Antineoplastic Agents Targeted via Glut Transporters

Abstract

The present invention relates to novel antineoplastic agents and cancer diagnostic agents that specifically target neoplastic cells via the GLUT transportation system. More specifically, the invention relates to conjugates of 2-deoxyglucose, wherein a linker, which includes a covalent bond, is attached to 2-deoxyglucose at the 2 position, and the linker is attached to a therapeutic or diagnostic agent. The inventions also relates to methods of treating tumor disease and methods of making the novel compounds of the present invention. The agents of the present invention are superior to previous agents as they are targeted via GLUT transporters.

1 - 36 . (canceled) 
     
     
         37 . A 2-deoxyglucose conjugate, wherein said conjugate is represented by the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein L is a linker group; and D is pyropheophorbide (pyro-2DG). 
       
     
     
         38 . The conjugate of  claim 37 , wherein said linker group, L, is selected from the group consisting of a covalent bond, —NH—, -peptide-, -nucleic acid-, —O—, (CH 2 ) r —O—, —NH—CH 2 —CH 2 —NH—, —NH—CH(COOH)—CH 2 —NH—, —NH—CH 2 —CH(COOH)—NH—, —NH—CH 2 —CH 2 —CH 2 —NH, —O—(CH 2 ) r —NH—, S—(CH 2 ) r —NH—, —S—(CH 2 ) r —C(O)—, —NH—CH 2 —C(O)—, —O—CH 2 —CH 2 —O—CH 2 —CH 2 —O, —NH—NH—C(O)—CH 2 —, —NH—C(CH 2 ) 2 —C(O)—, and —NH—NH—C(O)—(CH 2 ) r —C(O)NH—N═, wherein r, in each instance, is from 2-5. 
     
     
         39 . The conjugate of  claim 38 , wherein said linker group is susceptible to cleavage by cytosolic enzymes. 
     
     
         40 . The conjugate of  claim 39 , wherein said linker group is a peptide consisting of from about 1 to about 6 amino acids. 
     
     
         41 . A method of treating tumor disease in an animal, comprising administering the compound of  claim 37  to an animal in need thereof to treat the tumor disease of the animal. 
     
     
         42 . A method of inhibiting the growth of a cancer cell comprising: (a) contacting said cancer cell with the conjugate of  claim 37  and
 (b) exposing said cancer cell to an effective amount of artificial irradiation.   
     
     
         43 . The method of  claim 42 , wherein said cancer cell is selected from the group consisting of breast, lung, pancreas, bladder, ovarian, testicular, prostate, liver, retinoblastoma, Wilm's tumor, adrenocarcinoma or melonoma. 
     
     
         44 . The method of  claim 42 , wherein said artificial irradiation is selected from the group consisting of artificial ultraviolet, infrared (IR), gamma-irradiation, x-ray and visible light. 
     
     
         45 . The method of  claim 44 , wherein said artificial irradiation is IR. 
     
     
         46 . The method of  claim 44 , wherein said IR is near-infrared (NIR). 
     
     
         47 . The method of  claim 42 , wherein said artificial irradiation is applied at the maximum absorption of the photosensitizer. 
     
     
         48 . The method of  claim 42 , wherein said artificial irradiation is applied about 5 minutes to about 3 hours after administering the conjugate of  claim 38 . 
     
     
         49 . The method of  claim 42 , wherein said artificial irradiation is applied about 10 to about 60 minutes after administering the conjugate of  claim 38 . 
     
     
         50 . The method of  claim 42 , wherein said artificial irradiation is applied for about 5 seconds to about 60 minutes. 
     
     
         51 . The method of  claim 42 , wherein said artificial irradiation is applied for about 1 minute to about 45 minutes. 
     
     
         52 . The method of  claim 42 , wherein said artificial irradiation is applied for about 10 to about 30 minutes. 
     
     
         53 . A pharmaceutical composition comprising the conjugate of  claim 37  and a pharmaceutically acceptable carrier. 
     
     
         54 . A method for the treatment of cancer in a subject comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 53  to a subject in need thereof.