The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform

Schenone Silvia - One of the best experts on this subject based on the ideXlab platform.

  • Pyrrolo[2,3-d]pyrimidines as kinase inhibitors
    'Bentham Science Publishers Ltd.', 2017
    Co-Authors: Musumeci Francesca, Sanna Monica, Grossi Giancarlo, Ullo Chiara, Fallacara, Anna Lucia, Schenone Silvia
    Abstract:

    The pyrrolo[2,3-d]pyrimidine nucleus is a deaza-isostere of adenine, the Nitrogenous Base of ATP, and is present in many ATP-competitive inhibitors of different kinases. In the last few years the number of articles and patents that have appeared involving this type of inhibitors has dramatically increased and some compounds have been approved for the treatment of inflammatory or myeloproliferative diseases. Other derivatives are currently being evaluated in clinical trials. This review deals with pyrrolo[2,3-d]pyrimidine derivatives active as kinase inhibitors that have been reported in the literature from 2011 to 2016, with a particular interest on the recently patented compounds. The molecules are classified depending on the inhibited kinase, focusing on their chemical structures

  • Pyrrolo[2,3-d]pyrimidines active as Btk inhibitors
    'Informa UK Limited', 2017
    Co-Authors: Musumeci Francesca, Sanna Monica, Fallacara, Anna Lucia, Greco Chiara, Giacchello Ilaria, Amato Rosario, Schenone Silvia
    Abstract:

    Introduction: Btk is a tyrosine kinase dysregulated in several B-cell malignancies and autoimmune diseases, and this has given rise to a search for Btk inhibitors. Nevertheless, only one Btk inhibitor, ibrutinib, has been approved to date, although other compounds are currently being evaluated in clinical trials or in preclinal stages. Area covered: This review, after a brief introduction on Btk and its inhibitors already in clinical trials, focusses on pyrrolo[2,3-d]pyrimidine derivatives patented in the last five years as Btk inhibitors. Indeed, the pyrrolo[2,3-d]pyrimidine scaffold, being a deaza-isostere of adenine, the Nitrogenous Base of ATP, is an actively pursued target for Btk inhibitors. The patent literature since 2012 have been extensively investigated, pointing out the general features of the patented compounds and, when it is possible, their mechanism of action. Expert opinion: The recently patented pyrrolo[2,3-d]pyrimidines, acting as reversible or irreversible inhibitors, showed a very interesting in vitro activity. For this reason, the development of compounds endowed with this scaffold could afford a significant impact in the search for drug candidates for the treatment of immune diseases or B-cell malignancies

Miguel Castro - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE Inhibitory Effect of Bridged Nucleosides on Thermus aquaticus DNA Polymerase and Insight into the Binding Interactions
    2016
    Co-Authors: Sung-ku Kim, Aaro Castro, Edward S. Kim, Austi P. Dinkel, Xiaoyu Liu, Miguel Castro
    Abstract:

    Modified nucleosides have the potential to inhibit DNA polymerases for the treatment of viral infections and cancer. With the hope of developing potent drug candidates by the modi-fication of the 2’,4’-position of the ribose with the inclusion of a bridge, efforts were focused on the inhibition of Taq DNA polymerase using quantitative real time PCR, and the results revealed the significant inhibitory effects of 2’,4’-bridged thymidine nucleoside on the poly-merase. Study on the mode of inhibition revealed the competitive mechanism with which the 2’,4’-bridged thymidine operates. With a Ki value of 9.7 ± 1.1 μM, the 2’,4’-bridged thymi-dine proved to be a very promising inhibitor. Additionally, docking analysis showed that all the nucleosides including 2’,4’-bridged thymidine were able to dock in the active site, indi-cating that the substrate analogs reflect a structural complementarity to the enzyme active site. The analysis also provided evidence that Asp610 was a key binding site for 2’,4’-bridged thymidine. Molecular dynamics (MD) simulations were performed to further under-stand the conformational variations of the binding. The root-mean-square deviation (RMSD) values for the peptide backbone of the enzyme and the Nitrogenous Base of the inhibitor stabilized within 0.8 and 0.2 ns, respectively. Furthermore, the MD analysis indicates sub-stantial conformational change in the ligand (inhibitor) as the Nitrogenous Base rotated anti-clockwise with respect to the sugar moiety, complemented by the formation of several new hydrogen bonds where Arg587 served as a pivot axis for binding formation. In conclusion, the active site inhibition of Taq DNA polymerase by 2’,4’-bridged thymidine suggests the potential of bridged nucleosides as drug candidates

  • Inhibitory Effect of Bridged Nucleosides on Thermus aquaticus DNA Polymerase and Insight into the Binding Interactions
    2016
    Co-Authors: Sung-ku Kim, Aaro Castro, Edward S. Kim, Austi P. Dinkel, Xiaoyu Liu, Miguel Castro
    Abstract:

    Modified nucleosides have the potential to inhibit DNA polymerases for the treatment of viral infections and cancer. With the hope of developing potent drug candidates by the modification of the 2’,4’-position of the ribose with the inclusion of a bridge, efforts were focused on the inhibition of Taq DNA polymerase using quantitative real time PCR, and the results revealed the significant inhibitory effects of 2’,4’-bridged thymidine nucleoside on the polymerase. Study on the mode of inhibition revealed the competitive mechanism with which the 2’,4’-bridged thymidine operates. With a Ki value of 9.7 ± 1.1 μM, the 2’,4’-bridged thymidine proved to be a very promising inhibitor. Additionally, docking analysis showed that all the nucleosides including 2’,4’-bridged thymidine were able to dock in the active site, indicating that the substrate analogs reflect a structural complementarity to the enzyme active site. The analysis also provided evidence that Asp610 was a key binding site for 2’,4’-bridged thymidine. Molecular dynamics (MD) simulations were performed to further understand the conformational variations of the binding. The root-mean-square deviation (RMSD) values for the peptide backbone of the enzyme and the Nitrogenous Base of the inhibitor stabilized within 0.8 and 0.2 ns, respectively. Furthermore, the MD analysis indicates substantial conformational change in the ligand (inhibitor) as the Nitrogenous Base rotated anticlockwise with respect to the sugar moiety, complemented by the formation of several new hydrogen bonds where Arg587 served as a pivot axis for binding formation. In conclusion, the active site inhibition of Taq DNA polymerase by 2’,4’-bridged thymidine suggests the potential of bridged nucleosides as drug candidates.

Mehrotra Ranjana - One of the best experts on this subject based on the ideXlab platform.

  • Structural-conformational aspects of tRNA complexation with chloroethyl nitrosourea derivatives: A molecular modeling and spectroscopic investigation
    'Elsevier BV', 2017
    Co-Authors: Agarwal Shweta, Tyagi Gunja, Chadha Deepti, Mehrotra Ranjana
    Abstract:

    Chloroethyl nitrosourea derivatives (CENUs) represent an important family of anticancer chemotherapeutic agents, which are used in the treatment of different types of cancer such as brain tumors, resistant or relapsed Hodgkin's disease, small cell lung cancer and malignant melanoma. This work focuses towards understanding the interaction of chloroethyl nitrosourea derivatives; lomustine, nimustine and semustine with tRNA using spectroscopic approach in order to elucidate their auxiliary anticancer action mechanism inside the cell. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), Fourier transform infrared difference spectroscopy, circular dichroism spectroscopy and UV-visible spectroscopy were employed to investigate the binding parameters of tRNA-CENUs complexation. Results of present study demonstrate that all CENUs, studied here, interact with tRNA through guanine Nitrogenous Base residues and possibly further crosslink cytosine residues in paired region of tRNA. Moreover, spectral data collected for nimustine-tRNA and semustine-tRNA complex formation indicates towards the groove-directed-alkylation as their anti-malignant action, which involves the participation of uracil moiety located in major groove of tRNA. Besides this, tRNA-CENUs adduct formation did not alter the native conformation of biopolymer and tRNA remains in A-form after its interaction with all three nitrosourea derivatives studied. The binding constants (K-a) estimated for tRNA complexation with lomustine, nimustine and semustine are 2.55 x 10(2) M-1, 4.923 x 10(2) M-1 and 4.223 x 10(2) M-1 respectively, which specify weak type of CENU's binding with tRNA. Moreover, molecular modeling simulations were also performed to predict preferential binding orientation of CENUs with tRNA that corroborates well with spectral outcomes. The findings, presented here, recognize tRNA binding properties of CENUs that can further help in rational designing of more specific and efficient RNA targeted chemotherapeutic agents

  • SERS as an advanced tool for investigating chloroethyl nitrosourea derivatives complexation with DNA
    'Elsevier BV', 2015
    Co-Authors: Agarwala Shweta, Ray Humika, Mehrotra Ranjana
    Abstract:

    We report surface-enhanced Raman spectroscopic (SERS) studies on free calf thymus DNA and its complexes with anti-tumor chloroethyl nitrosourea derivatives; semustine and nimustine. Since, first incident of SERS in 1974, it has rapidly established into an analytical tool, which can be used for the trace detection and characterization of analytes. Here, we depict yet another application of SERS in the field of drug-DNA interaction and thereby, its promising role in rational designing of new chemotherapeutic agents. Vibrational spectral analysis has been performed in an attempt to delineate the anti-cancer action mechanism of above mentioned nitrosourea derivatives. Strong SERS bands associated with the complexation of DNA with semustine and nimustine have been observed, which reveal binding of nitrosourea derivatives with heterocyclic Nitrogenous Base pair of DNA duplex. Formation of dG-dC interstrand cross-link in DNA double helices is also suggested by the SERS spectral outcomes of CENUs-DNA adduct. Results, demonstrated here, reflect recent progress in the newly developing field of drug-DNA interaction analysis via SERS

Musumeci Francesca - One of the best experts on this subject based on the ideXlab platform.

  • Pyrrolo[2,3-d]pyrimidines as kinase inhibitors
    'Bentham Science Publishers Ltd.', 2017
    Co-Authors: Musumeci Francesca, Sanna Monica, Grossi Giancarlo, Ullo Chiara, Fallacara, Anna Lucia, Schenone Silvia
    Abstract:

    The pyrrolo[2,3-d]pyrimidine nucleus is a deaza-isostere of adenine, the Nitrogenous Base of ATP, and is present in many ATP-competitive inhibitors of different kinases. In the last few years the number of articles and patents that have appeared involving this type of inhibitors has dramatically increased and some compounds have been approved for the treatment of inflammatory or myeloproliferative diseases. Other derivatives are currently being evaluated in clinical trials. This review deals with pyrrolo[2,3-d]pyrimidine derivatives active as kinase inhibitors that have been reported in the literature from 2011 to 2016, with a particular interest on the recently patented compounds. The molecules are classified depending on the inhibited kinase, focusing on their chemical structures

  • Pyrrolo[2,3-d]pyrimidines active as Btk inhibitors
    'Informa UK Limited', 2017
    Co-Authors: Musumeci Francesca, Sanna Monica, Fallacara, Anna Lucia, Greco Chiara, Giacchello Ilaria, Amato Rosario, Schenone Silvia
    Abstract:

    Introduction: Btk is a tyrosine kinase dysregulated in several B-cell malignancies and autoimmune diseases, and this has given rise to a search for Btk inhibitors. Nevertheless, only one Btk inhibitor, ibrutinib, has been approved to date, although other compounds are currently being evaluated in clinical trials or in preclinal stages. Area covered: This review, after a brief introduction on Btk and its inhibitors already in clinical trials, focusses on pyrrolo[2,3-d]pyrimidine derivatives patented in the last five years as Btk inhibitors. Indeed, the pyrrolo[2,3-d]pyrimidine scaffold, being a deaza-isostere of adenine, the Nitrogenous Base of ATP, is an actively pursued target for Btk inhibitors. The patent literature since 2012 have been extensively investigated, pointing out the general features of the patented compounds and, when it is possible, their mechanism of action. Expert opinion: The recently patented pyrrolo[2,3-d]pyrimidines, acting as reversible or irreversible inhibitors, showed a very interesting in vitro activity. For this reason, the development of compounds endowed with this scaffold could afford a significant impact in the search for drug candidates for the treatment of immune diseases or B-cell malignancies

Vidal, Benedicto C - One of the best experts on this subject based on the ideXlab platform.

  • Analysis Of The Dna Fourier Transform-infrared Microspectroscopic Signature Using An All-reflecting Objective.
    2015
    Co-Authors: Mello, Maria Luiza S, Vidal, Benedicto C
    Abstract:

    The Fourier transform-infrared (FT-IR) signature of dry samples of DNA and DNA-polypeptide complexes, as studied by IR microspectroscopy using a diamond attenuated total reflection (ATR) objective, has revealed important discriminatory characteristics relative to the PO2(-) vibrational stretchings. However, DNA IR marks that provide information on the sample's richness in hydrogen bonds have not been resolved in the spectral profiles obtained with this objective. Here we investigated the performance of an all reflecting objective (ARO) for analysis of the FT-IR signal of hydrogen bonds in DNA samples differing in Base richness types (salmon testis vs calf thymus). The results obtained using the ARO indicate prominent band peaks at the spectral region representative of the vibration of Nitrogenous Base hydrogen bonds and of NH and NH2 groups. The band areas at this spectral region differ in agreement with the DNA Base richness type when using the ARO. A peak assigned to adenine was more evident in the AT-rich salmon DNA using either the ARO or the ATR objective. It is concluded that, for the discrimination of DNA IR hydrogen bond vibrations associated with varying Base type proportions, the use of an ARO is recommended.6149-5