Glucose conjugates of triptolide, analogs and uses thereof

Abstract

Provided are compounds generated by conjugation of triptolide with glucose to form glucose-triptolide conjugates, provides compounds with effective anti-proliferative activity and improved tolerability as compared to naturally occurring triptolide compounds.

What is claimed is: 
     
         1 . A method of treating cancer in a subject comprising administering to the subject an anti-proliferative effective amount of a glucose-triptolide conjugate compound. 
     
     
         2 . The method of  claim 1 , wherein glucose-triptolide conjugate compound has a structure of Formula I:
   T&A-L 1 -Sugar   wherein the T&A moiety is triptolide or one of its analogs, and can be selected from compounds 1 to 18:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein L 1  can be selected from —X—Y—Z—, wherein X and Z can individually and independently be a direct bond, —CH 2 —, —C(O)—, —SO—, —SO 2 —, —OPO—, —OPO 2 —, and wherein Y is a substituted or unsubstituted —(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 1 -C 6 )alkyl-, substituted or unsubstituted —(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n NH(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkenyl-, substituted or unsubstituted —(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)O(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n NH(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)NH(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n S(C 2 -C 6 )alkynyl-, substituted or unsubstituted —(CH 2 ) n C(O)(CH 2 ) n S(C 2 -C 6 )alkynyl-, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, hydroxyl, oxo, aryl, heteroaiyl, carboxyl, cyano, nitro, or trifluoromethyl; 
         wherein n is an integer independently selected from 0, 1, 2, 3, 4, 5, and 6; 
         wherein the sugar can be selected from compounds 19 to 30, 33 to 48, and 51 to 53: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 2 , wherein the T&A moiety is compound 1. 
     
     
         4 . The method of  claim 3 , wherein the sugar is compound 19, 20, 37, or 38. 
     
     
         5 . The method of  claim 4 , wherein L 1  is —COCH 2 CH 2 CO— or —CH 2 —. 
     
     
         6 . The method of  claim 5 , wherein L 1  is —COCH 2 CH 2 CO—. 
     
     
         7 . The method of  claim 6 , wherein the sugar is compound 19. 
     
     
         8 . The method of  claim 1 , wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, ovarian cancer, pancreatic cancer, and gastric cancer, cervical cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, leukemia, non-hodgkin's lymphoma, prostate cancer, rectal cancer, malignant melanomas, alimentary/gastrointestinal tract cancer, liver cancer, skin cancer, lymphoma, kidney cancer, muscle cancer, bone cancer, brain cancer, eye or ocular cancer, rectal cancer, colon cancer, cervical cancer, bladder cancer, oral cancer, benign and malignant tumors, stomach cancer, corpus uteri, testicular cancer, renal cancer, throat cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma, basal cell carinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer, larynx cancer, neurofibromatosis, tuberous sclerosis, hemangiomas, and lymphangiogenesis. 
     
     
         9 . The method of  claim 8 , wherein the cancer is prostate cancer. 
     
     
         10 . The method of  claim 8 , wherein the cancer is metastatic cancer. 
     
     
         11 . The method of  claim 1 , wherein the compound is administered intravenously. 
     
     
         12 . The method of  claim 11 , wherein the compound is administered at a dosage of about 0.1 mg/kg to 2 mg/kg per dosage. 
     
     
         13 . The method of  claim 11 , wherein the compound is administered once daily. 
     
     
         14 . The method of  claim 11 , wherein the compound is administered for up to about 4 weeks. 
     
     
         15 . The method of  claim 1 , further comprising administering a chemotherapeutic compound. 
     
     
         16 . The method of  claim 15 , wherein the chemotherapeutic compound is administered prior to, simultaneously with, or following administration of the glucose-triptolide conjugate compound. 
     
     
         17 . The method of  claim 15 , wherein the chemotherapeutic compound is selected from the group consisting of taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof.