Patent RU-2755572-C1 (RU)
Title: Method for producing amino acid analogues of the antitumour antibiotic rebeccamycin
Inventor: Goryunova Olga Vasilevna
IPC: A61P35/00
Filed: 2020-09-28
Granted: 2021-09-17
Abstract: FIELD: medicine. 
     SUBSTANCE: invention relates to a method for producing amino acid analogues of the antitumour antibiotic rebeccamycin – derivatives of N13-methylindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione by the formulas [II] and [III], containing a methyl group by the N13-atom of heterocyclic nitrogen, carbohydrate residues of five- or six-membered sugars by the N12-atom of heterocyclic nitrogen, and, independently, residues of S- or R-amino acids by the N6-atom of heterocyclic nitrogen. In the formulas [II] and [III], respectively, G equals  , R=Ac for compounds by the formula [II] and R=H for compounds by the formula [III]; n=3, 4; Q is the side chain of an amino acid selected from -H, -CH 3  (2S and 2R), -CH(CH 3 ) 2  (2S or 2R), -CH 2 -OH (2S or 2R), -CH(OH)-CH 3 (2S or 2R), -CH 2 -S 6 H  5  (2S or 2R), -CH  2 -p-C  6 H 4 OH (2S), -(CH 2 ) 2  -S-CH 3  (2S or 2R), -(CH 2 ) 2 -SOCH 3  (2S or 2R) -(CH 2 ) 2 -COOH (2S), -(CH 2 ) 3 -C(=NH)-NH(-NO 2 ) (2S), -(CH 2 ) 4 -NH-CO-O-CH 2 -C 6 H 5 (2S), -CH 2 -Ind (2S or 2R, Ind is the side chain of tryptophan). The method consists in the fact that the corresponding per-O-acetylated N12-β-D-ribopyranoside of indolo[2,3-a]furano[3,4-c]carbazole-5,7-dione, or per-O-acetylated N12-β-D-glucopyranoside of indolo[2,3-a]furano[3,4-c]carbazole-5,7-dione, or per-O-acetylated N12-β-D-galactopyranoside of indolo[2,3-a]furano[3,4-c]carbazole-5,7-dione by the formula [I] is boiled in dry pyridine with an amino acid in the presence of 3 moles of pyridine hydrochloride for 7 to 12 hours, controlling the course of the reaction according to the TLC data on silufol; for the directed course of the reaction in the proposed conditions, protection is only required for nitrogen-containing fragments of the side chain Q of arginine (NO 2 /Arg) and lysine (Cbz/Lys), at the end of the reaction, pyridine is evaporated, the residue is crystallised with water, then the formed N6-amino acid derivatives by the formula [II] are isolated using the methods for extraction and liquid chromatography on silica gel: per-O-acetylated N12-β-D-ribopyranosides, or N12-β-D-glucopyranosides, or N12-β-D-galactopyranosides of indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione. The carbohydrate residue is deacetylated by the impact of anhydrous potassium carbonate in methanol on acetylglycoside by the formula [II], the end of the reaction is registered by the TLC data on silufol, then water is added until the residue is dissolved, a cation exchanger (H + ) is introduced into the solution until a pH of 5, the reaction mixture is washed from the resin with water and evaporated to dryness; liquid chromatography on silica gel is used to isolate N6-amino acid derivatives by the formula [III]: N12-β-D-ribopyranosides, or N12-β-D-glucopyranosides, or N12-β-D-galactopyranosides of indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione. 
     EFFECT: production of amino acid analogues of the antitumour antibiotic rebeccamycin. 
     
       
       
     
     1 cl, 1 tbl