Neoglycorandomization and digitoxin analogs
The present invention provides methods of producing libraries of compounds with enhanced desirable properties and diminished side effects as well as the compounds produced by the methods. In preferred embodiments, methods of the present invention use a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation. In a preferred embodiment, the invention provides a library of neoglycoside digitoxin analogs that includes compounds with significantly enhanced cytotoxic potency toward human cancer cells and tumor-specificity, but are less potent Na + /K + -ATPase inhibitors in a human cell line than digitoxin.
1. A neoglycoside library comprising at least two different neoglycosides having the structure:
wherein: R 1 , R 2 , R 3 , and R 4 of the sugar are independently selected from —H, —OH, —N 3 , —NH 2 , —CH 3 , —CH 2 OH, —CN 3 , —CH 2 NH, —CH 2 SH, —CNH 2 , —CH 2 N 3 , —COOH, —COCH 3 , —CXH 2 , or —CX 2 H, where X is Cl, Br, F, or I; R 5 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , allyl, benzyl, —CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , cyclopentyl or cyclohexyl; and the aglycon is a cardiac glycoside aglycon, a non-digoxigenin steroid, an indolocarbazole, an anthracyline, or a macrolide.
2. A method of making a neoglycoside library comprising the steps of:
providing a plurality of reducing sugars having the structure:
wherein R 1 , R 2 , R 3 and R 4 are independently selected from —H, —OH, —N 3 —NH 2 , —CH 3 —CH 2 OH, —CN 3 —CH 2 NH —CH 2 SH —CNH 2 , —CH 2 N 3 , —COOH, —COCH 3 —CXH 2 , or —CX 2 H, where X is Cl, Br, F, or I; and
contacting the reducing sugars with at least one aglycon having a secondary oxyamine of formula >N—O—R 5 wherein R 5 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , allyl, benzyl, —CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 cyclopentyl or cyclohexyl, and wherein the aglycon is a cardiac glycoside aglycon, a non-digoxigenin steroid, an indolocarbazole, an anthracyline, or a macrolide, to form a plurality of neoglycosides.
3. The method of claim 2 wherein the aglycon is:
wherein R is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , allyl, benzyl, —CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , cyclopentyl or cyclohexyl.