10343-71-2Relevant articles and documents
In search of Flavivirus inhibitors part 2: Tritylated, diphenylmethylated and other alkylated nucleoside analogues
Saudi, Milind,Zmurko, Joanna,Kaptein, Suzanne,Rozenski, Jef,Neyts, Johan,Van Aerschot, Arthur
, p. 98 - 109 (2014/03/21)
Several flaviviruses, such as the yellow fever virus and the dengue virus cause severe and potentially lethal infection in man. Following up on our initial hit 3′,5′-bistritylated uridine 1, a series of alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against dengue fever virus and yellow fever virus. Hereto, alkyl and aryl groups were attached at various positions of the sugar ring combined with subtle variation of the heterocyclic base. Among the new series of derivatives, 3′,5′-di-O-trityl-5-fluoro-2′-deoxyuridine (39) was the most efficient in this series and inhibited both yellow fever virus and dengue virus replication with a 50% effective concentration (EC50) of ～1 μg/mL without considerable cytotoxicity. The other fluorinated derivatives proved more toxic. Almost all diphenylmethylated pyrimidine nucleosides with 3′,5′-di-O-benzhydryl-2′-deoxyuridine (50) as the example were endowed with strong cytotoxic effects down to 1 μg/mL.
Synthesis and activity evaluation of 3'-floxuridinyl 4-[3-(3, 5-di-t-butyl-4-methoxyphenyl)-3-oxo-propenyl]benzoate: In vitro and in vivo as a potential dual-acting antitumor prodrug
Du, Lixue,Jin, Juqing,Wu, Wei,Chen, Jiangang,Shan, Ailin,Zhang, Sanqi
experimental part, p. 73 - 81 (2012/08/07)
BOBA (4-[3-(3, 5-di-tert-butyl-4-methoxyphenyl)-3-oxo-propenyl]benzoic acid), a substituted chalcone derivative, exhibits an excellent inducing differentiation on neoplastic cellular differentiation. FUDR (5-fluoro-2'-deoxyuridine, floxuridine) inhibits D
Modified 5'-Trityl Nucleosides as Inhibitors of Plasmodium falciparum dUTPase
Ruda, Gian Filippo,Nguyen, Corinne,Ziemkowski, Przemyslaw,Felczak, Krzysztof,Kasinathan, Ganasan,Musso-Buendia, Alexander,Sund, Christian,Zhou, Xiao Xiong,Kaiser, Marcel,Ruiz-Perez, Luis M.,Brun, Reto,Kulikowski, Tadeusz,Johansson, Nils Gunnar,Gonzalez-Pacanowska, Dolores,Gilbert, Ian H.
scheme or table, p. 309 - 320 (2012/01/12)
2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action. Fewer trips to the dUMP: dUTPase is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this P.falciparum enzyme. Herein we report further structure-activity studies of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base.
3′-Bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of mycobacterium tuberculosis
Shakya, Neeraj,Srivastav, Naveen C.,Desroches, Nancy,Agrawal, Babita,Kunimoto, Dennis Y.,Kumar, Rakesh
experimental part, p. 4130 - 4140 (2010/09/04)
Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2′- or 3′-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3′-bromo-3′-deoxy- arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC 50 = 1 μg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC50 = 1-2 μg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 μg/mL concentration) than extracellular mycobacteria (75% reduction at 10 μg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC50 > 100-200 μg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.
Antiviral activity of various 1-(2′-Deoxy-β- d -lyxofuranosyl), 1-(2′-Fluoro-β- d -xylofuranosyl), 1-(3′-Fluoro-β- d -arabinofuranosyl), and 2′-fluoro-2′,3′-didehydro-2′, 3′-dideoxyribose pyrimidine nucleoside analogues against duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) replication
Srivastav, Naveen C.,Shakya, Neeraj,Mak, Michelle,Agrawal, Babita,Tyrrell, D. Lorne,Kumar, Rakesh
experimental part, p. 7156 - 7166 (2010/12/19)
Despite the existence of successful vaccine and antiviral therapies, infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease and high mortality. We synthesized and evaluated several lyxofuranosyl, 2′-fluoroxylofuranosyl, 3′- fluoroarabinofuranosyl, and 2′-fluoro-2′,3′-didehydro- 2′,3′-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy-β-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-β-d- lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-β-d- xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)thymine (39), 2′,3′-dideoxy-2′,3′-didehydro-2′- fluorothymidine (48), and 2′,3′-dideoxy-2′,3′-didehydro- 2′-fluoro-5-ethyluridine (49) were found to possess significant anti-HBV activity against DHBV in primary duck hepatocytes with EC50 values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 μM, respectively. Compounds 23, 25, 39, 48, and 49 (EC50 = 41.3, 33.7, 19.2, 2.0-4.1, and 39.0 μM, respectively) exhibited significant activity against wild-type human HBV in 2.2.15 cells. Intriguingly, 25, 39, 48, and 49 retained sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC50 of 4.1 μM. In contrast, 50% inhibition could not be achieved by lamivudine at 44 μM concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested.
Phospholipid prodrugs of anti-proliferative drugs
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Page/Page column 16-17, (2010/02/08)
The invention discloses prodrugs comprising anti-proliferative drugs covalently linked, via bridging group, to a phospholipid moiety such that the active species is preferentially released, preferably by enzymatic cleavage, at the required site of action. The invention further discloses pharmaceutical compositions said prodrugs and the uses thereof for the treatment of diseases and disorders related to inflammatory, to degenerative or atrophic conditions, and to uncontrolled cell growth. FIG.1depicts a graph of animal survival during the course of an experiment wherein mice were i.p. transplanted with 11210 mouse leukemia cells and then treated with vehicle only (squares), MTX (triangles) or molar equivalent dose of DP-MTX071 (circles) according to the regiment described example in Example 11.
Synthesis and antitumor activities of 5′-O-aminoacyl-3′-O-benzyl derivatives of 2′-deoxy-5-fluorouridine and related compounds
Uemura, Atsuhiko,Tada, Yukio,Takeda, Setsuo,Uchida, Junji,Yamashita, Jun-Ichi
, p. 150 - 155 (2007/10/03)
Various O-alkyl derivatives of 2′-deoxy-5-fluorouridine (FUdR) were synthesized and their antitumor activities in mice bearing sarcoma 180 (s.c.-p.o.) were evaluated in terms of the ED50 values (mg/kg/d). Most of these compounds were superior to FUdR in antitumor activity. In particular, the antitumor activity of 3′-O-(p-chlorobenzyl)-FUdR (3e) (ED50 = 0.87 mg/kg/d) was as much as 100 times that of FUdR (ED50 = 84 mg/kg/d). Further, various 5′-O-aminoacyl derivatives of 3e were synthesized and evaluated in terms of ED50 value and therapeutic index (T.I.). Both the ED50 value (0.41 mg/kg/d) and the T.I. (4.18) of 3′-O-(p-chlorobenzyl)-5′-O-glycyl-FUdR hydrochloride (6a) were significantly improved, compared with those of 3e and FUdR. FUdR plasma concentration after a single p.o. dosing of 6a was maintained for as long as 24 h.
Synthesis and Biological Evaluation of 5-Fluoro-2'-deoxyuridine Phosphoramidate Analogs
Fries, Kristin M.,Joswig, Carolyn,Borch, Richard F.
, p. 2672 - 2680 (2007/10/03)
A series of alkylating phosphoroamidate analogs of 5-fluoro-2'-deoxyuridine has been prepared and their growth inhibitory activity evaluated against murine L1210 leukemia and B16 melanoma cells in vitro.These compounds were designed to undergo intracellular release of the phosphoramidate anions, which it was hoped would function as irreversible inhibitors of thymidylate synthase.The expectation was that binding of the nucleoside moiety would be followed by alkylation of the enzyme via the phosphoramidate.The chloride, bromide, iodide, and tosylate analogs were highlypotent inhibitors of L1210 cell proliferation, with increased inhibition observed at both higher drug concentrations and longer exposure times.Addition of thymidine completely reversed the inhibition for all compounds, suggesting that these compounds are acting via inhibition of thymidylate synthase.Although the nonalkylating morpholine analog 1f was ca. 50-fold less potent than the methyl(chloroethyl)amino compound, the piperidine analog 1g was only 2-fold less potent, confirming that nitrogen basicity may be as important as the presence of an alkylating group.Addition of thymidine reversed the growth inhibition of the morpholine and piperidine analogs, suggesting that these compounds may also undergo intracellular conversion to 5-fluoro-2'-deoxyuridine 5'-monophosphate.The thymidine and deoxyuridine derivatives 2 and 3 showed minimal growth inhibition in the L1210 assay.The alkylating analogs showed modest cytotoxicity against B16 melanoma cells, and the potency of the analogs was more dependent upon the alkylating moiety than on the 5-substituent.
5-fluorouracil, 2'-deoxy-5-fluorouridine and 1-carbomoyl-5-fluorouracil compounds
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, (2008/06/13)
A 5-fluorouracil derivative represented by the formula (1): STR1 wherein A represents a group represented by STR2 wherein R1 represents a hydrogen atom or OR5 group, R2, R3 and R5 may be the same or different and each represents a hydrogen atom or a group represented by the following formula (2): STR3 wherein R6 represents an acyl group, R7 represents a hydrogen atom, a straight or branched alkyl group, a cycloalkyl group, an aralkyl group, a lower alkenyl group or a phenyl group, and n is an integer of 0 to 6, provided that at least one of R2, R3 and R5 is a group represented by the formula (2), and the case wherein R2 and R5 are both hydrogen atoms is excluded, R4 represents a group represented by the formula (2), and X represents an alkylene group or a cycloalkylene group, and an antitumor agent containing the same as an active ingredient.
5-fluorouracil derivatives
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, (2008/06/13)
An anticancer compound is disclosed which is represented by the formula STR1 wherein one of R1 and R2 is a phenyl-lower alkyl optionally having a substituent, phenyl-lower alkenyl or naphthyl-lower alkyl, the other of R1 and R2 is hydrogen or acyl, and R3 is hydrogen, acyl or tetrahydrofuranyl, or represented by the formula STR2 wherein Rx is an optionally substituted pyridyl, Y is arylene and α is a known 5-fluorouracil derivative residue which can be converted to 5-fluorouracil in vivo and which is linked to the carbonyl by an ester or amide linkage.
