The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism

Jain, Harsh V.; Rasheed, Roshni; Kalman, Thomas I.

doi:10.1016/j.bmcl.2010.01.076

Cited by 5 publications

(9 citation statements)

References 18 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%

“…The maximum plasma concentration (Cmax) of 5 representative compounds (18, 20, 21, 25, 27) was shown in Table 4. The Cmax of 3 compounds (21, 25, 27) having the imino group was lower than that of other two compounds (18,20). It was thought that the low Cmax of these 3 compounds (21, 25, 27) depended on the low hydrophobicity and high electronic negativity of the imino group.…”

Section: Lead Optimization By Docking Study and Qsar Analysismentioning

confidence: 96%

“…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: 96%

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 3 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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Tumors of the Gallbladder

Qian

2017

Surgical Pathology of Hepatobiliary Tumors

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Design of Novel Inhibitors of Human Thymidine Phosphorylase: Synthesis, Enzyme Inhibition, in Vitro Toxicity, and Impact on Human Glioblastoma Cancer

Sperotto¹,

Roth²,

Rodrigues-Junior³

et al. 2019

J. Med. Chem.

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Overexpressed human thymidine phosphorylase (hTP) has been associated with cancer aggressiveness and poor prognosis by triggering proangiogenic and antiapoptotic signaling. Designed as transition-state analogues by mimicking the oxacarbenium ion, novel pyrimidine-2,4-diones were synthesized and evaluated as inhibitors of hTP activity. The most potent compound (8g) inhibited hTP in the submicromolar range with a noncompetitive inhibition mode with both thymidine and inorganic phosphate substrates. Furthermore, compound 8g was devoid of apparent toxicity to a panel of mammalian cells, showed no genotoxicity signals, and had low probability of drug–drug interactions and moderate in vitro metabolic rates. Finally, treatment with 8g (50 mg/(kg day)) for 2 weeks (5 days/week) significantly reduced tumor growth using an in vivo glioblastoma model. To the best of our knowledge, this active compound is the most potent in vitro hTP inhibitor with a kinetic profile that cannot be reversed by the accumulation of any enzyme substrates.

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The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism

Cited by 5 publications

References 18 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

Tumors of the Gallbladder

Design of Novel Inhibitors of Human Thymidine Phosphorylase: Synthesis, Enzyme Inhibition, in Vitro Toxicity, and Impact on Human Glioblastoma Cancer

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