Prodrugs and conjugates of thiol- and selenol-containing compounds and methods of use thereof
Disclosed is a prodrug of the formula: where A is a sulfur or a selenium, and R is derived from a mono- di- or oligo- saccharide. Also disclosed is a prodrug of the formula: where A is sulfur or selenium, R′ is derived from a sugar and R′ has the formula (CHOH) n CH 2 OH, where n is 1 to 5, or R′ is an alkyl or aryl group, or R′ is ═O, and the R″ groups may be the same or different and may be hydrogen, alkyl, alkoxy, carboxy. Also disclosed is a conjugate of an antioxidant vitamin and a thiolamine or selenolamine. Also disclosed is a prodrug of the formula; where A is sulfur or selenium, and R′ is derived from a sugar and R′ has the formula (CHOH) n CH 2 OH, where n is 1 to 5, or R′ is also be an alkyl or aryl group, or R′ is ═O, and R ‡ is an alkoxy, or an amine group. Also disclosed is a prodrug of the formula: where R is COOH or H, and R′ is derived from a sugar and R′ has the formula (CHOH) n CH 2 OH,where n is 1 to 5, or R′ is an alkyl or aryl group, or R′ is ═O.
1. A prodrug of the formula:
where A is selenium, and R is a mono- di- or oligo- saccharide.
2. A prodrug of claim 1 wherein R is ribose, galactose, glucose, or mannose.
3. A prodrug of the formula:
where A is selenium, and
R′ is a sugar having the formula (CHOH) n CH 2 OH, where n is 1 to 5, or
R′ is an alkyl or aryl group, or
R′ is ═O, and
R ‡ is an alkoxy, or an amine group.
4. A prodrug of claim 3 wherein R ‡ is —OR 1 where R 1 is ethyl, or methyl.
5. A prodrug of claim 3 wherein R′ is methyl, ethyl, benzyl, carboxyl, or phenyl.
6. A prodrug as in claim 3 wherein R ‡ is —NR † 2 , wherein the R † groups are the same or different and are hydrogen or alkyl.
7. A prodrug as in claim 5 wherein at least one R † is methyl.
8. A method for reducing unwanted side effects of radiotherapy of cancer, in a mammal comprising administering to the mammal the prodrug of claim 1 .
9. A method for reducing unwanted side effects of radiotherapy of cancer, in a mammal comprising administering the mammal a prodrug having the formula
wherein
(1) A is selenium,
R 1 is a sugar having the formula (CHOH) n CH 2 OH, where n is 1 to 5, or R 1 is an alkyl or aryl group, or R 1 is ═O,
R 2 is CH 2 CH 2 CH 2 N(R 4 ) 2 , wherein R 4 may be the same or different and may be hydrogen, alkyl, alkoxy, or carboxy; and
R 3 is hydrogen;
(2) A is selenium,
R 1 is a sugar having the formula (CHOH) n CH 2 OH, where n is 1 to 5, or R 1 is an alkyl or aryl group, or R 1 is ═O,
R 2 is hydrogen, R 3 is COR 5 , wherein R 5 an alkoxy, or an amine group; or
(3) A is selenium,
R 1 is a sugar having the formula (CHOH) n CH 2 OH, where n is 1 to 5, or R 1 is an alkyl or aryl group, or R 1 is ═O,
R 2 is hydrogen, and R 3 is hydrogen or COOH.
10. A prodrug of the formula
where A is sulfur or selenium, and
R 1 is an alkyl or aryl group, or
R 1 is ═O, and
R ‡ is an alkoxy, or an amine group.