Spisulosine compounds

Abstract

The present invention is directed to the isolation and bioactive characterization of compounds isolated from the clam Spisula polynyma. These compounds include three sphingoid-type bases, spisulosines 285, 299 and 313 (1-3), each of which shows unique cytotoxicity against L1210 murine lymphocytic leukemia cells. In addition, sphingosine (also referred to as 4-sphingenine or octadeca-4-shpingenine, 4) and two related compounds, nonadeca-4-sphingenine (a one carbon longer homolog, 5) and sphinga-4,10-diene (a dehydrosphingosine deravitive, 6) were also obtained, These compounds also contribute to the cytotoxicity of the Spisula polynyma extracts, but did not cause the morphology changes observed with compounds 1-3.

1. A synthetic method for the formation of spisulosine compounds comprising the steps of:
 protecting the α-amino group of a compound having the formula 20: 
                 
   to form a compound of formula 30: 
                 
   reducing the compound of formula 30 to provide a compound of formula 40: 
                 
   oxidizing the compound of formula 40 to provide a compound of formula 50: 
                 
   reacting the compound of formula 50 with Grignard reagent having the formula CH 3 (CH 2 ) n MgBr to form a compound having the formula 60: 
                 
   wherein n=14, 15 or 16; and    deprotecting the amino group in compound 60 by catalytic hydrogenation to afford a spisulosine compound.    
     
     
       2. The process of  claim 1 , wherein n is 14 and the spisulosine compound generated is Spisulosine 285. 
     
     
       3. The process of  claim 1 , wherein n is 15 and the spisulosine compound generated is Spisulosine 299. 
     
     
       4. The process of  claim 1 , wherein n is 16 and the spisulosine compound generated is Spisulosine 313. 
     
     
       5. A synthetic method for the formation of spisulosine compounds comprising the steps of:
 protecting the α-amino group of a compound having the formula  20 : 
                 
   to form a compound of formula  30 : 
                 
   reducing the compound of formula  30  to provide a compound of formula  40 : 
                 
   oxidizing the compound of formula  40  to provide a compound of formula  50 : 
                 
   reacting the compound of formula  50  with Grignard reagent having the formula CH 3   (CH   2   )   n   MgBr to form a compound having the formula  60 :  
                 
   wherein n= 12 ,  13  or  14 ; and    deprotecting the amino group in compound  60  by catalytic hydrogenation to afford a spisulosine compound.   
     
     
       6. The process of  claim 5 , wherein n is  12  and the spisulosine compound generated is Spisulosine  285 . 
     
     
       7. The process of  claim 5 , wherein n is  13  and the spisulosine compound generated is Spisulosine  299 .  
     
     
       8. The process of  claim 5 , wherein n is  14  and the spisulosine compound generated is Spisulosine  313 .  
     
     
       9. A synthetic method for the formation of spisulosine compounds comprising the steps of:
 oxidizing a compound of formula  40 : 
                 
   to provide a compound of formula  50 : 
                 
   reacting the compound of formula  50  with Grignard reagent having the formula CH 3(   CH   2   )   n   MgBr to form a compound having the formula  60 :  
                 
   wherein n= 12 ,  13 , or  14 ; and    deprotecting the amino group in compound  60  by catalytic hydrogenation to afford a spisulosine compound.    
     
     
       10. The process of  claim 9 , wherein n is  12  and the spisulosine compound generated is Spisulosine  285 .  
     
     
       11. The process of  claim 9 , wherein n is  13  and the spisulosine compound generated is Spisulosine  299 .  
     
     
       12. The process of  claim 9 , wherein n is  14  and the spisulosine compound generated is Spisulosine  313 .