Probing a 3,4′-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway

Diez‐Cecilia, Elena; Carson, R. E.; Kelly, Brendan; Schaeybroeck, Sandra Van; Murray, James T.; Rozas, Isabel

doi:10.1016/j.bmcl.2015.07.082

Cited by 8 publications

(10 citation statements)

References 15 publications

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“…Compound 1 in particular was found to be the best cell growth inhibitor for the human leukemia HL-60 cancer cell line with an IC 50 of 9.72 μM. 15,16 In order to assess the effect of the guanidinium/isouronium substitution as well as the effect of the conformational change, induced by an amide linker, on the growth inhibition properties of compound 1, the cytotoxicity of the newly synthesised compounds 2, 3 and 4 as well as that of the lead compound 1 was evaluated in vitro against the HL-60 (leukemia), MCF-7 (breast) and HeLa (cervical) cancer cell lines using the known type II kinase inhibitor sorafenib as a control (Table 1 and Fig. 2).…”

Section: Biological Results and Physicochemical Propertiesmentioning

confidence: 95%

“…1) as a PKI capable of inhibiting the MAPK/ERK pathway through a type-III allosteric mechanism providing a new lead for further refinement of kinase selectivity and potency. 15,16 Earlier and on-going molecular-modelling studies carried out in our laboratory indicate that this compound forms hydrogen bonds (HBs) and electrostatic interactions with the phosphate chain of ATP through the mono-substituted guanidinium cation, thus positioning the lipophilic (4-Cl-3-CF 3 )-Ph moiety (see compound 1 in Fig. 1) in a hydrophobic pocket of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

“…1) in a hydrophobic pocket of the enzyme. 15,17 Guanidine's high basicity (pK aH in water is 13.6 (ref. 18)) indicates that at physiological pH, it will be protonated forming the guanidinium cation.…”

Section: Introductionmentioning

confidence: 99%

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Effect of isouronium/guanidinium substitution on the efficacy of a series of novel anti-cancer agents

et al. 2018

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Considering our hypothesis that the guanidinium moiety in the protein kinase type III inhibitor interacts with a phosphate of ATP within the hinge region, the nature of the interactions established between a model isouronium and the phosphate groups of ATP was computationally analysed indicating that an isouronium derivative of will interact in a similar manner with ATP. Thus, a number of compounds were prepared to assess the effect of the guanidinium/isouronium substitution on cancer cell growth; additionally, the molecular shortening and conformational change induced by replacing the di-substituted guanidine-linker of by an amide was explored. The effect of these compounds on cell viability was tested in human leukaemia, breast cancer and cervical cancer cell lines and the resulting IC values were compared with those of the lead compound . Replacement of the di-substituted guanidine-linker by an amide results in the loss of cytotoxicity; however, substitution of the mono-substituted guanidinium by an isouronium cation seems to be beneficial for cell growth inhibition. Additionally, the effect of these compounds on the MAPK/ERK pathway was studied by means of Western blotting and the results indicate that the isouronium derivative decreases the levels of phosphorylated, and thus activated, ERK (pERK) both in leukaemia and breast cancer cells, whereas lead compound only shows an effect on pERK levels in breast cancer cells. This confirms that both compounds could interfere with the MAPK/ERK pathway although other targets cannot be ruled out.

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Section: Biological Results and Physicochemical Propertiesmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Effect of isouronium/guanidinium substitution on the efficacy of a series of novel anti-cancer agents

et al. 2018

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“…Since MEK/P38 and PI3-K/Akt is the primary downstream cascades of receptor tyrosine kinases (RTKs), meanwhile, EGFR is the most important RTK in cancer cells [17, 18]. Therefore, we speculated that VOSL may act as an EGFR inhibitor to suppress EGFR activation.…”

Section: Resultsmentioning

confidence: 99%

Volatile oil from Saussurea lappa exerts antitumor efficacy by inhibiting epithelial growth factor receptor tyrosine kinase-mediated signaling pathway in hepatocellular carcinoma

Lin

Zhang

et al. 2016

Oncotarget

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Hepatocellular carcinoma (HCC) treatment remains lack of effective chemotherapeutic drugs, therefore, discovering novel anti-HCC drugs is a very attractive and urgent task. In this study, we reported VOSL (volatile oil from Saussurea lappa root) exhibits potent therapeutic effect on SMMC-7721 xenografts without obvious side effects. In the in vitro experiments, VOSL inhibited HCC cell proliferation by arresting cell cycle at S and G2/M phases, and induced HCC cell apoptosis by activating the Caspase3 pathway. VOSL also decreased the capability of HCC cell migration and invasion through MMP-9 depression. Moreover, mechanistic study indicated that VOSL can act as an epithelial growth factor receptor (EGFR) inhibitor to suppress EGFR activation and then to suppress its downstream MEK/P38 and PI3-K/Akt pathways. These results suggested that VOSL may be a novel anti-HCC drug candidate.

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“…Cancer, one of the most serious illnesses, considered the second leading cause of death worldwide after cardiovascular diseases. According to the World Health Organization (WHO) reports, more than 13 million dying of cancer worldwide are awaiting to happen in 2030 ( 1 2 3 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and cytotoxic evaluation of some novel diarylamide possessing quinoxalinedione based on sorafenib

Khandan¹,

Sadeghian-Rizi²,

Khodarahmi³

et al. 2018

Res Pharma Sci

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A series of novel sorafenib analogues containing a quinoxalinedione ring and amide linker were synthesized. A total of 9 novel compounds in 6 synthetic steps were synthesized. Briefly, the amino group of p-aminophenol was first protected which then followed by O-arylation with 5-chloro-2-nitroaniline to provide compound d. Reduction of the nitro group of compound d and cyclization of the diamine group of compound e with oxalic acid afforded compound f which on deacetylation yeilded compound g. Then compound g was reacted with different acyl halides to afford the target compounds 1h-1p. Chemical structures of synthesized compounds were confirmed by 1H NMR and FT-IR analysis. All compounds were evaluated at 1, 10, 50 and 100 μM concentrations for their cytotoxicity against HeLa and MCF-7 cancer cell lines. Some of the compounds showed good cytotoxic activity, especially compounds 1i and 1k-1n with the IC50 values of 19, 16, 22, 18, and 16 μM against MCF-7 cell line and 20, 18, 25, 20, and 18 μM against HeLa cell line, respectively.

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Probing a 3,4′-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway

Cited by 8 publications

References 15 publications

Effect of isouronium/guanidinium substitution on the efficacy of a series of novel anti-cancer agents

Effect of isouronium/guanidinium substitution on the efficacy of a series of novel anti-cancer agents

Volatile oil from Saussurea lappa exerts antitumor efficacy by inhibiting epithelial growth factor receptor tyrosine kinase-mediated signaling pathway in hepatocellular carcinoma

Synthesis and cytotoxic evaluation of some novel diarylamide possessing quinoxalinedione based on sorafenib

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