Neoglycorandomization and digitoxin analogs
AssigneeWisconsin Alumni Research Foundation
InventorsJon Thorson, Joseph Langenhan
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Abstract
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.
Claims23
A neoglycoside produced by the reaction of an aglycon having a secondary alkoxylamine and a reducing sugar selected from the group consisting of a L-sugar, a D-sugar, a deoxy-sugar, a dideoxy-sugar, a glucose epimer, a substituted sugar, a uronic acid, an oligosaccharide and mixtures thereof and where the aglycon is a digitoxin analog, an indolocarbazole, an anthracyline, a macrolide, a peptide or an alkaloid.
A neoglycoside of the formula:
- where R1, R2, R3, and R4 are independently selected from —H, —OH, —N3, —NH2, —CH3, —CH2OH, —CN3, —CH2NH, —CH2SH, —CNH2, —CH2N3, —COOH, —COCH3, —CXH2, —CX2H, and where X is Cl, Br, F, or I and the aglycon is a digitoxin analog, an indolocarbazole, an anthracyline, a macrolide, a peptide or an alkaloid.
A neoglycoside selected from the group consisting of L-riboside (5β), D-riboside (6β), L-fucoside (7β), D-fucoside (8β), 2-deoxy-D-galactoside (9β), 3-deoxy-D-glucoside (10β), 6-deoxy-D-glucoside (11β), 2-deoxy-2-fluoro-D-glucoside (12β), 6-deoxy-6-fluoro-D-glucoside (13β), L-lyxoside (14β), D-lyxoside (15β), L-rhamnoside (16β), L-alloside (17β), D-alloside (18β), L-altroside (19β), D-altroside (20β), L-galactoside (21β), D-galactoside (22β), L-xyloside (23β), D-xyloside (24β), D-guloside (25β), L-mannoside (26β), D-mannoside (27β), L-idoside (28β), D-idoside (29β), L-mycaroside (30β), 6-keto-D-galactoside (31β), L-arabinoside (32β), D-arabinoside (33β), N-acetyl-D-galactosaminoside (34β), melibioside (35β), lactoside (36β), maltoside (37β), D-galacturonoside (38β), L-taloside (39β), D-taloside (40β), 6-deoxy-6-azido-D-mannoside (41β), L-glucoside (42β), D-glucoside (4β), O-D-glucoside (43β), R-C(3)aglycon (3β), S-C(3) aglycon (3α), L-riboside (5α), D-riboside (6α), L-fucoside (7α), D-fucoside (8α), 2-deoxy-D-galactoside (9α), 3-deoxy-D-glucoside (10α), 6-deoxy-D-glucoside (11α), 2-deoxy-2-fluoro-D-glucoside (12α), 6-deoxy-6-fluoro-D-glucoside (13α), L-lyxoside (14α), D-lyxoside (15α), L-rhamnoside (16α), L-alloside (17α), D-alloside (18α), L-altroside (19α), D-altroside (20α), L-galactoside (21α), D-galactoside (22α), L-xyloside (23α), D-xyloside (24α), D-guloside (25α), L-mannoside (26α), D-mannoside (27α), L-idoside (28α), D-idoside (29α), L-mycaroside (30α), 6-keto-D-galactoside (31α), L-arabinoside (32α), D-arabinoside (33α), N-acetyl-D-galactosaminoside (34α), melibioside (35α), lactoside (36α), maltoside (37α), D-galacturonoside (38α), L-taloside (39α), D-taloside (40α), 6-deoxy-6-azido-D-mannoside (41α), L-glucoside (42α) and D-glucoside (4α).
A library of neoglycosides comprising a plurality of neoglycosides produced by the reaction of an aglycon having a secondary alkoxylamine and a reducing sugar selected from the group consisting of a L-sugar, a D-sugar, a deoxy-sugar, a dideoxy-sugar, a glucose epimer, a substituted sugar, a uronic acid, and an oligosaccharide.
A method of making a neoglycoside library comprising the steps of:
- providing a plurality of reducing sugars selected from the group consisting of a L-sugar, a D-sugar, a deoxy-sugar, a dideoxy-sugar, a glucose epimer, a substituted sugar, a uronic acid, an oligosaccharide and mixtures thereof;
- and
- contacting the reducing sugars with at least one aglycon having a secondary alkoxylamine to form a plurality of neoglycosides.
Dependencies are inferred from the claim text.