Synthesis and Biological Evaluation of 2,4,5-Substituted Pyrimidines as a New Class of Tubulin Polymerization Inhibitors

Xie, Fang; Zhao, Hongbing; Li, Dewen; Chen, Hong; Quan, Hui; Shi, Xiaojing; Lou, Liguang; Hu, Youhong

doi:10.1021/jm101388d

Cited by 42 publications

(23 citation statements)

References 32 publications

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“…Hu et al (88) discovered 2-(2-amino-5-(1-ethyl- 1H -indol-5-yl)pyrimidin-4-yl)phenol ( 97 ) from 2-(2-amino-5-(4-(ethyl (methyl)amino)phenyl)pyrimidin-4-yl)phenol ( 96 , IC 50 range from 90 to 550 nM) by forming a 5-indolyl substitution via cyclization of N -methyl to phenyl ring. Compound 97 displays activity as an inhibitor of tubulin polymerization (IC 50 =0.79 μM, 3.39 fold more active than colchicine IC 50 =2.68 μM), and it possesses the ability to arrest cells at the G2/M phase of the cell cycle and antiproliferative activities against several tumor cell lines with IC 50 values ranging from 16 to 62 nM.…”

Section: Reported Cbsi In Preclinical Studiesmentioning

confidence: 99%

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

et al. 2012

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Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

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Section: Reported Cbsi In Preclinical Studiesmentioning

confidence: 99%

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

et al. 2012

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“…[13][14][15] In addition, biaryl moieties have been frequently observed in the development of anti-tubulin agents. [15][16][17] Compound 6, with both benzenesulfonamide and biaryl moieties, was found in our previous study to have remarkable antiproliferative activity. 15 Literature surveys indicate that the N-sulfonyl-aminobiaryl moiety has been comprehensively included in various heterocycles such as carbazole 18 , phenanthridinones, and phenanthridines 19,20 ; but little investigation of its biological potential has been reported., This study therefore, is aimed at synthesis of a series of Nsulfonyl-aminobiaryl derivatives (7-26) and assays of their activity against the growth of cancer cells.…”

Section: Introductionmentioning

confidence: 95%

N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling

et al. 2015

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A series of N-sulfonyl-aminobiaryl derivatives have been examined as novel antitubulin agents. Compound 21 [N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide] exhibits remarkable antiproliferative activity against four cancer cell lines (pancreatic AsPC-1, lung A549, liver Hep3B, and prostate PC-3) with a mean GI50 value of 57.5 nM. Additional assays reveal that 21 inhibits not only tubulin polymerization but also the phosphorylation of STAT3 inhibition with an IC50 value of 0.2 μM. Four additional compounds (8, 10, 19, and 35) are also able to inhibit this phosphorylation. This study describes novel N-sulfonyl-aminobiaryl (biaryl-benzenesulfonamides) as potent anticancer agents targeting both STAT3 and tubulin.

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“…More interestingly, Hu et al . documented that compound 8 , generated by introducing indole moiety into pyrimidine 7 , showed threefold improvement compared to compound 7 in inhibiting tubulin polymerization . Meanwhile, H. Marita et al .…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors

Zhang

Yang

et al. 2015

Chem Biol Drug Des

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A series of novel hybrids of indole-pyrimidine-containing piperazine moiety were designed, synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. The results indicated that most of these compounds possessed significant cytotoxic potency against four cancer cell lines, HT-29, A549, MDA-MB-231 and MCF-7. Particularly, the most promising compound 34 showed more potent and broad-spectrum cytotoxic activities with the IC50 values ranged from 5.01 to 14.36 μm against A549, MDA-MB-231 and MCF-7 cell lines. Meanwhile, 34 also displayed the most potent tubulin polymerization inhibitory activity with IC50 value of 11.2 μm. Furthermore, molecular docking analysis demonstrated 34 interacts and binds efficiently with the tubulin protein at the colchicine-binding site. It was worth noting that the compound did not affect the normal human embryonic kidney cells, HEK-293. These results suggest that this novel class of indole-pyrimidine hybrids may have potential to be developed as new a class of tubulin polymerization inhibitors.

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Synthesis and Biological Evaluation of 2,4,5-Substituted Pyrimidines as a New Class of Tubulin Polymerization Inhibitors

Cited by 42 publications

References 32 publications

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling

Design, Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors

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