Miroslav Bobek

A Practical Synthesis of The Antibiotic Toyocamycin

Abstract The nucleoside antibiotic toyocamycin was synthesized by condensation of the silylated 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, followed by debromination and deblocking.

Synthesis of 5′-Fluoro-5′-deoxy-and 5′-Amino-5′-Deoxytoyocamycin and Sangivamycin and Some Related Derivatives

Abstract A series of 5′-substituted analogs of toyocamycin were prepared by condensation of silylated 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine with protected 5-azido-5-deoxy- or 5-fluoro-5-deoxyribofuranose followed by debromination and deblocking. Alternatively, 5′-azido-5′-deoxytoyocamycin was prepared by azidation of toyocamycin. Conversion of the 5-nitrile function of the toyocamycin derivatives into a carboxamide or a thiocarboxamide gave the corresponding analogs of sangivamycin or thiosangivamycin while reduction of the 5′-azido-5′-deoxy nucleosides provided 5′-amino-5′-deoxy derivatives.

Synthesis of 5′-Substituted Derivatives of the Pyrrolo[2,3-d]-Pyrimidine Nucleoside Sangivamycin and Their Effect on Protein Kinase A and C Activity

Abstract Under cell-free conditions, where the antibiotic sangivamycin is not phosphorylated, it is an effective inhibitor of PKC and to a lesser extent of PKA activity. In intact cells, the antibiotic is phosphorylated, thereby, extending its range of activity to other targets including DNA and RNA. To preserve selective inhibitory activity for the protein kinases, analogs potentially resistant to phosphorylation were prepared by replacing the 5′-hydroxy group with O-nitro, O-sulfamoyl, O-methane-sulfonyl or azido groups. These compounds were more potent inhibitors of PKA and PKC activity than was the parent nucleoside.

2′-Azido-2′-deoxy- and 2′-amino-2′-deoxy-β-d-arabino-furanosyl purine nucleosides

Abstract A general method for the preparation of 2′-azido-2′-deoxy- and 2′-amino-2′-deoxyarabinofuranosyl-adenine and -guanine nucleosides is described. Selective benzoylation of 3-azido-3-deoxy-1,2- O -isopropylidene-α- d -glucofuranose afforded 3-azido-6- O -benzoyl-3-deoxy-1,2- O -isopropylidene-α- d -glucofuranose ( 1 ). Acid hydrolysis of 1 , followed by oxidation with sodium metaperiodate and hydrolysis by sodium hydrogencarbonate gave 2-azido-2-deoxy-5- O -benzoyl- d -arabinofuranose ( 3 ), which was acetylated to give 1,3-di- O -acetyl-2-azido-5- O -benzoyl-2-deoxy- d -arabinofuranose ( 4 ). Compound 4 was converted into the 1-chlorides 5 and 6 , which were condensed with silylated derivatives of 6-chloropurine and 2-acetamido-hypoxanthine. The condensation reaction gave α and β anomers of both 7- and 9-substituted purine nucleosides. The structures of the nucleosides were determined by n.m.r. and u.v. spectroscopy, and by correlation of the c.d. spectra of the newly prepared nucleosides with those published for known purine nucleosides.

Relationship Between the Structure of Sangivamycin-Derived Nucleosides and Their Effect on Leukemic Cell Growth and on Protein Kinase A and C Activity

Abstract The nucleoside antibiotic sangivamycin (4-amino-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide, (1) is an effective inhibitor of protein kinase A (PKA) and protein kinase C (PKC) but, upon its phosphorylation in intact cells, it gains the ability to affect other targets as well. To retain its selectivity for the protein kinases, a series of nonphosphorylatable sangivamycin derivatives was prepared by replacing the 5′-hydroxyl group with other functions including N3, F, SO2NH2, NO2, and NH2, These derivatives were more potent inhibitors of PKA and PKC than were the phosphorylatable compounds, although the latter were more potent inhibitors of leukemic cell growth.

Cyano Sugars: Synthesis by Opening of an Epoxide Ring in Pentofuranosides with Diethylaluminum Cyanide

Abstract Reaction of diethylaluminum cyanide (DEAC) with methyl 2,3-anhydroribo-furanosides was examined as a potentially useful method for the introduction of the cyano group at C-2 and C-3 of furanosyl sugars. Thus, treatment of methyl 2,3-anhydro-5-O-benzyl-β-D-ribofuranoside with DEAC provided methyl 5-O-benzyl-3-cyano-3-deoxy-β-D-xylyofuranoside (2), while similar treatment of methyl 2,3-anhydro-5-O-benzyl-α-D-ribofuranoside gave a mixture of methyl 5-O-benzyl-3-cyano-3-deoxy-α-D-xylofuranoside (5) and methyl 5-O-benzyl-2-cyano-2-deoxy-α-D-arabinofuranoside (6). Epimerization of 2 at C-3 was readily effected in the presence of base to give methyl 5-O-benzyl-3-cyano-3-deoxy-β-D-ribofuranoside (9). In contrast, 5 and 6 were resistant to base-promoted epimerization. Sequential acetylation and acetolysis converted the cyano sugars 2 and 9 into the corresponding tri-O-acetyl derivatives 13, 14 and 15.

Synthesis of N-Aminopyrazinium Analogs of Cytidine and 2′-Deoxycytidine

Abstract N-Aminopyrazine analogues of cytidine and 2′-deoxycytidine were prepared from 1-(β-D-ribofuranosyl)-1,2-dihydro-2-oxopyrazine and 1-(2-deoxy-β-D-ribofuranosyl)-1,2-dihydro-2-oxopyrazine, respectively, by amination with O-mesitylenesulfonylhydroxylamine.