Compounds and methods for thiol-containing compound efflux and cancer treatment

Abstract

Methods for therapy of cystic fibrosis and other conditions such as cancer are provided. The methods comprise one or more agents capable of increasing thiol-containing compound transport via a transporter system (i.e. ABC transporters such as MDR-1 or MRP-2) in cells. Other embodiments include the use of agents to modulate transport of thiol-containing compounds within the cell. Therapeutic methods involve the administration of such agents to a patient afflicted with cystic fibrosis, cancer and/or another condition responsive to stimulation of thiol-containing compound transport.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is an optionally substituted heteroaryl; 
         where R4′ is hydrogen; and 
         each of R2′, R3′, R5′ and R6′ is independently hydrogen or —OR o , where R c  is hydrogen or a hydroxy protecting group and wherein at least one of R2′, R3′, R5′, or R6′ is —OH. 
       
     
     
         2 . The compound of  claim 1 , wherein the optionally substituted heteroaryl is an optionally substituted nitrogen atom containing 5-membered heteroaryl ring. 
     
     
         3 . The compound of  claim 1 , wherein R2′ or R3′ is —OH. 
     
     
         4 . The compound of  claim 1 , wherein R2′ and R6′ or R2′ and R5′ or R2′ and R3′ are hydroxyl groups. 
     
     
         5 . The compound of  claim 4 , wherein R2′ and R6′ are hydroxyl groups. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is an optionally substituted imidazolyl. 
     
     
         7 . The compound of  claim 6 , wherein one of R2′, R3′, R5′ and R6′ is —OH and the others are hydrogen. 
     
     
         8 . The compound of  claim 7 , wherein R 1  is an imidazol-2-yl, imidazol-4-yl or imidazol-5-yl each of which is substituted with one or two C 1-4  alkyl substituents. 
     
     
         9 . The compound of  claim 7 , wherein R 1  is an N—C 1-4  alkyl imidazol-2-yl, N—C 1-4  alkyl imidazol-4-yl or N—C 1-4  alkyl imidazol-5-yl each of which is further substituted with one or two C 1-4  alkyl substituents. 
     
     
         10 . The compound of  claim 1 , wherein R 1  is an optionally substituted oxazolyl. 
     
     
         11 . The compound of  claim 10 , wherein R 1  is an oxazol-2-yl, oxazol-4-yl or oxazol-5-yl each of which is substituted with one or two C 1-4  alkyl substituents. 
     
     
         12 . The compound of  claim 10 , wherein R 1  is an N—C 1-4  alkyl oxazol-2-yl, N—C 1-4  alkyl oxazol-4-yl or N—C 1-4  alkyl oxazol-5-yl each of which is further substituted with one or two C 1-4  alkyl substituents. 
     
     
         13 . The compound of  claim 1 , wherein R 1  is an optionally substituted thiazolyl. 
     
     
         14 . The compound of  claim 13 , wherein R 1  is an thiazol-2-yl, thiazol-4-yl or thiazol-5-yl each of which is substituted with one or two C 1-4  alkyl substituents. 
     
     
         15 . The compound of  claim 13 , wherein R 1  is an N—C 1-4  alkyl thiazol-2-yl, N—C 1-4  alkyl thiazol-4-yl or N—C 1-4  alkyl thiazol-5-yl each of which is further substituted with one or two C 1-4  alkyl substituents. 
     
     
         16 . The compound of  claim 1 , wherein R 1  is an optionally substituted pyrazolyl. 
     
     
         17 . The compound of  claim 16 , wherein R 1  is an pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl each of which is substituted with one or two C 1-4  alkyl substituents. 
     
     
         18 . The compound of  claim 16 , wherein R 1  is an N—C 1-4  alkyl pyrazol-3-yl, N—C 1-4  alkyl pyrazol-4-yl or N—C 1-4  alkyl pyrazol-5-yl each of which is further substituted with one or two C 1-4  alkyl substituents. 
     
     
         19 . The compound of  claim 1 , wherein R 1  is an optionally substituted purinyl. 
     
     
         20 . The compound of  claim 19 , wherein R 1  is an purin-2-yl, purin-6-yl or purin-8-yl each of which is substituted with one or two C 1-4  alkyl substituents. 
     
     
         21 . The compound of  claim 1 , wherein R 1  is an optionally substituted carbzaolyl. 
     
     
         22 . The compound of  claim 21 , wherein R 1  is a carbazol-6-yl, carbazol-7-yl carbazol-8-yl, carbazol-9-yl, carbazol-10-yl, carbazol-11-yl, carbazol-12-yl or carbazol-13-yl each of which is substituted with one or two C 1-4  alkyl substituents. 
     
     
         23 . A method comprising:
 identifying a subject having or at risk of developing cancer;   contacting one or more cells with an agent to increase transport of at least one thiol-containing compound;   modulating secretion of thiol-containing compound(s) from the cell; contacting one or more cells with an anti-cancer treatment; and   attenuating the onset or progression of the cancer.   
     
     
         24 . The method of  claim 23 , wherein the agent to increase transport of at least one thiol-containing compound comprises a flavone or chalcone or combination thereof. 
     
     
         25 . The method of  claim 23 , wherein the agent to increase transport of at least one thiol-containing compound comprises a compound of  claim 1  of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 24 , wherein the chalcone comprises a chalcone of the formula: 
       
         
           
           
               
               
           
         
         where R4′ is hydrogen; and 
         each of R2′, R3′, R5′ and R6′ is independently hydrogen or —OR c , 
         where R c  is hydrogen or a hydroxy protecting group and 
         wherein at least one of R2′, R3′, R5′, or R6′ is —OH. 
       
     
     
         27 . The method of  claim 26 , wherein the chalcone is selected from the group consisting of 2′ hydroxychalcone, 3′ hydroxychalcone, 4-hydroxychalcoue, 2′2 dihydroxychalcone, 2′3 dihydroxychalcone, 2′4 dihydroxychalcone, 2′4′ dihydroxychalcone, 2′5′ dihydroxychalcone, 2′, 4′, 4 trihydroxychalcone and 2′, 3′, 4′ trihydroxychalcone. 
     
     
         28 . The method of  claim 24 , wherein the flavone comprises a flavone of the formula: 
       
         
           
           
               
               
           
         
       
       wherein each of R2′, R3′, R4′, R5′, R5, R6, and R7 is independently a hydrogen or a —OR c ,
 where R c  is a non-ring forming hydroxy protecting group. 
 
     
     
         29 . The method of  claim 28 , wherein the flavone is selected from the group consisting of 5-hydroxyflavone, 7-hydroxyflavone, chrysin (5,7 dihydroxyflavone), galangin (3,5,7 trihydroxyflavone), baicalein (5,6,7 trihydroxyflavone), apigenin (tetrahydroxyflavone), kaempferol (3,5,7,4′ quadrahydroxyflavone) fisetin, quercetin, morin, myricetin, pinocembrin, pinobanskin and rutin (3=0-rutinose). 
     
     
         30 . The method of  claim 29 , wherein the flavone comprises a flavone wherein R7 is a hydroxyl; and
 wherein no more than two of R2′, R3′, R4′, R5′, R5, and R6 is independently a —OR C , where R c  is a non-ring forming hydroxy protecting group.   
     
     
         31 . The method of  claim 23 , wherein the thiol-containing compound comprises glutathione (GSH). 
     
     
         32 . The method of  claim 23 , wherein the cell comprises a cell in the lung, liver, brain, pancreas, ovary, cervix, heart, gallbladder, neck, bone, throat, thyroid, kidney, bladder, prostate, esophagus, breast, colon, rectum, stomach, lymph node, blood or skin. 
     
     
         33 . The method of  claim 23 , wherein the agent activates a thiol-containing compound transporter system localized on the apical surface of the cell(s). 
     
     
         34 . The method of  claim 33 , wherein the transporter system comprises an ABC (ATP-binding cassette) transporter. 
     
     
         35 . The method of  claim 34 , wherein the ABC transporter comprises at least one transporter selected from the group consisting of an MRP-2 (multi-drug resistance-associated protein) transporter; an MRP-1 (multi-drug resistance-associated protein) transporter; an MDR-1 (multi-drug resistance) transporter and cystic fibrosis transmembrane conductance regulator (CFTR). 
     
     
         36 . The method of  claim 23 , wherein the anti-cancer treatment comprises radio-sensitizing treatment, hyperthermia treatment or combination thereof. 
     
     
         37 . The method of  claim 36 , wherein the radio-sensitizing treatment comprises directed beam radiation therapy, system radiation or combination thereof. 
     
     
         38 . The method of  claim 37 , wherein the radio-sensitizing treatment comprises external radiation beam therapy, photon beam therapy, radiation seed therapy, targeted-beam radiation therapy, or combination thereof. 
     
     
         39 . A method comprising:
 identifying a subject having or at risk of developing cancer; contacting one or more cells with a composition for inducing transport of at least one thiol-containing compound;   contacting one or more cells with an anti-cancer agent; and attenuating the onset or progression of the cancer.   
     
     
         40 . The method of  claim 39 , wherein inducing transport of at least one thiol-containing compound comprises inducing apical, basal or lateral transport of at least one thiol-containing compound. 
     
     
         41 . The method of  claim 39 , wherein inducing transport of at least one thiol-containing compound comprises inducing transport by an ABC-transporter. 
     
     
         42 . The method of  claim 41 , wherein contacting one or more cells with a composition for inducing an ABC transporter and contacting one or more cells with an anti-cancer agent comprises contacting one or more cells with a composition for inducing an ABC transporter simultaneous with contacting one or more cells with an anti-cancer agent. 
     
     
         43 . The method of  claim 39 , wherein the anticancer agent is selected from the group consisting of alkylating agents, anti-metabolites, natural products, anti-proliferative agents, anticancer antibodies or combination thereof. 
     
     
         44 . The method of  claim 43 , wherein the anticancer agent is selected from the group consisting of Cyclophosphamide, Melphalan, Chlorambucil, busulfan, carmustine, lomustine, streptozocin, dacarbazine, methotrexate, 5-fluorouracil, cytarabine, mercaptopurine, thioguanine, vinblastine, vincristine, etoposide, teniposide, dacinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin C, cisplatin, hydroxyurea, procarbazine, mitotane, tamoxifen, or combination thereof. 
     
     
         45 . The method of  claim 39 , wherein increasing transport of thiol-containing compounds comprises increasing the excretion of thiol-containing compounds from the cell. 
     
     
         46 . The method of  claim 39 , wherein the anti-cancer agent is administered in a pharmaceutically acceptable delivery vehicle. 
     
     
         47 . The method of  claim 39 , wherein the composition comprises a flavone or a chalcone. 
     
     
         48 . The method of  claim 39 , wherein the composition comprises a composition including a compound of  claim 1  of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         49 . A kit for treating a subject having or at risk of developing cancer comprising:
 at least one delivery lumen;   a first agent delivered from a delivery lumen wherein the first agent comprises an agent capable of increasing transport of thiol-containing compounds; and   at least a second agent delivered from a delivery lumen wherein the second agent comprises an anti-cancer agent.