New SIRT2 inhibitors: Histidine-based bleomycin spin-off

Ali, Taha F. S.; Çiftçi, Halil; Radwan, Mohamed O.; Koga, Ryoko; Ohsugi, Takeo; Okiyama, Yoshio; Honma, Teruki; Nakata, Akiko; Ito, Akihiro; Yoshida, Minoru; Fujita, Mikako; Otsuka, Masami

doi:10.1016/j.bmc.2019.03.003

Cited by 20 publications

(10 citation statements)

References 37 publications

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“…The MTT test was performed as previously described in the literature with small modifications (Ali et al, ; Ciftci, Radwan et al, ). Cells were cultured in the presence of various concentrations (0.3–100 µM) of the tested compounds for 24 hr and then stained with MTT solution and incubated for an additional 4 hr at 37°C.…”

Section: Methodsmentioning

confidence: 99%

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

et al. 2020

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Herein, we report the synthesis and cytotoxic effects of novel chlorinated plastoquinone analogs (ABQ1–17) against different leukemic cells. Compounds ABQ3, ABQ11, and ABQ12 demonstrated a pronounced antiproliferative effect against chronic myelogenous leukemia (CML) K562 cell line with IC50 values of 0.82 ± 0.07, 0.28 ± 0.03, and 0.98 ± 0.22 μM, respectively. Among them, ABQ11 showed approximately three times higher selectivity than imatinib on CML. ABQ11‐treated CML cells induced significant apoptosis at low concentration. Inhibitory effect of ABQ11 against eight different tyrosine kinases, including ABL1, was investigated. ABQ11 inhibited ABL1 with IC50 value of 13.12 ± 1.71 μM, indicating that the moderate inhibition of ABL1 kinase is just an in‐part mechanism of its outstanding cellular activity. Molecular docking of ABQ11 into ABL1 kinase ATP‐binding pocket revealed the formation of some key interactions. Furthermore, DNA cleavage assay showed that ABQ11 strongly disintegrated DNA at 1 μM concentration in the presence of iron (II) complex system, assuming that the major mechanism for the anticancer effects of ABQ11 is DNA cleavage. In silico ADMET prediction revealed that ABQ11 is a drug‐like small molecule with a favorable safety profile. Taken together, ABQ11 is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from imatinib.

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Section: Methodsmentioning

confidence: 99%

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

et al. 2020

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“…All the identified compounds (1-10) were docked using the rigid-receptor method. 59 Three hundred docking poses were calculated for each compound. All other options were left at their default standards.…”

Section: Molecular Docking Studymentioning

confidence: 99%

<p>Anti-Inflammatory Potential of Green Synthesized Silver Nanoparticles of the Soft Coral <em>Nephthea</em> Sp. Supported by Metabolomics Analysis and Docking Studies</p>

Abdelhafez

Ali

Fahim

et al. 2020

IJN

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Background: Soft corals have been endorsed as a plentiful source of bioactive compounds with promising anti-inflammatory activities; therefore, exploring their potential as source of anti-inflammatory metabolites has stimulated a growing research interest. Purpose: To investigate the anti-inflammatory potential of the soft coral, Nephthea sp., in its bulk and silver nanostructure. Metabolomics analysis of Nephthea sp., followed by molecular docking studies, was also conducted in order to explore and predict the secondary metabolites that might provide its inhibitory actions on inflammation. Materials and Methods: The petroleum ether and ethyl acetate fractions were used to synthesize silver nanoparticles. The prepared silver nanoparticles were characterized through UV-vis spectrophotometric, transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) analyses. Testing for the anti-inflammatory activity was performed against COX-1 and COX-2. Furthermore, liquid chromatography-mass spectrometry (LC-MS) based metabolomics analysis and molecular docking were also applied. Results: A variety of secondary metabolites were identified, among them, sesquiterpenes were found to prevail. The petroleum ether and acetone fractions of Nephthea sp. showed the highest COX-2 inhibitory activities, possibly attributable to their substantial contents of terpenoids. Additionally, the green synthesized silver nanoparticles of both the petroleum ether and ethyl acetate fractions of Nephthea sp. demonstrated higher anti-COX-2 properties. Conclusion: The obtained results showed the effectiveness of non-targeted metabolomics technique in metabolic profiling of Nephthea sp., helping the search for new bioactive metabolites in future chemical studies on this soft coral. The interesting anti-inflammatory potential of the tested extracts and their nanoparticles could also be relevant to the development of new, effective anti-inflammatory agents.

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“…Two noncommercially available aldehydes, 4-(dimethylamino)picolinaldehyde and 4-(diethylamino)picolinaldehyde, were prepared as described previously [31,32,33]. Thereafter, the in vitro SIRT2 inhibitory activities of these synthesized compounds were examined using electrophoretic mobility shift assays [29] (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…SIRT2 inhibitors showed antiproliferative effects against different cancer cell lines such as luminal and triple-negative breast cancers [22,24], leukemia of different genotypes [24,25,26,27], and cervical cancer [28]. Recently, we have identified and characterized a new class of potent and selective SIRT2 inhibitors; the lead compound, TH-3 , has a half maximal inhibitory concentration (IC 50 ) of 1.3 μM [29]. With its trityl histidine scaffold, TH-3 shares features in common with the reported SIRT2 inhibitor SirReal2 (IC 50 = 0.21 μM) [30].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative S-Trityl-l-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement

et al. 2019

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S-trityl-l-cysteine (STLC) is a well-recognized lead compound known for its anticancer activity owing to its potent inhibitory effect on human mitotic kinesin Eg5. STLC contains two free terminal amino and carboxyl groups that play pivotal roles in binding to the Eg5 pocket. On the other hand, such a zwitterion structure complicates the clinical development of STLC because of the solubility issues. Masking either of these radicals reduces or abolishes STLC activity against Eg5. We recently identified and characterized a new class of nicotinamide adenine dinucleotide-dependent deacetylase isoform 2 of sirtuin protein (SIRT2) inhibitors that can be utilized as cytotoxic agents based on an S-trityl-l-histidine scaffold. Herein, we propose new STLC-derived compounds that possess pronounced SIRT2 inhibition effects. These derivatives contain modified amino and carboxyl groups, which conferred STLC with SIRT2 bioactivity, representing an explicit repurposing approach. Compounds STC4 and STC11 exhibited half maximal inhibitory concentration values of 10.8 ± 1.9 and 9.5 ± 1.2 μM, respectively, against SIRT2. Additionally, introduction of the derivatizations in this study addressed the solubility limitations of free STLC, presumably due to interruption of the zwitterion structure. Therefore, we could obtain drug-like STLC derivatives that work by a new mechanism of action. The new derivatives were designed, synthesized, and their structure was confirmed using different spectroscopic approaches. In vitro and cellular bioassays with various cancer cell lines and in silico molecular docking and solubility calculations of the synthesized compounds demonstrated that they warrant attention for further refinement of their bioactivity.

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New SIRT2 inhibitors: Histidine-based bleomycin spin-off

Cited by 20 publications

References 37 publications

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

<p>Anti-Inflammatory Potential of Green Synthesized Silver Nanoparticles of the Soft Coral <em>Nephthea</em> Sp. Supported by Metabolomics Analysis and Docking Studies</p>

Antiproliferative S-Trityl-l-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement

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