Noscapine analogs and their use in treating cancers, including drug-resistant cancers

Abstract

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are noscapine analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers. While the antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans, structure-function analyses pointed to a proton at position 9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Noscapine analogs with various functional moieties at position 9 on the isoquinoline ring kill human cancer cells resistant to other anti-microtubule agents, such as vincas and taxanes. Representative analogs include the 9-nitro, 9-bromo-, 9-iodo-, and 9-fluoro-noscapines, which bind tubulin and induce apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine and teniposide. Surprisingly, treatment with one of the analogs, 9-nitro-nos, at doses as high as 100 μM, did not affect the cell cycle profile of normal human fibroblasts. This selectivity for cancer cells represents a unique edge over the other available antimitotics. The compounds can perturb the progression of cell cycle by mitotic arrest, followed by apoptotic cell death associated with increased caspase-3 activation and appearance of TUNEL-positive cells. Thus, the compounds are novel therapeutic agents for a variety of cancers, including ovarian and T-cell lymphoma cancers, even those that have become drug-resistant to currently available chemotherapeutic drugs.

1 . A compound having the following formula: 
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts thereof, 
       wherein Z is, individually, selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, —OR′, —NR′R″, —CF 3 , —CN, —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —O(CR′R″) r C(═O)R′, —O(CR′R″) r NR″C(═O)R′, —O(CR′R″) r NR″SO 2 R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, 
       where R′ and R″ are individually hydrogen, C 1 -C 8  alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and r is an integer from 1 to 6, or R′ and R″ can combine to form a cyclic functionality, 
       wherein the term “substituted” as applied to alkyl, aryl, cycloalkyl and the like refers to the substituents described above, starting with halo and ending with —NR′SO 2 R″. 
     
   
   
       2 . A compound having the following formula: 
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts thereof, wherein Z is nitro, bromo, iodo, or fluoro. 
     
   
   
       3 . The compound of  claim 2 , wherein Z is nitro. 
   
   
       4 . The compound of  claim 2 , wherein Z is bromo. 
   
   
       5 . The compound of  claim 2 , wherein Z is iodo. 
   
   
       6 . The compound of  claim 2 , Z is fluoro. 
   
   
       7 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
   
   
       8 . A pharmaceutical composition comprising a compound of  claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
   
   
       9 . The composition of  claim 8 , wherein Z is nitro. 
   
   
       10 . The composition of  claim 8 , wherein Z is bromo. 
   
   
       11 . The composition of  claim 8 , wherein Z is iodo. 
   
   
       12 . The composition of  claim 8 , wherein Z is fluoro. 
   
   
       13 . A method of treating or preventing cancer in a patient, comprising administering an effective amount of a compound of  claim 1  to a patient in need of treatment thereof. 
   
   
       14 . The method of  claim 13 , wherein the cancer is selected from the group consisting of drug-resistant ovarian cancer, drug resistant T-cell lymphoma, T-cell lymphoma, leukemia, non-small cell lung, colon, central nervous system (CNS), melanoma, renal, ovarian, breast and prostate cancer. 
   
   
       15 . The method of  claim 13 , wherein the cancer is drug-resistant ovarian cancer or T-cell lymphoma. 
   
   
       16 . The method of  claim 13 , wherein the cancer is a drug-resistant cancer. 
   
   
       17 . A method of treating or preventing cancer in a patient, comprising administering an effective amount of a compound of  claim 2  to a patient in need of treatment thereof. 
   
   
       18 . The method of  claim 17 , wherein Z is nitro. 
   
   
       19 . The method of  claim 17 , wherein Z is bromo. 
   
   
       20 . The method of  claim 17 , wherein Z is iodo. 
   
   
       21 . The method of  claim 17 , Z is fluoro. 
   
   
       22 . The method of  claim 17 , wherein the cancer is selected from the group consisting of drug-resistant ovarian cancer, drug resistant T-cell lymphoma, T-cell lymphoma, leukemia, non-small cell lung, colon, central nervous system (CNS), melanoma, renal, ovarian, breast and prostate cancer. 
   
   
       23 . The method of  claim 17 , wherein the cancer is drug-resistant ovarian cancer or T-cell lymphoma. 
   
   
       24 . The method of  claim 17 , wherein the cancer is a drug-resistant cancer.