6,072 research outputs found
Benzothiadiazole derivatives endowed with STAT3 inhibition
No full textBENZOTHIADIAZOLE DERIVATIVES ENDOWED WITH STAT3
INHIBITION
Arianna Gelain (1), Matteo Mori (1), Ettore Gilardoni (1), Luca Regazzoni (1), Alessandro Pedretti (1),
Diego Colombo (2), Gary Parkinson (3), Akira Asai (4), Fiorella Meneghetti (1), Stefania Villa (1)
1) Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133 Milan, Italy
2) Department of Medical Biotechnology and Translational Medicine, University of Milan, via C. Saldini 50, 20133 Milan,
Italy
3) Department of Pharmaceutical and Biological Chemistry – UCL School of Pharmacy, University College London, 29/39
Brunswick Square, WC1N 1AX London, United Kingdom
4) Center for Drug Discovery – Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
422-8526 Shizuoka, Japan
Signal Transducer and Activator of Transcription 3 (STAT3) is a latent cytoplasmic protein over-expressed in
various cancer cell lines1,2. As a part of our ongoing research focused on compounds showing STAT3 SH2
domain inhibiting activity3,4, by a virtual screening approach, we identified 5,6-dimethyl-1H,3H
-2,1,3-benzothiadiazole-2,2-dioxide (1) as potential inhibitor. Several derivatives were synthesized (Figure 1)
and tested. Since compound 1 exhibited the most interesting activity (IC50 = 15.8 ± 0.6 μM by
AlphaScreen-based assay), we decided to investigate the mechanism of its activity by liquid chromatography,
MS and UV studies, discovering compound 1 unexpected interaction also with cysteine residues5.
Figure 1 . Benzothiadiazole-2,2-dioxide derivatives set
References
1) Darnell, J. Jr Science, 1997, 277, 1630-1635
2) Turkson, J. and Jove R. Oncogene, 2000, 19, 6613-6626
3) Meneghetti, F.; Villa, S.; Masciocchi, D.; Barlocco, D.; Toma, L.; Han, D.C.; Kwon, B.M.; Ogo, N.; Asai, A.; Legnani, L.;
Gelain, A. European J. Org. Chem. 2015, 2015, 4907–4912
4) Porta, F.; Facchetti, G.; Ferri, N.; Gelain, A.; Meneghetti, F.; Villa, S.; Barlocco, D.; Masciocchi, D.; Asai, A.; Miyoshi,
N.; Marchianò, S.; Kwon, B.M.; Jin, Y.; Gandin, V.; Marzano, C.; Rimoldi, Eur. J. Med. Chem. 2017, 131, 196–206
5) Mori, M.; Gilardoni, E.; Regazzoni, L.; Pedretti, A.; Colombo, D.; Parkinson, G.; Asai, A,; Meneghetti, F.; Villa, S.;
Gelain, A., Molecules 2020, 25(15), 3509
P-adic asai L-functions of bianchi modular forms
No full textThe Asai (or twisted tensor) L-function of a Bianchi modular form Ψ is the L-function attached to the tensor induction to ℚ of its associated Galois representation. In this paper, when Ψ is ordinary at p we construct a p-adic analogue of this L-function: that is, a p-adic measure on ℤ×p that interpolates the critical values of the Asai L-function twisted by Dirichlet characters of p-power conductor. The construction uses techniques analogous to those used by Lei, Zerbes and the first author in order to construct an Euler system attached to the Asai representation of a quadratic Hilbert modular form
Some Remarks on Cognacy Judgments of Ainu Dialects : On Asai (1974)
No full textThere are two lexicostatistical studies on Ainu dialects that still have a great influence on currentAinu linguistics: they are by Hattori and Chiri (1960) and Asai (1974). However, Hattori and Chiri (1960) and Asai (1974) analyzed different parts of lexicostatistical data based on different cognacy judgments. This led to an inconsistency in the classification of Ainu dialects in recent studies. Furthermore, the difficulties in the specification of 110 words and the corresponding cognacy judgments by Asai have prevented researchers from examining, comparing, and integrating the works of Hattori and Chiri (1960) and Asai (1974).This paper is an attempt to identify 110 words from 135 candidates and the corresponding cognacy judgments by Asai, and adopt an approach that enables Ainu linguists to discuss the validation of the cognacy judgments by Asai. The approach can identify the assumptions on Asai`s data with the results on the specification of the words and the corresponding cognacy judgments. Therefore, the properties of the approach enable the author to examine the specification of the words and the corresponding cognacy judgments from a linguistic perspective and revise the assumptions on Asai's data from the viewpoints of Hattori and Chiri (1960). The primary results in this paper demonstrate that (1) the descriptions by Asai are insufficient for specifying all 110 words and (2) part of the non-cognate judgments in Asai, specified by our approach, differ from a phonetic correspondence among Hokkaido Ainu dialects and Sakhalin Ainu dialects on Ainu linguistics (Hattori 1967: 209). Furthermore, the statistical findings demonstrate that the view on lexicostatistical data in Asai (1974) classifies Tarantomari and Maoka into different clusters, and Tarantomari and Maoka form one cluster from the viewpoints of Hattori and Chiri (1960), which is consistent to linguistic and philological studies (e.g., Sakaguchi 2019). This suggests a need for the classification of Ainu dialects through the integration of Hattori and Chiri's (1960) and Asai's (1974) works
Some Remarks on Cognacy Judgments of Ainu Dialects : On Asai (1974)
No full textThere are two lexicostatistical studies on Ainu dialects that still have a great influence on currentAinu linguistics: they are by Hattori and Chiri (1960) and Asai (1974). However, Hattori and Chiri (1960) and Asai (1974) analyzed different parts of lexicostatistical data based on different cognacy judgments. This led to an inconsistency in the classification of Ainu dialects in recent studies. Furthermore, the difficulties in the specification of 110 words and the corresponding cognacy judgments by Asai have prevented researchers from examining, comparing, and integrating the works of Hattori and Chiri (1960) and Asai (1974).This paper is an attempt to identify 110 words from 135 candidates and the corresponding cognacy judgments by Asai, and adopt an approach that enables Ainu linguists to discuss the validation of the cognacy judgments by Asai. The approach can identify the assumptions on Asai`s data with the results on the specification of the words and the corresponding cognacy judgments. Therefore, the properties of the approach enable the author to examine the specification of the words and the corresponding cognacy judgments from a linguistic perspective and revise the assumptions on Asai's data from the viewpoints of Hattori and Chiri (1960). The primary results in this paper demonstrate that (1) the descriptions by Asai are insufficient for specifying all 110 words and (2) part of the non-cognate judgments in Asai, specified by our approach, differ from a phonetic correspondence among Hokkaido Ainu dialects and Sakhalin Ainu dialects on Ainu linguistics (Hattori 1967: 209). Furthermore, the statistical findings demonstrate that the view on lexicostatistical data in Asai (1974) classifies Tarantomari and Maoka into different clusters, and Tarantomari and Maoka form one cluster from the viewpoints of Hattori and Chiri (1960), which is consistent to linguistic and philological studies (e.g., Sakaguchi 2019). This suggests a need for the classification of Ainu dialects through the integration of Hattori and Chiri's (1960) and Asai's (1974) works
STAT3 direct inhibitors: from MD77 to AC33
No full textSTAT3 (Signal Transducer and Activator of Transcription 3) is a latent cytosolic protein overexpressed in various cancer cell lines which was found to participate in oncogenesis by stimulating cell proliferation and preventing apoptosis [1]. Furthermore, previous studies have shown that blocking constitutively activated STAT3 signaling leads to tumor cell apoptosis, with minimal effect on normal cells [2,3]. This work aims at the synthesis, the structural analysis and the biological evaluation of novel potential antitumor agents, able to inhibit STAT3 protein-protein interaction, starting from MD77 previously identified by our research group [4,5]. Among them, AC33 was selected for further investigations since the AlphaScreen-based assay highlighted its ability to disrupt the STAT3 dimerization, with high selectivity over STAT1 and Grb2. These data induced us to modulate its pharmacokinetic and pharmacodynamic properties. The interesting results obtained will be presented.
This work was supported by a PRIN2010 Grant from MIUR, Italy.
References:
[1] H. Yu, R. Jove, Nat Rev Cancer, 2004, 4, 97-105.
[2] R. Buettner, L.B. Mora, R. Jove, Clin Cancer Res, 2002, 8(4), 945-954.
[3] T. Bowman, R. Garcia, J. Turkson, R. Jove, Oncogene, 2000, 19, 2474-2488.
[4] D-S. Shin, D. Masciocchi, A. Gelain, S. Villa, D. Barlocco, F. Meneghetti, A. Pedretti, Y-M Han, D. C. Han, B.M. Kwon, L. Legnani, L. Toma, Med. Chem. Comm., 2010, 1, 156-164.
[5] D. Masciocchi, S. Villa, F. Meneghetti, A. Pedretti, D. Barlocco, L. Legnani, L. Toma, B. M. Kwon, S. Nakano, A. Asai, A. Gelain, Med. Chem. Comm., 2012, 3, 592-599
Juminhyo 住民票, certificate of residence
No full textA certified copy of resident register issued by Katsuhiko Asai, Mayor of Yokohama City Naka Ward on April 24, 1959. It records Kanamori family members' permanent domicile, dates of birth, family relationship, dates of becoming resident of Yokohama City Naka Ward. The family members include Tsugitada Kanamori, the head of the household, Kazuko Kanamori, wife, and Kenji Kanamori, third son. It confirms that Kanamori family's resident registration was withdrawn on March 10, 1959 due to renunciation of their Japanese citizenship.This collection contains one box of documents belonging to Tsugitada Kanamori. Materials in this collection mostly pertain to Kanamori’s efforts regarding canceling his renunciation and reinstating his American citizenship
Unraveling the interaction mechanism of a benzothiadiazole-2.2-dioxide derivative with STAT3 : towards novel direct inhibitors
No full textUnraveling the interaction mechanism of a benzothiadiazole-2,2-
dioxide derivative with STAT3: towards novel direct inhibitors
Matteo Mori 1, Ettore Gilardoni 1, Luca Regazzoni 1, Alessandro Pedretti 1, Diego Colombo 2,
Gary Parkinson 3, Akira Asai 4, Giulia Cazzaniga 1, Fiorella Meneghetti 1, Stefania Villa 1 and
Arianna Gelain 1
1 Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133 Milan, Italy
2 Department of Medical Biotechnology and Translational Medicine, University of Milan, via C. Saldini 50,
20133 Milan, Italy
3 Department of Pharmaceutical and Biological Chemistry – UCL School of Pharmacy, University College
London, 29/39 Brunswick Square, WC1N 1AX London, United Kingdom
4 Center for Drug Discovery – Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1
Yada, Suruga-ku, 422-8526 Shizuoka, Japan
Signal Transducer and Activator of Transcription 3 (STAT3) participates in oncogenesis by
stimulating cell proliferation and preventing apoptosis; this protein has been validated as a suitable
and selective target for anticancer therapy [1,2]. Starting from a virtual screening approach on
STAT3-SH2 domain, we identified 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (I) as
a potential inhibitor. Therefore, we synthesized and tested a series of derivatives (Figure 1), among
which benzosulfamide I showed a significant activity (IC50 = 15.8 ± 0.6 μM by AlphaScreen-based
assay) as a direct STAT3 inhibitor. Hence, an in-depth investigation through mass spectrometry,
liquid chromatography and UV spectroscopy studies was carried out, shedding light on its intriguing
mechanism of interaction, also involving cysteine residues located around the SH2 domain [3].
Figure 1. Benzothiadiazole derivatives of compound I.
[1] T. Bowman,. M. A. Broome, D. Sinibaldi, W. Wharton, W. J. Pledger, J. M. Sedivy, R. Irby,
T. Yeatman, S. A. Courtneidge, R. Jove, Proc. Natl. Acad. Sci. 2001, 98, 7319.
[2] J. Turkson, D. Ryan, J. S Kim, Y. Zhang, Z. Chen, E. Haura, A. Laudano, S. Sebti, A. D.
Hamilton, R. Jove, J. Biol. Chem. 2001, 276, 45443.
[3] M. Mori, E. Gilardoni, L. Regazzoni, A. Pedretti, D. Colombo, G. Parkinson, A. Asai, F.
Meneghetti, S. Villa, A. Gelain, Molecules 2020, 25(15), 3509
A novel composite polymer electrolyte:effect of mesoporous SiO2 on ionic conduction in poly (ethylene oxide)-LiCF3SO3 complex
No full textInternal modified-mesoporous SiO2 using ionic liquid (IL-MPSi) as one of the additives has been prepared and added to the poly(ethylene oxide) (PEO)-based solid electrolytes for improving the ionic conductivity. In this study, 1-ethyl-3-methylimidazolium tetrafluoroborate (EMImBF(4)) has been used as an ionic liquid. The conductivity was significantly improved by the addition of IL-MPSi, to be more than 10(-5) S cm(-1) at room temperature and at the filler contents of 15 wt.%, in the solid state. From the combination of dc polarization and ac impedance measurement for lithium cells, it was revealed that the addition of IL-MPSi increased the Li+ transference number (t(+)), because the EMImBF4 used in this study possesses higher t(+) (approximately 0.5) than the PEO-salt simple mixture. This means that the MPSi domains can act as "bypass" for transport of carrier ions to the PEO matrix through the inside IL phase
Nitrogen oxide in protostellar envelopes and shocks: the ASAI survey
No full textThe high sensitivity of the IRAM 30-m Astrochemical Surveys At IRAM (ASAI) unbiased spectral survey in the mm window allows us to detect NO emission towards both the Class I object SVS13-A and the protostellar outflow shock L1157-B1. We detect the hyperfine components of the 2Π1/2J = 3/2 → 1/2 (at 151 GHz) and the 2Π1/2J = 5/2 → 3/2 (at 250 GHz) spectral pattern. The two objects show different NO profiles: (i) SVS13-A emits through narrow (1.5 km s−1) lines at the systemic velocity, while (ii) L1157-B1 shows broad (∼5 km s−1) blueshifted emission. For SVS13-A, the analysis leads to Tex ≥ 4 K, N(NO) ≤ 3 × 1015 cm−2, and indicates the association of NO with the protostellar envelope. In L1157-B1, NO is tracing the extended outflow cavity: Tex ≃ 4–5 K, and N(NO) = 5.5 ± 1.5 × 1015 cm−2. Using C18O, 13C18O, C17O, and 13C17O ASAI observations, we derive an NO fractional abundance less than ∼10−7 for the SVS13-A envelope, in agreement with previous measurements towards extended photodissociation regions (PDRs) and prestellar objects. Conversely, a definite X(NO) enhancement is measured towards L1157-B1, ∼6 × 10−6, showing that the NO production increases in shocks. The public code UCLCHEM was used to interpret the NO observations, confirming that the abundance observed in SVS13-A can be attained in an envelope with a gas density of 105 cm−3 and a kinetic temperature of 40 K. The NO abundance in L1157-B1 is reproduced with pre-shock densities of 105 cm−3 subjected to a ∼45 km s−1 shock
A CONSTRUCTION OF -ADIC ASAI -FUNCTIONS OVER CM FIELDS (Analytic, geometric and -adic aspects of automorphic forms and -functions)
No full textThis article is a survey on the author's preprint [Na], where the author constructs a p-adic Asai £-functions for irreducible cohomological cuspidal autmorphic representations of GL₂ over CM fields
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