- Synthesis of Fluorescent Probes Targeting Tumor-Suppressor Protein FHIT and Identification of Apoptosis-Inducing FHIT Inhibitors
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For the early diagnosis of cancer, leading to a better chance of full recovery, marker genes whose expression is already altered in precancerous lesions are desirable, and the tumor-suppressor gene FHIT is one candidate. The gene product, FHIT protein, has a unique dinucleoside triphosphate hydrolase (AP3Aase) activity, and in this study, we designed and synthesized a series of FHIT fluorescent probes utilizing this activity. We optimized the probe structure for high and specific reactivity with FHIT and applied the optimized probe in a screening assay for FHIT inhibitors. Screening of a compound library with this assay identified several hits. Structural development of a hit compound afforded potent FHIT inhibitors. These inhibitors induce apoptosis in FHIT-expressing cancers via caspase activation. Our results support the idea that FHIT binders, no matter whether inhibitors or agonists of AP3Aase activity, might be promising anticancer agents.
- Kawaguchi, Mitsuyasu,Sekimoto, Eriko,Ohta, Yuhei,Ieda, Naoya,Murakami, Takashi,Nakagawa, Hidehiko
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supporting information
p. 9567 - 9576
(2021/07/19)
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- Quantitative structure-activity relationship and complex network approach to monoamine oxidase A and B inhibitors
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The work provides a new model for the prediction of the MAO-A and -B inhibitor activity by the use of combined complex networks and QSAR methodologies. On the basis of the obtained model, we prepared and assayed 33 coumarin derivatives, and the theoretical prediction was compared with the experimental activity data. The model correctly predicted 27 compounds, and most of the active derivatives showed IC50 values in the μM-nM range against both the MAO-A and MAO-B isoforms. Compound 14 shows the same MAO-A inhibitory activity (IC50 = 7.2 nM), as clorgyline used as a reference inhibitor and has the highest MAO-A specificity (1000-fold higher compared to MAO-B). On the other hand, compounds 24 (IC50 = 1.2 nM) and 28 (IC50 = 1.5 nM) show higher activity than selegiline (IC 50 = 19.6 nM) and high MAO-B selectivity with 100-fold and 1600-fold inhibition levels, with respect to the MAO-A isoform.
- Santana, Lourdes,González-Díaz, Humberto,Quezada, Elías,Uriarte, Eugenio,Yá?ez, Matilde,Vi?a, Dolores,Orallo, Francisco
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experimental part
p. 6740 - 6751
(2009/10/23)
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- Modified coumarins. 7. Synthesis and biological activity of mannich bases of substituted 7,8,9,10-tetrahydrobenzo[c]chromen-6-ones
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Condensation of 1- and 3-hydroxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-ones with substituted 1,1-diaminomethanes produced Mannich bases containing a dialkylaminomethyl group in the 2- and 4-positions of 7, 8,9,10-tetrahydrobenzo[c]chromen-6-one. Pharmacological screening of 2-chloro-3-hydroxy-4-(1-pyrrolidinylmethyl)-7,8,9,10-tetrahydro-6H-benzo[c] chromen-6-one in Wistar rats showed that it possesses low toxicity and acts as a stimulant of the central and peripheral nervous systems with indications of neuroleptic and tranquilizing activities.
- Garazd,Panteleimonova,Garazd,Khilya
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p. 532 - 538
(2007/10/03)
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