Synthesis of modified pyrimidine bases and positive impact of chemically reactive substituents on their in vitro antiproliferative activity (original) (raw)
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Journal of Chemical Research, 2007
A series of new uracil non-nucleosides analogues of S-DABO's was synthesised by reaction of 5-alkyl-6-(p-chlorobenzyl)-2-thiouracils with chloroethyl dialkylamine hydrochloride, N-(2-chloroethyl)-pyrrolidine hydrochloride, N-(2-chloroethyl)-piperidine hydrochloride or appropriate haloethers. Novel emivirine analogues were synthesised by silylation of 5-alkyl-6-(p-chlorobenzyl)uracils and treatment with bromomethyl methyl ether, chloromethyl ethyl ether or benzyl chloromethyl ether. Compounds 6-(p-chlorobenzyl)-5-ethyl-1-ethyloxymethyluracil (9d) and 1-benzyloxymethyl-6-(4-chlorobenzyl)-5-ethyluracil (9f) showed activity against wild-type HIV-1 strain III B in MT-4 cells.
ChemInform, 2010
Nove l pyrid of2,3-dJprimidines 4 have been synthesised regioseleelively by the reaelion or 6-[(dimelhylamino)melh yleneJamino-1 ,3-dimelhyl uracil 1 wilh various a ,~un s alural e d carbonyl compounds in high yields. The importance of uracil and its annulated substrates is well recognised by synthetic l as well as biological chemists 2. With the development of clinically useful anticancer and antiviral drugs (AZT, DDI, DDC, BYDU) there has recently been remarkable interest in the synthetic manipulation of uracils. However, until the emergence of HEPT 3 as a potent and selective inhibitor of HIY-l, no attention was given to the synthetic manipulation at the 6-position of uracils. Also the synthetic exploitation of the nucleophilic double bond of uracil is an undeveloped field in view of a great variety of potential products 4 • 4-Deazatoxaflavin (l ,6-dimethyl-1 ,S,6,7-tetrahydropyrimido[4,S-c]pyridazine-S,7-dione), a member of thepyrimido[4,Sc]pyridazines, inhibits the growth of Pseudomonas 568 and also binds to herrin g sperm DNA 5. Broom et.al 6. synthesised pyrido[2,3-d]pyrimidine from the reacti on of DMAD and 6-aminouracil in protic solvent, but obtained uncycli zed co ndensed acetyl enic adduct when the reaction was carri ed out in DM F. Also Wamhoff's group reported substituted pyrido-[2 ,3-d]pyrimidines from 6-substituted uracil via [4+2] cycloaddition with electron-defi cient 0lefins7. The main di sadva nt ages in thi s meth od are the limitati on to elec tron-d eficient olefins and the low yi eld du e to side reac ti ons. Hi ro ta et .al~. sy nhes ised pyrido[2 ,3d /py rimidin es by th e pall adium-medi ated CC CO Llpiing reac ti on of elec tron-defi cient olefins with urac il 1 in reflu xin g aceti c acid , but th ey used a stoichi ometric amount of ex pensive Pd (OAc)2 as a coupling reagent. In co ntinuati on of oLir studi es on urac il analog ues 9 , now we report a new, simple, effici ent and one-pot sy nth esis of no ve l pyri do[2,3-d]pyrimidin es by ex ploiting th e nucl eophilic doubl e bond of 6-[(di meth y lami no)methy lene ]ami no-I ,3-di meth y I uraci I 1. The reaction of uracil 1 with q~-un s aturated com
Indian Journal of Chemistry Section B-organic Chemistry Including Medicinal Chemistry, 2002
Nove l pyrid of2,3-dJprimidines 4 have been synthesised regioseleelively by the reaelion or 6-[(dimelhylamino)melh yleneJamino-1 ,3-dimelhyl uracil 1 wilh various a ,~un s alural e d carbonyl compounds in high yields. The importance of uracil and its annulated substrates is well recognised by synthetic l as well as biological chemists 2. With the development of clinically useful anticancer and antiviral drugs (AZT, DDI, DDC, BYDU) there has recently been remarkable interest in the synthetic manipulation of uracils. However, until the emergence of HEPT 3 as a potent and selective inhibitor of HIY-l, no attention was given to the synthetic manipulation at the 6-position of uracils. Also the synthetic exploitation of the nucleophilic double bond of uracil is an undeveloped field in view of a great variety of potential products 4 • 4-Deazatoxaflavin (l ,6-dimethyl-1 ,S,6,7-tetrahydropyrimido[4,S-c]pyridazine-S,7-dione), a member of thepyrimido[4,Sc]pyridazines, inhibits the growth of Pseudomonas 568 and also binds to herrin g sperm DNA 5. Broom et.al 6. synthesised pyrido[2,3-d]pyrimidine from the reacti on of DMAD and 6-aminouracil in protic solvent, but obtained uncycli zed co ndensed acetyl enic adduct when the reaction was carri ed out in DM F. Also Wamhoff's group reported substituted pyrido-[2 ,3-d]pyrimidines from 6-substituted uracil via [4+2] cycloaddition with electron-defi cient 0lefins7. The main di sadva nt ages in thi s meth od are the limitati on to elec tron-d eficient olefins and the low yi eld du e to side reac ti ons. Hi ro ta et .al~. sy nhes ised pyrido[2 ,3d /py rimidin es by th e pall adium-medi ated CC CO Llpiing reac ti on of elec tron-defi cient olefins with urac il 1 in reflu xin g aceti c acid , but th ey used a stoichi ometric amount of ex pensive Pd (OAc)2 as a coupling reagent. In co ntinuati on of oLir studi es on urac il analog ues 9 , now we report a new, simple, effici ent and one-pot sy nth esis of no ve l pyri do[2,3-d]pyrimidin es by ex ploiting th e nucl eophilic doubl e bond of 6-[(di meth y lami no)methy lene ]ami no-I ,3-di meth y I uraci I 1. The reaction of uracil 1 with q~-un s aturated com
Journal of Medicinal Chemistry, 1976
Reaction of the trimethylsilyl derivative of 2,3-dihydro-6H-l,3-oxazine-2,6-dione (2, "uracil anhydride") with protected 1-0-acetylribofuranoses in the presence of stannic chloride gave the corresponding blocked nucleosides. 3-(2,3,-5-Tri-0-2',2',2'-trichloroethoxycarbonyl-~-~-ribofuranosyl)-2,3-dihydro-6H-l,3-oxazine-2,6-dione (4c) thus prepared from the protected sugar 3c, 1-0-acetyl-2,3,5-tri-0-(2,2,2-trichloroethoxycarbonyl)ribofuranose, gave, on removal of the protecting groups with zinc dust, 3-(~-~ribofuranosyl)-2,3-dihydro-6H-l,3-oxazine-2,6-dione (1). The structure of 1 was confirmed by uv, ir, NMR, and CD spectral data and was shown to be an N nucleoside. Uracil anhydride, 2, and, to a lesser extent, its ribonucleoside 1 exert a moderate growth inhibition of mouse leukemia L5178Y, HeLa, and Novikoff hepatoma cells in culture. Both compounds produce weak inhibition of vaccinia viral replication in HeLa cells.
Molecules
Pyrimidine nucleoside analogues are widely used to treat infections caused by the human immunodeficiency virus (HIV) and DNA viruses from the herpes family. It has been shown that 5-substituted uracil derivatives can inhibit HIV-1, herpes family viruses, mycobacteria and other pathogens through various mechanisms. Among the 5-substituted pyrimidine nucleosides, there are not only the classical nucleoside inhibitors of the herpes family viruses, 2′-deoxy-5-iodocytidine and 5-bromovinyl-2′-deoxyuridine, but also derivatives of 1-(benzyl)-5-(phenylamino)uracil, which proved to be non-nucleoside inhibitors of HIV-1 and EBV. It made this modification of nucleoside analogues very promising in connection with the emergence of new viruses and the crisis of drug resistance when the task of creating effective antiviral agents of new types that act on other targets or exhibit activity by other mechanisms is very urgent. In this paper, we present the design, synthesis and primary screening of t...
2016
Molecular docking method was applied to research steric complementarity of 27 uracil derivatives modified into positions N, N, C, C by cyclic and acyclic substituents with the active site of thymidylate synthetase of mice Mus musculus. AutoDock 4.2 scoring function evaluated the thermodynamic characteristics of all compounds’ binding with the active site of the given enzyme. 17 uracil derivatives characterized by predominantly unsubstituted position N3 revealed the capacity of being effective inhibitors of thymidylate synthase and promising as hit compounds for further pre-clinical research and development of new drugs with marked antitumor effect for chemotherapy.
European Journal of Medicinal Chemistry, 1999
5-(acylethynyl)uracils 4 were synthesized from 5-iodo-2,4-dimethoxypyrimidine 1 through a palladium-catalyzed reaction with acetylenic carbinols 5, subsequent oxidation with manganese dioxide in dichloromethane, demethylation with 6 N hydrochloric acid, followed by treatment with sodium hydroxide in 95% ethanol. The corresponding 5-acylethynyl-2≠-deoxyuridines 9 and 5-acylethynyl-1-(2hydroxyethoxy-methyl)uracils 13 were synthesized following a similar procedure. The 5-acylethynyluracils 4 were cytotoxic against murine L1210 and human T-lymphocyte (Molt 4/C8, CEM) cells. The 2≠-deoxyuridine derivatives 9 were less cytotoxic; however the acyclonucleosides 13 were as active as the free bases 4. The compounds did not have antiviral activities at subtoxic concentrations. © Elsevier, Paris 5-(Acylethynyl)uracils / 5-(Acylethynyl)-2≠-deoxyuridines / 5-(Acylethynyl)-1-(2-hydroxyethoxy)methyluracils
Bioorganic Chemistry, 2018
A series of new 2,4,6-trisubstituted pyrimidines and their N-alkyl bromide derivatives were prepared based upon methoxy substituted azachalcones as the starting materials. All newly synthesized compounds were screened for their anti-proliferative, cytotoxic, antibacterial activities and DNA/protein binding affinity. In vitro cell proliferation inhibitory and cell cytotoxic effects of 2,4,6-trisubstituted pyrimidines (1-9) and their N-alkyl bromide derivatives (2a-c, 3a-c, 5a-c, 6a-c, 8a-c, 9a-c) were obtained with the help of the 3-[4,5dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cell proliferation, LDH cytotoxicity detection, and microdilution assays. The antimicrobial activity for these compounds was also evaluated following the European Pharmacopoeia 8.0 protocol. The interactions of these compounds with DNA or bovine serum albumin were investigated by the spectrophotometric titration method. When the cytotoxic analysis and anticancer properties of the compounds were examined, most of the compounds significantly exhibited an antiproliferative potency on cancer cells (IC 50 ~2-10 µg/mL) and caused a cytotoxic effect as low as control drugs, 5-fluorouracil, and cisplatin (~7-15 %). Because the compound-DNA adducts are hyperchromic or hypochromic, they caused variations in their spectra. This situation shows they can be linked to DNA by the groove binding mode at a binding constant range of 2.0 x 10⁴ and 2.4 x 10⁵ M-1. The antimicrobial screening results revealed that our new compounds for some human Gram(+) and Gram(-) pathogen bacteria showed remarkable activity with MIC values between <7.81-125 µg/mL. Overall, incorporation of alkyl chain to pyrimidines in the generation of N-alkyl bromides has resulted in showing differences in DNA/protein binding affinity, along with anti-proliferative and cytotoxic activity in favor of new compounds.