Inhibitors of cellular niacinamide mononucleotide formation and their use in cancer therapy

A pharmaceutical composition comprising a biologically active compound represented by formula (A), or a pharmaceutically acceptable salt thereof,

• 45
• wherein
• Z is CH or N,
• R1, R2, R3, and R4, are selected independently from each other from carbohydrate groups, and from carbohydrate groups containing one or more of the elements selected from the group consisting of N, O, P, F, Cl, Br and I;
• and pharmaceutically acceptable salts thereof.

A method for treatment of cancer in mammals comprising administering an effective amount of a biologically active compound represented by formula (A), or a pharmaceutically acceptable salt thereof,

• 47
• wherein
• Z is CH or N,
• R1, R2, R3 , and R4, are selected independently from each other from carbohydrate groups, and from carbohydrate groups containing one or more of the elements selected from the group consisting of N, O, P, F, Cl, Br and I;
• and pharmaceutically acceptable salts thereof.

A method for immunosuppression in mammals comprising administering an effective amount of a biologically active compound represented by formula (A), or a pharmaceutically acceptable salt thereof,

• 49
• wherein
• Z is CH or N,
• R1, R2, R3, and R4, are selected independently from each other from carbohydrate groups, and from carbohydrate groups containing one or more of the elements selected from the group consisting of N, O, P, F, Cl, Br and I;
• and pharmaceutically acceptable salts thereof.

A method for preparing a pharmaceutical composition effective for treatment of cancer in mammals comprising blending a biologically active compound represented by formula (A), or a pharmaceutically acceptable salt thereof, to provide a pharmaceutical composition, formula (A) having the structure

• 51
• wherein
• Z is CH or N,
• R1, R2, R3, and R4, are selected independently from each other from carbohydrate groups, and from carbohydrate groups containing one or more of the elements selected from the group consisting of N, O, P, F, Cl, Br and I;
• and pharmaceutically acceptable salts thereof.

A method for screening and detecting biologically active compounds effective for inhibiting cellular formation of niacinamide mononucleotide, the method comprising:

• incubating cultured cells selected from the group consisting of HepG2 cells, U-87 MG cells, MCF-7 M1 cells, Caki-1 cells, HL-60 cells, PC3 cells, U-373 MG cells, A549 cells and KG-1a cells in the presence of [14C] niacinamide and a compound to be tested for its activity to inhibit the cellular formation of niacinamide mononucleotide;
• effecting lysis of the cells;
• isolating and separating [14C]-labeled compounds;
• and
• measuring the amount of formed labeled niacinamide mononucleotide, NAD and NADP.

A method for determining the dependency of a cell type on niacinamide as a precursor for NAD synthesis comprising:

• incubating cells to be assayed in the presence of a compound represented by general formula (A) in a medium containing only niacinamide as a NAD synthesis precursor;
• and performing a cytotoxicity assay after the incubation period, wherein formula (A) is
• 53
• wherein
• Z is CH or N,
• R1, R2, R3, and R4, are selected independently from each other from carbohydrate groups, and from carbohydrate groups containing one or more of the elements selected from the group consisting of N, O, P, F, Cl, Br and I;
• and pharmaceutically acceptable salts thereof.