Kahalalide F and Related Compounds

Abstract

A process is provided for preparing kahalalide F and which leads to other kahalalide mimic compounds having useful biological activity.

1 - 10 . (canceled) 
   
   
       11 . A compound having the following Formula II: 
     
       
         
         
             
             
         
       
     
     wherein R 7  is selected such that Aaa-7 is D-allo-Ile and R 8  is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-; 
     and further wherein
 R 1 , R 3 , R 4 , R 5 , and R 6  are each independently selected from hydrogen or an alkyl group, an aryl group, or an aralkyl group each optionally substituted with a hydroxy group, a mercapto group, an amino group, a guanidino group, or a halogen group; 
 any of R 1 , R 3 , R 4 , R 5 , and R 6  can optionally replace the hydrogen on the α-nitrogen to form a proline ring; 
 R 2  is selected from hydrogen, an alkyl group, and an aralkyl group; 
 X 1  is selected from O, S, and N, with the proviso that when X 1  is O or S then R 2  is not present; 
 X 2  is selected from an alkenyl group, an alkyl group, an aryl group, and an aralkyl group, each optionally substituted with a hydroxy group, a mercapto group, an amino group, a guanidino group, and a halogen group; 
 and further wherein one or both Aaa-5 and Aaa-6 are optionally not present such that the remaining subunits form a ring, or an additional Aaa-7′ subunit is optionally inserted into the ring between Aaa-6 and Aaa-1, wherein Aaa-7′ is independently an amino acid; 
 wherein said compound of Formula II is not 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val). 
 
   
   
       12 . The compound according to  claim 11 , wherein Aaa-1 is D-allo-Thr. 
   
   
       13 . The compound according to  claim 11 , wherein Aaa-2 is D-allo-Ile. 
   
   
       14 . The compound according to  claim 11 , wherein Aaa-3 is D-Val. 
   
   
       15 . The compound according to  claim 11 , wherein Aaa-4 is Phe. 
   
   
       16 . The compound according to  claim 11 , wherein Aaa-5 is Z-Dhb. 
   
   
       17 . The compound according to  claim 11 , wherein Aaa-6 is Val. 
   
   
       18 . A composition comprising a compound according to  claim 11  and a pharmaceutically acceptable carrier or diluent. 
   
   
       19 . A method of synthesizing a compound having the following Formula II: 
     
       
         
         
             
             
         
       
     
     wherein R 7  is selected such that Aaa-7 is D-allo-Ile and R 8  is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-; 
     and further wherein
 R 1 , R 3 , R 4 , R 5 , and R 6  are each independently selected from hydrogen or an alkyl group, an aryl group, or an aralkyl group each optionally substituted with a hydroxy group, a mercapto group, an amino group, a guanidino group, or a halogen group; 
 any of R 1 , R 3 , R 4 , R 5 , and R 6  can optionally replace the hydrogen on the α-nitrogen to form a proline ring; 
 R 2  is selected from hydrogen, an alkyl group, and an aralkyl group; 
 X 1  is selected from O, S, and N, with the proviso that when X 1  is O or S then R 2  is not present; 
 X 2  is selected from an alkenyl group, an alkyl group, an aryl group, and an aralkyl group, each optionally substituted with a hydroxy group, a mercapto group, an amino group, a guanidino group, and a halogen group; 
 and further wherein one or both Aaa-5 and Aaa-6 are optionally not present such that the remaining subunits form a ring, or an additional Aaa-7′ subunit is optionally inserted into the ring between Aaa-6 and Aaa-1, wherein Aaa-7′ is independently an amino acid; 
 said method comprising a step of forming an amide bond between a carboxylic group and an amino group to accomplish a ring closure and form said cyclic portion, and wherein the starting material and product are optionally protected by one or more protecting groups, and wherein the carboxylic group participating in the amide bond formation and/or the amino group participating in the amide bond formation may optionally be protected or activated. 
 
   
   
       20 . The method according to  claim 19 , comprising a ring closure according to the following scheme: 
     
       
         
         
             
             
         
       
     
     wherein the starting material and product are optionally protected by one or more protecting groups, and wherein a carboxylic group of Aaa 3  and/or an amino group of Aaa 4  of the starting material may optionally be protected or activated. 
   
   
       21 . The method according to  claim 19 , wherein the amide bond forms between a carboxylic group of a D-Val and an amino group of a Phe. 
   
   
       22 . A method of treating cancer in a patient comprising administering a therapeutically-effective amount of a compound according to  claim 11  to a patient in need thereof, wherein said cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, lymphoma, and melanoma.