Enteroviruses rank among the most common human pathogens; millions of people suffer from diseases caused by them every year. However, no specific treatment of infections caused by this genus from the Picornaviridae family has been introduced to clinical practice so far. Therefore, a search for potential therapeutics aiming at these viruses is urgently needed. Due to advances in biochemistry and molecular biology, we are able to aim at specific viral proteins as well as possible host factors essential for virus replication in cells. Recently, a number of compounds inhibiting replication of various enteroviruses have been reported, based on both rational targetbased drug design and phenotypic screening. This article is a review of common structure patterns of the compounds that have been recently found to inhibit the replication of enteroviruses.
- MeSH
- antivirové látky farmakokinetika farmakologie chemie klasifikace MeSH
- Enterovirus fyziologie genetika růst a vývoj účinky léků ultrastruktura MeSH
- farmakologie klinická metody trendy MeSH
- inhibitory proteas chemie MeSH
- lidé MeSH
- Picornaviridae * fyziologie genetika růst a vývoj účinky léků ultrastruktura MeSH
- pikornavirové infekce * farmakoterapie genetika MeSH
- replikace viru účinky léků MeSH
- virové plášťové proteiny * antagonisté a inhibitory účinky léků MeSH
- Check Tag
- lidé MeSH
(1R*,4S*,6S*)-6-(6-Chloro-9H-purin-9-yl)bicyclo[2.2.2]octane-2,2-dimethanol (22) and (1R*,4R*,5S*)-5-(6-chloro-9H-purin-9-yl)bicyclo[2.2.2]octane-2,2-dimethanol (17) were prepared from (1R*,4R*)-bicyclo[2.2.2]oct-5-ene-2,2-dimethanediyl dibenzoate (7) using two approaches. The first procedure consists in hydroboration of 7, separation of obtained 6-exo-hydroxy derivative 8 and 5-exo-hydroxy derivative 9, conversion of 8 and 9 to endo-hydroxy derivatives 12 and 13, respectively, and the Mitsunobu reaction with 6-chloropurine. Only 5-(6-chloropurinyl) analogue 16 was obtained in an acceptable yield. The target analog 17 was prepared by reductive debenzoylation of 16. The further reactions were hydroboration of 7, treatment with hydroxylamine-O-sulfonic acid and debenzoylation. Chloropurine analogues 17 and 22 were built on the obtained 6-exo-amino- and 5-exo-aminobicyclo[2.2.2]octane-2,2-dimethanols 18 and 19, respectively. Compounds 17 and 22 were converted to adenine (23, 24) and 6-(cyclopropylamino)purine analogues (25, 26).
Hydroboration of [(1R*,2R*,4R*)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]methyl benzoate (5), which was prepared by Diels–Alder reaction of furan with acrolein and subsequent reduction and benzoylation of the Diels–Alder product, afforded [(1R*,2S*,4S*,6S*)-6-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (6) and [(1R*,2R*,4R*,5S*)-5-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (7). The key intermediates, [(1R*,2S*,4S*,6R*)-6-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (10) and [(1R*,2R*,4R*,5R*)-5-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (11), were prepared from 6 and 7, respectively, by oxidation with pyridinium dichromate and subsequent reduction of the thus obtained ketones. The Mitsunobu reaction of 10 and 11 with 6-chloropurine and subsequent reductive deprotection with diisobutylaluminium hydride afforded 6-chloropurine derivatives, which were converted to other purine analogues. Thymine analogues were prepared by Mitsunobu reaction of 10 and 11 with 3-benzoyl-5-methylpyrimidine-2,4(1H,3H)-dione and subsequent methanolysis. The target compounds were tested for the activity against Coxsackie virus.
(1R*,2R*,3R*,4S*)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dimethanol (10) and (1R*,2R*,3R*,4S*)-bicyclo[2.2.2]oct-5-ene-2,3-dimethanol (14), which were prepared by the Diels–Alder reaction and subsequent reduction with lithium aluminium hydride, were treated with benzyl azidoformate to give benzyl N-[(1R*,2R*,3S*,6S*,7S*,9S*)-9-(hydroxymethyl)-4,8-dioxatricyclo[4.2.1.03,7]nonan-2-yl]carbamate (11) and benzyl N-[(1R*,2R*,3R*,6R*,7S*,10S*)-10-(hydroxymethyl)-4-oxatricyclo[4.3.1.03,7]decan-2-yl]carbamate (15). Hydrogenolysis of carbamates 11 or 15 afforded (1R*,2R*,3S*,6S*,7S*,9S*)-2-amino-4,8-dioxatricyclo[4.2.1.03,7]nonane-9-methanol (12) or (1R*,2R*,3R*,6R*,7S*,10S*)-2-amino-4-oxatricyclo[4.3.1.03,7]decane-10-methanol (16). The amines 12 and 16 were transformed to thymine and purine nucleoside analogues. The target compounds were tested for the activity against Coxsackie virus.
Starting ethyl (1R*,2R*,3R*,4S*)-3-bromobicyclo[2.2.1]hept-5-ene-2-carboxylate (9) was reduced with LiAlH4 and benzoylated giving [(1R*,2R*,3R*,4S*)-3-bromobicyclo[2.2.1]hept-5-en-2-yl]methyl benzoate (11). Treatment of 11 with NaN3 and CrO3 in acetic acid afforded [(1R*,2S*,3R*,4R*,5S*,6R*)-6-azido-3-bromo-5-hydroxybicyclo[2.2.1]hept-2-yl]methyl benzoate (12a) and [(1R*,2S*,3S*,4R*,5S*,6R*)-5-azido-3-bromo-6-hydroxybicyclo[2.2.1]heptan-2-yl]-methyl benzoate (12b). These key intermediates were separated and converted in five reaction steps to (1R*,2R*,3S*,4S*)-3-[(5-amino-6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)- bicyclo[2.2.1]hept-5-en-2-ol (17a) and (1R*,2R*,3S*,4S*)-3-[(5-amino-6-chloropyrimidin-4-yl)- amino]-6-(hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-ol (17b). Ring closure with triethyl orthoformate led to (1R*,2R*,3S*,4S*)-5-(chloromethyl)-3-(6-chloro-9H-purin-9-yl)bicyclo[2.2.1]hept-5-en-2-ol (18a) and (1R*,2R*,3S*,4S*)-6-(chloromethyl)-3-(6-chloro-9H-purin-9-yl)- bicyclo[2.2.1]hept-5-en-2-ol (18b) using hydrochloric acid as a catalyst or (1R*,2R*,3S*,4S*)-3-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-ol (19a) and (1R*,2R*,3S*,4S*)- 3-(6-chloro-9H-purin-9-yl)-6-(hydroxymethyl)bicyclo[2.2.1]hept-5-en-2-ol (19b) using trifluoro- acetic acid as a catalyst. From 19a and 19b, 6-amino- and 6-(cyclopropylamino)purine derivatives 20 and 21 were prepared.
Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibit significant inhibitory activity against this enzyme. The most potent compounds bear a five- or six-membered cyclic substituent containing a pi-electron system at C5 and a chlorine atom attached at C6. 6-Chloro-5-cyclopent-1-en-1-yluracil 7a is the most efficient derivative in this study, with Ki = 0.20 +/- 0.03 microM (Ki/dThdKm = 0.0017) for thymidine phosphorylase expressed in V79 cells and Ki = 0.29 +/- 0.04 microM (Ki/dThdKm = 0.0024) for the enzyme purified from placenta.
(1R*,2R*,3R*,6R*,7S*)-2-Amino-4-oxatricyclo[4.2.1.03,7]nonane-9-methanol (9) was prepared from (1R*,2R*,3R*,4S*)-bicyclo[2.2.1]hept-5-ene-2,3-dimethanol by treatment with benzyl azidoformate followed by hydrogenolysis. The amine 9 was transformed to thymine and purine nucleoside analogues. The prepared analogues were converted to corresponding Pro-Tides by treatment with methyl N-[chloro(phenoxy)phosphoryl]-L-alaninate in the presence of 1-methylimidazole or tert-butylmagnesium chloride.
We report on a series of novel 5,6-disubstituted uracils with significant inhibitory activity against human and Escherichia coli thymidine phosphorylases. Bis-uracil conjugates were identified as the most potent inhibitors of TPs in this study.
- MeSH
- aminy chemie MeSH
- Escherichia coli enzymologie účinky léků MeSH
- financování organizované MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory enzymů farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- racionální návrh léčiv MeSH
- thymidinfosforylasa antagonisté a inhibitory metabolismus MeSH
- uracil analogy a deriváty farmakologie chemická syntéza chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
