Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

McNally, Virginia; Rajabi, Mehdi; Gbaj, Abdul M; Stratford, Ian J.; Edwards, Philip N.; Douglas, Kenneth T.; Bryce, Richard A.; Jaffar, Mohammed; Freeman, Sally

doi:10.1211/jpp.59.4.0008

Cited by 24 publications

(19 citation statements)

References 40 publications

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“…The GRID analysis showed that C-6 of 5-chlorouracil (3) was desirable as the position of substituent introduction in order to improve inhibitory activity. The 6-substituted 5-chlorouracil derivatives (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) had some inhibitory activity, and compounds 21, 22, 25-27 having an imino group on the C-6 position had potent inhibitory activity. But the Cmax of compounds (21, 25, 27) among them was very low in comparison with that of compounds 18 and 20.…”

Section: Resultsmentioning

confidence: 99%

“…It was estimated that the ammonium ion of site A, B and C made hydrogen bond with T118, S117 and phosphate, individually ( Figure 3). At first compounds (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were designed corresponding to the docking pose of model compound A using the calculated logP (CLOGP) and electron density of the nitrogen atom (Ncharge) as QSAR parameter ( Table 2). The CLOGP value of designed compounds (10-20) was calculated as logP by Bio-Loom for Windows [28].…”

Section: Lead Optimization By Docking Study and Qsar Analysismentioning

confidence: 99%

“…The value of Ncharge was considered an index of basicity of the substituent and it was calculated by the PM3 method [29] in Scigress MO Compact [30]. [10][11][12][13][14][15][16][17][18][19][20]. In QSAR equation n is the number of compounds, r is the correlation coefficient, s is the standard deviation, and the figures in parentheses are 95% confidence intervals.…”

Section: Lead Optimization By Docking Study and Qsar Analysismentioning

confidence: 99%

“…All compounds which were synthesized to develop the potent HTP inhibitor were reported in our previous papers [10,11]. Since then, several other HTP inhibitors have been developed [12][13][14][15][16][17][18][19][20], but TPI is still assumed to be the most potent HTP inhibitor. …”

Section: Introductionmentioning

confidence: 99%

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Molecular modeling study of the thymidine phosphorylase inhibitor by SBDD and classical QSAR analysis

Tada

Kazuno

Sato

et al. 2017

CBIJ

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Trifluorothymidine (TFT) has antitumor activity, but it is easily metabolized to inert trifluorothymine by thymidine phosphorylase (TP). Accordingly, TFT alone cannot show satisfactory clinical antitumor effects. Human TP (HTP) is the main enzyme of pyrimidine nucleoside phosphorylase in human. Therefore, it has been necessary to develop a HTP inhibitor to maintain antitumor activity of TFT. Here we reveal the drug design process of HTP inhibitor based on SBDD and classical QSAR analysis. Thymine was selected as a seed compound and then 5-chlorouracil (3) was selected as a lead compound. The introduction of the imino moiety to C6 position of the lead compound (3) enhanced the inhibitory activity of TP. As a result, 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI) was chosen as the candidate for the clinical trials. And TAS-102 (the combination of TFT and TPI in a 1:0.5 molar ratio) has been approved as Trifluridine/Tipiracil (Lonsurf) for the treatment of metastatic colorectal cancer in Japan, United States and EU.

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Section: Resultsmentioning

confidence: 99%

Section: Lead Optimization By Docking Study and Qsar Analysismentioning

confidence: 99%

Section: Lead Optimization By Docking Study and Qsar Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular modeling study of the thymidine phosphorylase inhibitor by SBDD and classical QSAR analysis

Tada

Kazuno

Sato

et al. 2017

CBIJ

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“…Highly lipophilic molecules will partition into the lipid interior of membranes and retain there. When log P is higher than the upper limit, the drug molecule will have low solubility whereas in lower log P, the drug has difficulty to penetrate the lipid membranes 33 . The pharmacokinetics results (Table 3) showed that all the compounds reported have good balance between compound solubility and its penetration of the lipid bilayers.…”

Section: In Vitro Cox Inhibitory Activitymentioning

confidence: 99%

Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies

Ugwu

Okoro

Ukoha

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Twelve new derivatives of benzothiazole bearing benzenesulphonamide and carboxamide were synthesised and investigated for their in vivo anti-inflammatory, analgesic and ulcerogenic activities. Molecular docking showed an excellent binding interaction of the synthesised compounds with the receptors, with 17c showing the highest binding energy (-12.50 kcal/mol). Compounds 17c and 17i inhibited carrageenan-induced rat paw oedema at 72, 76, and 80% and 64, 73, and 78% at 1 h, 2 h, and 3 h, respectively. In the analgesic activity experiment, compounds 17c, 17 g, and 17i had ED 50 (mM/kg) of 96, 127, and 84 after 0.5 h; 102, 134, and 72 after 1 h and 89, 156, and 69 mM/kg after 2 h, respectively, which were comparable with 156, 72, and 70 mM/kg for celecoxib. The ulcerogenic index of the most active derivatives 17c and 17i were 0.82 and 0.89, respectively, comparable to 0.92 for celecoxib. The physicochemical studies of the new derivatives showed that they will not have oral bioavailability problems. ARTICLE HISTORY

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Novel metal complexes with pyrano[3,2‐c]quinoline‐3‐carboxaldehyde: Synthesis, spectroscopic, molecular modeling, QSAR, antimicrobial, and antitumor studies

Ibrahim

Emara

Taha

et al. 2021

Applied Organom Chemis

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Reaction of 6‐ethyl‐4‐hydroxy‐2,5‐dioxo‐5,6‐dihydro‐2H‐pyrano[3,2‐c]quinoline‐3‐carboxaldehyde (HL) with some metal ions, namely, manganese (II), cobalt (II), nickel (II), zinc (II), cadmium (II), chromium (III), iron (III), cerium (III), oxovanadium (IV), and dioxouranium (VI), yielded a new series of metal complexes; with the general formula, [MHnLAm(H2O)x]Xy·zH2O, n = 0–1, A = NO3− or OAc−, m = 0–2, X = NO3− or SO42−, y = 0–1, and z = 0–3. The metal complexes were characterized by elemental analysis, molar conductance, magnetic moment, thermal analysis, and spectroscopic studies. The HL ligand coordinated with metal ions as monobasic or neutral bidentate via OO donor sites of aldehyde –O and phenolic –OH producing metal complexes with tetrahedral, octahedral, and pentagonal bipyramidal geometries. On the bases of PM3 level, molecular orbital calculations were performed for metal complexes using HyperChem 7.52 program, and the results were correlated with the experimental data. The biological activity of chelating agent and its metal complexes was screened towards Staphylococcus aureus and Bacillus subtilis as Gram‐positive bacteria; Salmonella typhimurium and Escherichia coli as Gram‐negative bacteria, as well as Candida albicans (yeast) and Aspergillus fumigatus (fungus). The antitumor activity of the HL ligand and its metal complexes was tested against Ehrlich Ascites Carcinoma cell line (EAC), which revealed promising IC50 values, comparable with that of cisplatin. Additional QSAR models were developed to predict the biodistribution of a smaller set of metal complexes and the calculated data correlated with antitumor results.

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Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

Cited by 24 publications

References 40 publications

Molecular modeling study of the thymidine phosphorylase inhibitor by SBDD and classical QSAR analysis

Molecular modeling study of the thymidine phosphorylase inhibitor by SBDD and classical QSAR analysis

Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies

Novel metal complexes with pyrano[3,2‐c]quinoline‐3‐carboxaldehyde: Synthesis, spectroscopic, molecular modeling, QSAR, antimicrobial, and antitumor studies

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