- 9-Sulfonyl-9(H)-Purine Derivatives Inhibit HCV Replication Via their Degradation Species
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Cell-based screening of a privileged small molecule library led to the discovery of 9-sulfonyl-9(H)-purine as new scaffold for hepatitis C virus (HCV) inhibitors. Structure–activity relationship study with respect to the 2-, 6- and 9-positions in the purine core resulted in the identification of several active compounds with moderate potency against the HCV genotype 1b. Subsequent stability studies demonstrated that HCV inhibitors of this type were unstable in Dulbecco’s modified eagle medium (DMEM) and plasma, as well as glutathione-containing water, and their instability was closely related to their HCV inhibitory activity. A preliminary study of the mechanism of action showed that the sulfonamide bond at the 9-position of purine would be the primary degradation site and the resulting sulfonylation degradation species would mediate the anti-HCV activity of 9-sulfonyl-9(H)-purines. Results of this study demonstrated that 9-sulfonyl-9(H)-purine is an unstable scaffold for HCV inhibitors and further detailed analysis of the degradation species is needed to determine the main active components and direct target for this type of molecules.
- Hu, Rong,Wang, Wan-Li,Xiao, Kun-Jie,Wang, Ning-Yu
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- Room-Temperature Amination of Chloroheteroarenes in Water by a Recyclable Copper(II)-Phosphaadamantanium Sulfonate System
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Buchwald-Hartwig amination of chloroheteroarenes has been a challenging synthetic process, with very few protocols promoting this important transformation at ambient temperature. The current report discusses about an efficient copper-based catalytic system (Cu/PTABS) for the amination of chloroheteroarenes at ambient temperature in water as the sole reaction solvent, a combination that is first to be reported. A wide variety of chloroheteroarenes could be coupled efficiently with primary and secondary amines as well as selected amino acid esters under mild reaction conditions. Catalytic efficiency of the developed protocol also promotes late-stage functionalization of active pharmaceutical ingredients (APIs) such as antibiotics (floxacins) and anticancer drugs. The catalytic system also performs efficiently at a very low concentration of 0.0001 mol % (TON = 980,000) and can be recycled 12 times without any appreciable loss in activity. Theoretical calculations reveal that the π-acceptor ability of the ligand PTABS is the main reason for the appreciably high reactivity of the catalytic system. Preliminary characterization of the catalytic species in the reaction was carried out using UV-VIS and ESR spectroscopy, providing evidence for the Cu(II) oxidation state.
- Dandela, Rambabu,Desai, Aman A.,Kapdi, Anant R.,Kori, Santosh,Maity, Dilip K.,Parmar, Udaysinh,Somvanshi, Dipesh
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p. 8900 - 8925
(2021/07/20)
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- The optimized microwave-assisted decomposition of formamides and its synthetic utility in the amination reactions of purines
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The microwave-assisted decomposition of DMF was thoroughly studied and the reaction conditions (temperature, solvent effect, and effect of additives, such as acids, bases, and salts) were optimized for its use in amination reactions. The applicability of this expedient methodology in purine chemistry and with various formamides is demonstrated.
- ?echová, Lucie,Jansa, Petr,?ála, Michal,Dra?ínsky, Martin,Holy, Antonín,Janeba, Zlatko
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experimental part
p. 866 - 871
(2011/03/19)
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- A new approach to the synthesis of N,N-dialkyladenine derivatives
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N,N-Dialkyladenine derivatives were prepared by two different reaction sequences starting from 5-amino-4-cyanoformimidoylimidazoles. When these imidazoles were treated with dimethylformamide diethyl acetal, a 5-aminomethyleneamino-4-cyanoformimidoylimidazole was isolated and evolved to the N,N-dialkyladenine in the presence of a secondary alkylamine. The same purine structure was isolated when the 5-amino-4-cyanoformimidoylimidazole was first treated with a secondary amine to give a stable 4-amidino-5- aminoimidazole. The desired product was generated when the 4-amidino-5- aminoimidazole was combined with dimethylformamide diethyl acetal, at room temperature. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Alves, M. Jose,Carvalho, M. Alice,Carvalho, Silvia,Dias, Alice M.,Fernandes, Francisco H.,Proenca, M. Fernanda
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p. 4881 - 4887
(2008/03/14)
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- Convenient dimethylamino amination in heterocycles and aromatics with dimethylformamide
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A convenient dimethylamino amination of various heterocyclic and aromatic compounds having activated chloro group has been carried out in good yields using dimethyl formamide (DMF).
- Agarwal, Anu,Chauhan, Prem M. S.
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p. 2925 - 2930
(2007/10/03)
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- Synthesis and cytostatic activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N6-substituted adenines, 2,6-diaminopurines and related compounds
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N6-Substituted adenine and 2,6-diaminopurine derivatives of 9-[2-(phosphonomethoxy)ethyl] (PME), 9-[(R)-2-(phosphonomethoxy)propyl] [(R)-PMP] and enantiomeric (S)-PMP series were synthesized by reactions of primary or secondary amines with 6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (26-28) or 2-amino-6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines (29-31) followed by treatment of the diester intermediates 32 with bromo(trimethyl)silane and hydrolysis. Diesters 32 were also obtained by reaction of N6-substituted purines with synthons 23-25 bearing diisopropoxyphosphoryl group. Alkylation of 2-amino-6-chloropurine (9) with diethyl [2-(2-chloroethoxy)ethyl]phosphonate (148) gave the diester 149 which was analogously converted to N6-substituted 2,6-diamino-9-[2-(2-phosphonoethoxy)ethyl]purines 151-153. Alkylation of N6-substituted 2,6-diaminopurines with (R)-[(trityloxy)methyl]oxirane (155) followed by reaction of thus-obtained intermediates 156 with dimethylformamide dimethylacetal and condensation with diisopropyl [(tosyloxy)methyl]phosphonate (158) followed by deprotection of the intermediates 159 gave N6-substituted 2,6-diamino-9-[(S)-3-hydroxy-2-(phosphononiethoxy)propyl]purines 160-163. The highest cytostatic activity in vitro was exhibited by the following N6-derivatives of 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP): 2,2,2-trifluoroethyl (53), allyl (54), [(2-dimethylamino)ethyl] (68), cyclopropyl (75) and dimethyl (91). In CCRF-CEM cells, the cyclopropyl derivative 75 is deaminated to the guanine derivative PMEG (3) which is then converted to its diphosphate.
- Holy, Antonin,Votruba, Ivan,Tloustova, Eva,Masojidkova, Milena
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p. 1545 - 1592
(2007/10/03)
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- 2'-Deoxypuromycin: Synthesis and antiviral evaluation
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A new synthesis of 2'-deoxypuromycin (18) as well as its α-anomer 17 is described. Reaction of 1,5-di-O-acetyl-2,3-dideoxy-3-phthalimido-β-D-erythro-pentofuranose (3) with silylated 6-dimethylaminopurine using trimethylsilyl trifluoromethanesulfonate as catalyst afforded the α and β nucleosides 7 and 12 in 15 and 25% yield, respectively. After deblocking of both amino and hydroxy groups with methylamine in ethanol, the nucleosides were condensed with Fmoc-4-O-methyl-L-tyrosine and subsequently deprotected to give the target compounds 17 and 18. Compound 3 is converted into its glycosyl bromide 4 in quantitative yield on treatment with trimethylsilyl bromide, and reacted with the sodium salt of 6-dimethylaminopurine to give the corresponding protected N-7 and N-9 α glycosyl nucleosides 7 and 8 in 34 and 39% yield, respectively. The 2'-deoxypuromycin is inactive against HIV-1 in MT-4 cells.
- Motawia,Meldal,Sofan,Stein,Pedersen,Nielsen
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p. 265 - 270
(2007/10/02)
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- ACIDIC HYDROLYSIS OF 6-SUBSTITUTED 9-(2-DEOXY-β-D-ERYTHRO-PENTOFURANOSYL)PURINES AND THEIR 9-(1-ALKOXYETHYL) COUNTERPARTS: KINETICS AND MECHANISM.
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The rate constants for the hydrolysis of several 6-substituted 9-(2-deoxy-β-D-erythro-pentofuranosyl)purines and 9-(1-alkoxyethyl)purines have been measured at different concentrations of oxonium ion.The effects that varying the polar nature of the alkoxy group exerts on the hydrolysis of unsubstituted 9-(1-alkoxyethyl)purines are interpreted to indicate that the reaction proceeds by a rate-limiting departure of the protonated base moiety with a concomitant formation of an alkoxyethyl oxocarbenium ion.The same mechanism is applied to the hydrolysis of 9-(2-deoxy-β-D-erythro-pentofuranosyl)purines by comparing the influences that 6-substituents have on the reactivity of these compounds and their 9-(1-alkoxyethyl) counterparts.No sign of anomerisation was detected, when the hydrolysis of 2'-deoxyadenosine was followed by 1H NMR spectroscopy.
- Oivanen, Mikko,Loennberg, Harri,Zhou, Xiao-xiong,Chattopadhyaya, Jyoti
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p. 1133 - 1140
(2007/10/02)
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- Preparation of 7-Substituted Pyrrolopyrimidines and 9-Substituted Purines as Potential Antiparasitic Agents
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A series of six 7-substituted pyrrolopyrimidines and two 9-substituted purines were prepared and evaluated for potential antiparasitic activity.All were inactive against P. berghei in mice.Six of the target compounds were also evaluated for antitrypanosomal activity against T. rhodensiense in mice.All six compounds were also inactive in this screen.
- LaMontagne, Maurice P.,Smith, David C.,Wu, Geng-Shuen
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p. 295 - 299
(2007/10/02)
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- SYNTHESES OF N,N,3- AND N,N,9-TRIALKYLADENINES BY ALKYLATION OF N,N-DIYLKYLADENINES
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Alkylation of N,B,N-dimethyl- (Ia) and N,N-diethyladenine (Ib) with methyl iodide, ethyl iodide, and benzyl bromide in N,N-dimethylacetamide in the presence of potassium carbonate gave the corresponding N,N,9-trialkyladenines (II) in 54-74percent yields, as well as minor amounts of N,N,3-trialkyladenines (III).The alkylation of I without base gave the latter compounds (III) in 76-90percent yields.Keywords - N,N,3-tryalkyladenines: N,N,9-trialkyladenines; regioselective N-alykaltion; N,N-dialkyladenines; isomer ratio.
- Itaya, Taisuke,Matsumoto, Hiroo,Ogawa, Kazuo
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p. 1920 - 1924
(2007/10/02)
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