Compositions and methods for glucose transport inhibition

Abstract

Glucose deprivation is an attractive strategy in cancer research and treatment. Cancer cells upregulate glucose uptake and metabolism for maintaining accelerated growth and proliferation rates. Specifically blocking these processes is likely to provide new insights to the role of glucose transport and metabolism in tumorigenesis, as well as in apoptosis. As solid tumors outgrow the surrounding vasculature, they encounter microenvironments with a limited supply of nutrients leading to a glucose deprived environment in some regions of the tumor. Cancer cells living in the glucose deprived environment undergo changes to prevent glucose deprivation-induced apoptosis. Knowing how cancer cells evade apoptosis induction is also likely to yield valuable information and knowledge of how to overcome the resistance to apoptosis induction in cancer cells. Disclosed herein are novel anticancer compounds that inhibit basal glucose transport, resulting in tumor suppression and new methods for the study of glucose deprivation in animal cancer research.

What is claimed is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, and heteroaryl; 
         wherein R 2  is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, heteroaryl, and fluorescent tags; and 
         wherein R 3  is selected from the group consisting of hydrogen, halo, alkyl, benzyl, aryl, heteroaryl, amino, cyano, and alkoxy; 
         or a salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  and R 2  are aryl. 
     
     
         3 . The compound of  claim 2 , wherein R 1  and R 2  are independently selected from the group consisting of 2-, 3-, and 4-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, and 3,4,5-trihydroxyphenyl, 2,3,4,5- and 2,3,4,6-tetrahydroxyphenyl, and perhydroxyphenyl. 
     
     
         4 . The compound of  claim 2 , wherein R 1  and R 2  are independently selected from the group consisting of methoxyphenyl, dimethoxyphenyl, and trimethoxyphenyl. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is aryl and R 2  is a fluorescent tag. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is selected from the group consisting of 2-, 3-, and 4-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, and 3,4,5-trihydroxyphenyl, 2,3,4,5- and 2,3,4,6-tetrahydroxyphenyl, and perhydroxyphenyl; and
 wherein R 2  is selected from the group consisting of coumarins, dansyl, rhodamine, fluorescein, carboxynaphthofluorescein, and fluorescent proteins.   
     
     
         7 . The compound of  claim 1 , wherein R 1  and R 2  are 3-hydroxyphenyl and R 3  is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein R 1  and R 2  are 3,4,5-trihydroxyphenyl and R 3  is hydrogen. 
     
     
         9 . The compound of  claim 1 , wherein R 1  and R 2  are 3,4,5-trimethoxyphenyl and R 3  is hydrogen. 
     
     
         10 . The compound of  claim 1 , wherein R 1  and R 2  are 2,6-dimethoxyphenyl and R 3  is hydrogen. 
     
     
         11 . The compound of  claim 1 , wherein R 1  and R 2  are 3,4-dimethoxyphenyl and R 3  is hydrogen. 
     
     
         12 . The compound of  claim 1 , wherein R 1  and R 2  are 3-methoxyphenyl and R 3  is hydrogen. 
     
     
         13 . A method of treating cancer, the method comprising:
 administering to a subject in need of such treatment a therapeutically effective amount of a basal glucose transport inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, and heteroaryl; 
         wherein R 2  is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, heteroaryl, and fluorescent tags; and 
         wherein R 3  is selected from the group consisting of hydrogen, halo, alkyl, benzyl, aryl, heteroaryl, amino, cyano, and alkoxy; and 
         whereby administration of said basal glucose transport inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject treats said cancer by inhibiting basal glucose transport in said subject, and wherein the cancer is selected from lung cancer, colon cancer, breast cancer, and cervical cancer. 
       
     
     
         14 . The method of  claim 13 , wherein the cancer upregulates basal glucose transport. 
     
     
         15 . The method of  claim 13 , wherein R 1  and R 2  are independently selected from the group consisting of 2-, 3-, and 4-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, and 3,4,5-trihydroxyphenyl, 2,3,4,5- and 2,3,4,6-tetrahydroxyphenyl, and perhydroxyphenyl, and R 3  is hydrogen. 
     
     
         16 . The method of  claim 13 , wherein R 1  and R 2  are 3-hydroxyphenyl and R 3  is hydrogen. 
     
     
         17 . The method of  claim 13 , wherein the basal glucose transport inhibitor compound of formula (I) or pharmaceutically acceptable salt thereof is administered by at least one of the following methods: oral, topical, intra-arterial, intrapleural, intrathecal, intraventricular, subcutaneous, intraperitoneal, intraveneous, intravesicular, and gliadel wafers. 
     
     
         18 . The method of  claim 13 , wherein the subject is a human. 
     
     
         19 . The method of  claim 13 , further comprising administering to the subject in need of such treatment a second cancer drug. 
     
     
         20 . The method of  claim 19 , wherein the second cancer drug is selected from the group consisting of methotrexate, doxorubicin hydrochloride, fluorouracil, everolimus, imiquimod, aldesleukin, alemtuzumab, pemetrexed disodium, palonosetron hydrochloride, chlorambucil, aminolevulinic acid, anastrozole, aprepitant, exemestane, nelarabine, arsenic trioxide, ofatumumab, bevacizumab, azacitidine, bendamustine hydrochloride, bexarotene, bleomycin, bortezomib, cabazitaxel, irinotecan hydrochloride, capecitabine, carboplatin, daunorubicin hydrochloride, cetuximab, cisplatin, cyclophosphamide, clofarabine, ifosfamide, cytarabine, dacarbazine, decitabine, dasatinib, degarelix, denileukin difitox, denosumab, dexrazoxane hydrochloride, docetaxel, rasburicase, epirubicin hydrochloride, oxaliplatin, eltrombopag olamine, eribulin mesylate, erlotinib hydrochloride, etoposide phosphate, raloxifene hydrochloride, toremifane, fulvestrant, letrozole, filgrastim, fludarabim phosphate, pralatrexate, gefitinib, gemcitabine hydrochloride, gemcitibine-cisplatin, gemtuzumab ozogamicin, imatinib mesylate, trastuzamab, topotecan hydrochloride, ibritumomab tiuxetan, romadepsin, ixabepilone, palifermin, lapatinib ditosylate, lenalidomide, leucovorin calcium, leuprolide acetate, liposomal procarbazine hydrochloride, temozolomide, plerixafor, acetidine, sorafenib tosylate, nilotinib, tamoxifen citrate, romiplostim, paclitaxel, pazopanib hydrochloride, pegaspargase, prednisone, procarbazine hydrochloride, proleukin, rituximab, romidepsin, sunitinib malate, thalidomide, temsirolimus, toremifene, pantiumumab, vinblastine sulfate, vincristine, vorinostat, zoledronic acid, and any combination thereof.