Analogues of (-)Picropodophyllin, Synthesis And Uses Thereof

Abstract

Compounds, compositions, methods of making, and methods of using analogues of (−)-picropodophyllin, as well as a transgenic animal model and its use for identifying anticancer agents.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein X, X′, Y, Y′ and Z are independently H, OCH 3 , OCH 2 CH 3 , O-i-CH 2 CH 2 CH 3 , O-n-CH 2 CH 2 CH 3 , SCH 3 , SCH 2 CH 3 , S-i-CH 2 CH 2 CH 3 , S-n-CH 2 CH 2 CH 3 , S(O)CH 3 , S(O)CH 2 CH 3 , S(O)-i-CH 2 CH 2 CH 3 , S(O)-n-CH 2 CH 2 CH 3 , S(O) 2 CH 3 , S(O) 2 CH 2 CH 3 , S(O) 2 -i-CH 2 CH 2 CH 3 , S(O) 2 -n-CH 2 CH 2 CH 3 , CN, SCN, OCN, N 3 , halogen, CH 3 , CH 2 CH 3 , i-CH 2 CH 2 CH 3 , n-CH 2 CH 2 CH 3 , CF 3 , CCH, CCCH 3 , CH═CH 2 , Ph, NH 2 , NHCH 3 , N(CH 3 ) 2 , NHCH 2 CH 3 , N(CH 2 CH 3 ) 2 , NO, NO 2 , CHO, COCH 3 , COCH 2 CH 3 , CO 2 H, CO 2 CH 3 , CO 2 CH 2 CH 3 , OC(O)H, OC(O)CH 3 , OSO 3 H, OSO 3 CH 3 , OSO 3 CH 2 CH 3 , OPO 3 H 2 , OPO 3 HCH 3 , OPO 3 HCH 2 CH 3 , OPO 3 (CH 3 ) 2 , OPO 3 (CH 2 CH 3 ) 2 , P(O)(OH) 2 , P(O)(OCH 3 )(OH), P(O)(OCH 2 CH 3 )(OH), P(O)(OCH 3 ) 2 , or P(O)(OCH 2 CH 3 ) 2  with the proviso that when X and X′ are H, Y, Y′, and Z cannot all be methoxy and that when X′ is H, and Y, Y′, and Z are methoxy, X cannot be a halogen. 
     
     
         2 . The compound of  claim 1  wherein X, X′, Y, Y′ and Z are independently H, OCH 3 , OCH 2 CH 3 , SCH 3 , SCH 2 CH 3 , S(O)CH 3 , S(O)CH 2 CH 3 , S(O) 2 CH 3 , CN, halogen, CH 3 , CH 2 CH 3 , CF 3 , N(CH 3 ) 2 , NHCH 2 CH 3 , N(CH 2 CH 3 ) 2 , NO, NO 2 , CHO, CO 2 CH 3 , or CO 2 CH 2 CH 3 . 
     
     
         3 . The compound of  claim 1  wherein X, X′, Y, Y′ and Z are independently H, OCH 3 , OCH 2 CH 3 , CN, halogen, CH 3 , CH 2 CH 3 , CF 3 , CHO, CO 2 CH 3 , or CO 2 CH 2 CH 3 . 
     
     
         4 . The compound of  claim 1  wherein X, X′, Y, Y′ and Z are independently H, CH 3 , OCH 3 , CN, halogen, CF 3 , or SCH 3 . 
     
     
         5 . The compound of  claim 1  wherein X, X′, Y, Y′ and Z are independently H, OCH 3 , OCH 2 CH 3 , SCH 3 , SCH 2 CH 3 , S(O)CH 3 , S(O)CH 2 CH 3 , S(O) 2 CH 3 , CN, CH 3 , CH 2 CH 3 , CF 3 , N(CH 3 ) 2 , NHCH 2 CH 3 , N(CH 2 CH 3 ) 2 , NO, NO 2 , CHO, CO 2 CH 3 , or CO 2 CH 2 CH 3 . 
     
     
         6 . The compound of  claim 1  wherein X, X′, Y, Y′ and Z are independently H, OCH 3 , OCH 2 CH 3 , CN, CH 3 , CH 2 CH 3 , CF 3 , CHO, CO 2 CH 3 , or CO 2 CH 2 CH 3 . 
     
     
         7 . The compound of  claim 1  wherein X, X′, Y, Y′ and Z are independently H, CH 3 , OCH 3 , CN, CF 3 , or SCH 3 . 
     
     
         8 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier thereof. 
     
     
         9 . A compound of formula II: 
       
         
           
           
               
               
           
         
       
       wherein X, X′, Y, Y′ and Z are independently hydrogen, a C 1 -C 8  alkyl, or C 1 -C 8  alkoxy group with the proviso that when X and X′ are H, Y, Y′, and Z cannot all be OCH 3 ; and
 R 1  may be oxo, —OH, —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OC 4 H 9 , —OCH 2 CH═CH 2 , —OCH 2 Ph, —OCH 2 CH 2 NH 2 , —OCOH, —OCOCH 3 , —OCH 2 OH, —OC 2 H 4 OH, —OC 3 H 6 OH, —OC 4 H 8 OH, or a glycoside. 
 
     
     
         10 . The compound of  claim 9  wherein X, X′, Y, Y′ and Z are hydrogen, methyl, or methoxy. 
     
     
         11 . The compound of  claim 9  wherein
 X, X′, Y, Y′═H, and Z═OCH 3 ; 
 X, X′, Y′, Z═H, and Y═OCH 3 ; 
 X, X′, Y′═H, and Y, Z═OCH 3 ; 
 X, X′, Z═H, and Y, Y′═OCH 3 ; or 
 X, X′, Y, Y′═H, and Z═CH 3 . 
 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 9  and a pharmaceutically acceptable carrier thereof. 
     
     
         13 . A method of preparing a compound of  claim 1  comprising the steps of: cyclizing a compound of formula (a) to form isobenzofuran (b), and reacting (b) in situ, via a Diels-Alder reaction to form Diels-Alder adduct (c) 
       
         
           
           
               
               
           
         
       
       selecting hydrogenating Diels-Alder adduct (c), reducing to a diol and acetylating to form meso diacetate (d) and desymmetrizing (d) with porcine pancreatic lipase (PPL) to produce (e), 
       
         
           
           
               
               
           
         
       
       subjecting (e) to silylation, deacetylation, and oxidation to produce a compound of formula (f) 
       
         
           
           
               
               
           
         
       
       wherein R 9  is a silyl protecting group such as a triisopropylsilyl-protecting group, converting the compound of formula (f) to a compound of formula (g) with a complementary silyl protecting group by retro-Michael ring opening and protection of the C 4 OH under neutral to basic conditions, followed by aldehyde oxidation, subjecting the compound of formula f to aldehyde oxidation under Lindgren conditions to form a compound of formula (g), 
       
         
           
           
               
               
           
         
       
       wherein R 10  is a C 4  protecting group such as a triethylsilyl-protecting group, converting the compound of formula (g) to a compound of formula (h) by transformation of the carboxylic acid into an acyl oxazolidinone functionality using carboxyl activation and then condensation with a metalated oxazolidinone, 
       
         
           
           
               
               
           
         
       
       introducing aromatic ring R to the compound of formula (h) to form a compound of formula (I) by Cu I -mediated conjugate addition of RMgBr at a temperature of −10 to 10° C., 
       
         
           
           
               
               
           
         
       
       converting the compound of formula (I) to a compound of formula (j) by desilylative lactonization by heating with a fluoride source and cyclization to produce the corresponding lactone 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1  wherein the halogen is selected from fluorine, chlorine, bromine, and iodine. 
     
     
         15 . The compound of  claim 1  wherein the halogen is selected from fluorine and iodine. 
     
     
         16 . The compound of  claim 1  wherein the halogen is fluorine. 
     
     
         17 . The compound of  claim 2  wherein the halogen is selected from fluorine, chlorine, bromine, and iodine. 
     
     
         18 . The compound of  claim 2  wherein the halogen is selected from fluorine and iodine. 
     
     
         19 . The compound of  claim 2  wherein the halogen is fluorine.