Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors

Abstract The serine-threonine checkpoint kinase 1 (Chk1) plays a critical role in the cell cycle arrest in response to DNA damage. In the last decade, Chk1 inhibitors have emerged as a novel therapeutic strategy to potentiate the anti-tumour efficacy of cytotoxic chemotherapeutic agents. In the search for new Chk1 inhibitors, a congeneric series of 2-aryl-2 H-pyrazolo[4,3-c]quinolin-3-one (PQ) was evaluated by in-vitro and in-silico approaches for the first time. A total of 30 PQ structures were synthesised in good to excellent yields using conventional or microwave heating, highlighting that 14 of them are new chemical entities. Noteworthy, in this preliminary study two compounds 4e2 and 4h2 have shown a modest but significant reduction in the basal activity of the Chk1 kinase. Starting from these preliminary results, we have designed the second generation of analogous in this class and further studies are in progress in our laboratories.

[1]  Stefano Moro,et al.  Deciphering the Complexity of Ligand-Protein Recognition Pathways Using Supervised Molecular Dynamics (SuMD) Simulations , 2016, J. Chem. Inf. Model..

[2]  Stefano Moro,et al.  DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations , 2015, Molecules.

[3]  A. Venook,et al.  Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  A. Eastman,et al.  Will targeting Chk1 have a role in the future of cancer therapy? , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Priyanka Gupta,et al.  Identification of novel inhibitors of human Chk1 using pharmacophore-based virtual screening and their evaluation as potential anti-cancer agents , 2014, Journal of Computer-Aided Molecular Design.

[6]  A. Massey,et al.  Chk1 Inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers , 2014, BMC Cancer.

[7]  E. L. Moyano,et al.  Microwave Assisted Synthesis of ethyl-quinolon-4-one-3-carboxylates and Hydrolysis to quinolon-4-one-3-carboxylic Acids , 2014 .

[8]  V. Ferreira,et al.  Structural evaluation of three 2-phenylpyrazolo[4,3-c]quinolin-3-one monohydrates , 2013 .

[9]  K. AmbrePremlata,et al.  Identification of new checkpoint kinase-1 (Chk1) inhibitors by docking, 3D-QSAR, and pharmacophore-modeling methods , 2012 .

[10]  Jon Read,et al.  Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors. , 2012, Bioorganic & medicinal chemistry letters.

[11]  R. Mekheimer,et al.  Recent Developments in the Chemistry of Pyrazolo[4,3-c]quinolines , 2012 .

[12]  J. Breed,et al.  Discovery of a novel class of triazolones as checkpoint kinase inhibitors--hit to lead exploration. , 2010, Bioorganic & medicinal chemistry letters.

[13]  David S. Mendelson,et al.  A phase I dose-escalation study of SCH 900776, a selective inhibitor of checkpoint kinase 1 (CHK1), in combination with gemcitabine (Gem) in subjects with advanced solid tumors. , 2010 .

[14]  E. L. Moyano,et al.  An alternative approach toward 2-aryl-2H-pyrazolo[4,3-c]-quinolin-3-ones by a multistep synthesis , 2010 .

[15]  P. Labute.  proteins STRUCTURE O FUNCTION O BIOINFORMATICS Protonate3D: Assignment of ionization , 2013 .

[16]  Stephen Green,et al.  AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies , 2008, Molecular Cancer Therapeutics.

[17]  S. Ashwell,et al.  DNA Damage Detection and Repair Pathways—Recent Advances with Inhibitors of Checkpoint Kinases in Cancer Therapy , 2008, Clinical Cancer Research.

[18]  Lawrence C Kuo,et al.  Optimization of a pyrazoloquinolinone class of Chk1 kinase inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[19]  J. Stewart.  Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements , 2007, Journal of molecular modeling.

[20]  Chang Park,et al.  Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors. , 2007, Journal of medicinal chemistry.

[21]  V. Hornak,et al.  Comparison of multiple Amber force fields and development of improved protein backbone parameters , 2006, Proteins.

[22]  Michael Reilly,et al.  Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[23]  Andrew Potter,et al.  Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity. , 2005, Journal of medicinal chemistry.

[24]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[25]  H. Pereira,et al.  Synthesis and Antiviral Activities of New Pyrazolo[4,3‐c]quinolin‐3‐ones and Their Ribonucleoside Derivatives , 2004, Nucleosides, nucleotides & nucleic acids.

[26]  G. Biggio,et al.  High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones. , 2003, Bioorganic & medicinal chemistry.

[27]  Jiri Bartek,et al.  Chk1 and Chk2 kinases in checkpoint control and cancer. , 2003, Cancer cell.

[28]  Michael J Bower,et al.  Structural basis for Chk1 inhibition by UCN-01. , 2002, The Journal of biological chemistry.

[29]  P. Hünenberger,et al.  A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations , 2001, J. Comput. Chem..

[30]  G. Biggio,et al.  High affinity central benzodiazepine receptor ligands. Part 2: quantitative structure-activity relationships and comparative molecular field analysis of pyrazolo[4,3-c]quinolin-3-ones. , 2001, Bioorganic & medicinal chemistry.

[31]  V. Segarra,et al.  Synthesis and biological evaluation of 2,5-dihydropyrazolo[4,3-c]quinolin-3-ones, a novel series of PDE 4 inhibitors with low emetic potential and antiasthmatic properties , 2000 .

[32]  M. Gniewosz,et al.  Structure-activity relationship investigations of the modulating effect of core substituents on the affinity of pyrazoloquinolinone congeners for the benzodiazepine receptor. , 1998, Farmaco.

[33]  G. Biggio,et al.  High affinity central benzodiazepine receptor ligands: synthesis and structure-activity relationship studies of a new series of pyrazolo[4,3-c]quinolin-3-ones. , 1998, Bioorganic & medicinal chemistry.

[34]  S. Elledge,et al.  Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. , 1997, Science.

[35]  E. Sausville,et al.  UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. , 1996, Journal of the National Cancer Institute.

[36]  Thomas A. Halgren,et al.  Merck molecular force field. V. Extension of MMFF94 using experimental data, additional computational data, and empirical rules , 1996, J. Comput. Chem..

[37]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[38]  T. Darden,et al.  A smooth particle mesh Ewald method , 1995 .

[39]  P. Skolnick,et al.  Synthesis of novel imidazobenzodiazepines as probes of the pharmacophore for "diazepam-insensitive" GABAA receptors. , 1995, Journal of medicinal chemistry.

[40]  T. Corbett,et al.  The antitumor activity of novel pyrazoloquinoline derivatives , 1995 .

[41]  B. Brooks,et al.  Langevin dynamics of peptides: The frictional dependence of isomerization rates of N‐acetylalanyl‐N′‐methylamide , 1992, Biopolymers.

[42]  J. Stewart.  Optimization of parameters for semiempirical methods II. Applications , 1989 .

[43]  J. Stewart.  Optimization of parameters for semiempirical methods I. Method , 1989 .

[44]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[45]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[46]  N Yokoyama,et al.  2-Arylpyrazolo[4,3-c]quinolin-3-ones: novel agonist, partial agonist, and antagonist of benzodiazepines. , 1982, Journal of medicinal chemistry.

[47]  TWO-WEEK Loan COpy,et al.  University of California , 1886, The American journal of dental science.

[48]  Xiaoyun Zhang,et al.  Computational studies on the binding mechanism between triazolone inhibitors and Chk1 by molecular docking and molecular dynamics. , 2015, Molecular bioSystems.

[49]  J. Janetka,et al.  Keeping checkpoint kinases in line: new selective inhibitors in clinical trials. , 2008, Expert opinion on investigational drugs.

[50]  Seshagiri Rao Casturi,et al.  1,2-Diaryl-1-ethanone and pyrazolo [4,3-c] quinoline-4-one as novel selective cyclooxygenase-2 inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[51]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..