid tumors comprising the steps of preparing a pharmaceutically active composition containing a quassinoid represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R represent hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y is a sidechain comprising hydrogen, oxygen, halogen, hydroxyl, ester, carbonyl, alkyl, hydroxyalkyl, aryl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, lipids, nucleic acids, derivatized polymeric substances which have from 1 to about 1,000 monomeric units and which enhance the impermeance of said compound, immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin, sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, and protein, wherein any of the foregoing attached to the C-15 carbon by an ether, ester, carbonyl, or glycosidic linkage, and  
       contacting the solid tumors with said pharmaceutically active composition.  
     
     
         12 . The method according to  claim 11 , wherein Y comprises an ester sidechain represented by the formula  
       
         
           
           
               
               
           
         
       
       wherein R 5 , R 6 , and R 7  represent hydrogen, halogen, methyl, ethyl, alkyl, aryl, hydroxyl, carboxyl, glycine, glycosaccharides, water soluble sidechains, amino acid, peptide, polypeptide, protein, and any of the foregoing attached to the central carbon by an ether, ester, carbonyl, or glycosidic linkage.  
     
     
         13 . The method according to  claim 12 , wherein R 5  represents a methyl group, R 6  represents hydrogen, and R 7  represents an ethyl group.  
     
     
         14 . The method according to  claim 11 , wherein Y includes a water soluble sidechain selected from the group consisting of dextrans, dextrins, cyclodextrins, polyethyleneglycols, polymers of ethyleneglycol, polymers of propyleneglycol, carbohydrate polymers, carboxymethylcellulose, polyamines, polyglutamine, N-(2-hydroxypropyl)methacrylamide copolymers, polyoxamines, polyoxyethylene block polymers, and polyoxypropylene block polymers.  
     
     
         15 . The method according to  claim 14 , wherein Y includes a protein selected from the group consisting of antibodies, immunoglobulins, growth hormones, interferons, plasma albumin, plasminogen activator, soybean trypsin inhibitor, L-asparaginase, and ribonuclease.