Synthesis and biological evaluation of 5‐substituted‐4‐nitroimidazole ribonucleosides

Abstract

The imidazole nucleosides, 4(5)‐bromo‐5(4)‐nitro‐1‐β‐D‐ribofuranosylimidazoles, have been prepared via glycosylation of the trimethylsilylated aglycone, 4(5)‐bromo‐5(4)‐nitroimidazole, with tetra‐O‐acetyl‐β‐D‐ribo‐furanose followed by removal of the acetyl protecting groups. The 5‐bromo‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole nucleoside was acetonated to produce 5‐bromo‐4‐nitro‐1‐(2,3‐O‐isopropylidene‐β‐D‐ribofuranosyl)‐imidazole which was cyclized to provide the corresponding anhydronucleoside 5,5′‐anhydro‐4‐nitro‐5‐oxo‐1‐(2,3‐O‐isopropylidene‐β‐D‐ribofuranosyl)imidazole. Sodium hydrosulfide treatment of 5‐bromo‐4‐nitroimidazole nucleoside provided 5‐mercapto‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole 5‐sodium salt which was alkylated with E‐1,5‐diiodopent‐1‐ene to yield 5‐(E‐1‐iodo‐1‐penten‐5‐yl)thio‐4‐nitro‐1‐β‐D‐ribofuranosylimidazole. The corresponding iodine‐125‐labeled compound was prepared similarly using radiolabeled diiodopentene. The 5‐bromo‐4‐nitroimidazole, 5‐mercapto‐4‐nitroimidazole, and 5‐iodopentenylthio‐4‐nitroimidazole nucleosides were cytotoxic to Molt‐3 cells in vitro at concentrations higher than 10 μg/mL. The radiolabeled 5‐iodopentenylthio‐4‐nitroimidazole nucleoside showed 2‐fold higher uptake in a rapidly growing tumor as compared to uptake in a relatively slower growing tumor in mice.

Efficient Synthesis of DNA Containing the Guanine Oxidation-Nitration Product 5-Guanidino-4-nitroimidazole: Generation by a Postsynthetic Substitution Reaction

“…24,25 Interestingly, 4-halo-5-nitroimidazoles have been reported to be resistant to nucleophilic displacement of the halo substituent. 26,27 In the present study, the 5-bromo-4-nitroimidazole isomer readily underwent reaction at the site of the bromo substituent, whereas the 4-bromo-5-nitroimidazole isomer was resistant to reaction at the bromo position under the same conditions.…”

“…Treatment of 2 with NaH in CH 3 CN, followed by condensation with 3,5-di- O -toluoyl- α -1-chloro-2-deoxy- d -ribofuranose gave exclusively two β -nucleosides, the 5-bromo-4-nitroimidazole isomer 3 in 50% yield and the 4-bromo-5-nitroimidazole isomer in 35% yield. The structures of these isomers were assigned by comparison of the UV spectra with those of literature analogues. , Interestingly, 4-halo-5-nitroimidazoles have been reported to be resistant to nucleophilic displacement of the halo substituent. , In the present study, the 5-bromo-4-nitroimidazole isomer readily underwent reaction at the site of the bromo substituent, whereas the 4-bromo-5-nitroimidazole isomer was resistant to reaction at the bromo position under the same conditions.

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“…Irradiating at the 1′ proton, we observed an NOE enhancement at the 4′ proton, and by irradiating the imidazolic proton NOE enhancements were observed at the 3′ proton and 5′ protons, thus confirming the structure. It is anticipated that 4 will serve as a branching point for generating libraries of 5-substituted-4-nitroimidazole nucleosides and, when incorporated into DNA, 5-substituted-4nitroimidazole-containing ODNs, since previous studies have shown the bromo substituent of 5-bromo-4-nitroimidazoles to be displaced by carbon, 25 sulfur and oxygen, 27 Compound 4 was protected as the 5′-O-dimethoxytrityl ether using DMT-Cl, triethylamine, and a catalytic amount of DMAP in pyridine (Scheme 2). Two rounds of purification of the tritylated product by flash chromatography were necessary and gave the desired compound 6 in 76% yield.…”

Reactions of halonitroimidazoles with nucleophiles (review)

“…Thus, the reaction of 5-halo-4-nitroimidazoles 13 with hydrogen sulfide in aqueous or alcohol solutions of ammonia [23][24][25][26][27][28][29][30], ammonium hydrosulfide [23], sodium sulfide [23], sodium hydrosulfide [31], potassium hydrosulfide [23], and thiourea [23] gave the ammonium, sodium, and potassium salts of 5-mercapto-4-nitroimidazoles 23-25, from which the free 5-mercapto-4-nitroimidazoles 26 were isolated by decomposition with hydrochloric or acetic acid [23][24][25][26][27][28][29][30][31][32]. In certain cases the reactions of halonitroimidazoles 13 with ammonium and alkali metal sulfides and hydrosulfides are accompanied by the formation of side products − di(nitroimidazolyl) sulfides 27 and di(nitroimidazolyl) disulfides 28 [23].…”

Methods of synthesis of halogenonitroimidazoles (review)

“…The radioprotective action of 5-bromo(chloro)-1-(2,3-dihydroxypropyl)-2-methyl-4-nitroimidazoles is comparable with that of the known drugs mesonidazole, 1-(2-hydroxy-3-methoxypropyl)-2-nitroimidazole [20]. Nucleosides based on 5-bromo-4-nitroimidazole possess radioprotective and antitumor activity [22]. Special reviews on the synthesis of halogenonitroimidazoles have not been published.…”