Maria Jose Camarasa

Summary

Country: Spain

Publications

  1. ncbi request reprint TSAO derivatives, inhibitors of HIV-1 reverse transcriptase dimerization: recent progress
    M J Camarasa
    Instituto de Química Médica C S I C Juan de la Cierva 3, 28006 Madrid, Spain
    Curr Pharm Des 12:1895-907. 2006
  2. ncbi request reprint TSAO derivatives the first non-peptide inhibitors of HIV-1 RT dimerization
    Maria Jose Camarasa
    Instituto de Quimica Medica CSIC, Madrid, Spain
    Antivir Chem Chemother 16:147-53. 2005
  3. ncbi request reprint Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: a single mode of inhibition for the three HIV enzymes?
    Maria Jose Camarasa
    Instituto de Química Médica C S I C, Juan de la Cierva 3, 28006 Madrid, Spain
    Antiviral Res 71:260-7. 2006
  4. ncbi request reprint TSAO compounds: the comprehensive story of a unique family of HIV-1 specific inhibitors of reverse transcriptase
    Maria Jose Camarasa
    Instituto de Química Médica C S I C, Juan de la Cierva 3, 28006 Madrid, Spain
    Curr Top Med Chem 4:945-63. 2004
  5. ncbi request reprint Design and discovery of a novel dipeptidyl-peptidase IV (CD26)-based prodrug approach
    Carlos García-Aparicio
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 49:5339-51. 2006
  6. ncbi request reprint N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors
    Ana Isabel Hernández
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 49:7766-73. 2006
  7. ncbi request reprint Novel [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2" -dioxide) derivatives with anti-HIV-1 and anti-human-cytomegalovirus activity
    Sonia de Castro
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 48:1158-68. 2005
  8. ncbi request reprint Structure-activity relationship studies on a novel family of specific HIV-1 reverse transcriptase inhibitors
    Maria Cruz Bonache
    Instituto de Quimica Medica CSIC, Madrid, Spain
    Antivir Chem Chemother 14:249-62. 2003
  9. ncbi request reprint Discovery of TSAO derivatives with an unusual HIV-1 activity/resistance profile
    Sonia de Castro
    Instituto de Química Médica C S I C, Juan de la Cierva 3, Madrid, Spain
    Antiviral Res 71:15-23. 2006
  10. ncbi request reprint Synthesis of 3' '-substituted TSAO derivatives with anti-HIV-1 and anti-HIV-2 activity through an efficient palladium-catalyzed cross-coupling approach
    Esther Lobatón
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 45:3934-45. 2002

Collaborators

Detail Information

Publications48

  1. ncbi request reprint TSAO derivatives, inhibitors of HIV-1 reverse transcriptase dimerization: recent progress
    M J Camarasa
    Instituto de Química Médica C S I C Juan de la Cierva 3, 28006 Madrid, Spain
    Curr Pharm Des 12:1895-907. 2006
    ..This review covers the recent work within this family of compounds aimed at enhancing their interaction with the dimer interface of HIV-1 RT...
  2. ncbi request reprint TSAO derivatives the first non-peptide inhibitors of HIV-1 RT dimerization
    Maria Jose Camarasa
    Instituto de Quimica Medica CSIC, Madrid, Spain
    Antivir Chem Chemother 16:147-53. 2005
    ..Moreover, the TSAO compounds are the first non-peptide molecules that interfere with the dimerization of the enzyme...
  3. ncbi request reprint Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: a single mode of inhibition for the three HIV enzymes?
    Maria Jose Camarasa
    Instituto de Química Médica C S I C, Juan de la Cierva 3, 28006 Madrid, Spain
    Antiviral Res 71:260-7. 2006
    ..This mini review summarizes some approaches that have been followed for the development of compounds that inhibit those three enzymes by interfering with the dimerization interfaces between the enzyme subunits...
  4. ncbi request reprint TSAO compounds: the comprehensive story of a unique family of HIV-1 specific inhibitors of reverse transcriptase
    Maria Jose Camarasa
    Instituto de Química Médica C S I C, Juan de la Cierva 3, 28006 Madrid, Spain
    Curr Top Med Chem 4:945-63. 2004
    ....
  5. ncbi request reprint Design and discovery of a novel dipeptidyl-peptidase IV (CD26)-based prodrug approach
    Carlos García-Aparicio
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 49:5339-51. 2006
    ..All conjugates have shown marked in vitro antiviral activities irrespective the the nature of the terminal and/or the penultimate amino acid moiety...
  6. ncbi request reprint N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors
    Ana Isabel Hernández
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 49:7766-73. 2006
    ....
  7. ncbi request reprint Novel [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2" -dioxide) derivatives with anti-HIV-1 and anti-human-cytomegalovirus activity
    Sonia de Castro
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 48:1158-68. 2005
    ..This has never been observed previously for TSAO derivatives. In particular, compound 26 represents the first TSAO derivative with dual anti-HIV-1 and -HCMV activity...
  8. ncbi request reprint Structure-activity relationship studies on a novel family of specific HIV-1 reverse transcriptase inhibitors
    Maria Cruz Bonache
    Instituto de Quimica Medica CSIC, Madrid, Spain
    Antivir Chem Chemother 14:249-62. 2003
    ..Our studies demonstrate that both the carboxymethyl moiety at the nucleobase and tert-butyldimethylsilyl groups at the sugar are important structural components since deletion of either of them is detrimental to the antiviral activity...
  9. ncbi request reprint Discovery of TSAO derivatives with an unusual HIV-1 activity/resistance profile
    Sonia de Castro
    Instituto de Química Médica C S I C, Juan de la Cierva 3, Madrid, Spain
    Antiviral Res 71:15-23. 2006
    ..The deaminated TSAO compound must fit differently in the HIV-1 RT enzyme than its prototype TSAO-m(3)T...
  10. ncbi request reprint Synthesis of 3' '-substituted TSAO derivatives with anti-HIV-1 and anti-HIV-2 activity through an efficient palladium-catalyzed cross-coupling approach
    Esther Lobatón
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 45:3934-45. 2002
    ....
  11. ncbi request reprint Improving the antiviral efficacy and selectivity of HIV-1 reverse transcriptase inhibitor TSAO-T by the introduction of functional groups at the N-3 position
    Maria Cruz Bonache
    Instituto de Química Médica C S I C, Madrid, Spain
    J Med Chem 48:6653-60. 2005
    ..On the other hand, the N-3 methylcarboxamide TSAO derivative 12 turned out to have the highest selectivity index yet reported for this class of compounds (around > or =12 000)...
  12. ncbi request reprint Unusual lability of 5'-O-tert-butyldimethylsilyl group on 4''-acyl TSAO derivatives
    Sonia de Castro
    Instituto de Química Médica C S I C, Madrid, Spain
    Nucleosides Nucleotides Nucleic Acids 22:959-61. 2003
  13. ncbi request reprint N-3 substituted TSAO derivatives as a probe to explore the dimeric interface of HIV-1 reverse transcriptase
    Maria Cruz Bonache
    Instituto de Química Médica C S I C, Madrid, Spain
    Nucleosides Nucleotides Nucleic Acids 22:947-9. 2003
  14. doi request reprint Intramolecular cation-pi interactions as the driving force to restrict the conformation of certain nucleosides
    Elena Casanova
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Org Chem 75:1974-81. 2010
    ..Thus the here described nucleosides can be considered as a new class of pH-dependent conformationally switchable molecules...
  15. ncbi request reprint Synthesis and evaluation of thymine-derived carboxamides against mitochondrial thymidine kinase (TK-2) and related enzymes
    Eva Maria Priego
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, E 28006 Madrid, Spain
    Bioorg Med Chem 12:5079-90. 2004
    ..From the new synthesized compounds, the N-trityl-6-(thymin-1-yl)hexanamide (IIIe) was the most active TK-2 inhibitor (IC(50)=19+/-2microM)...
  16. ncbi request reprint Acyclic nucleoside analogues as novel inhibitors of human mitochondrial thymidine kinase
    Ana Isabel Hernández
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    J Med Chem 45:4254-63. 2002
    ..They also proved to be inhibitory against HSV-1 TK in intact human osteosarcoma cells that were transduced with the HSV-1 TK gene...
  17. doi request reprint 4"-Benzoylureido-TSAO derivatives as potent and selective non-nucleoside HCMV inhibitors. Structure-activity relationship and mechanism of antiviral action
    Sonia de Castro
    Instituto de Quimica Medica CSIC, Juan de Cierva 3, E 28006 Madrid, Spain
    J Med Chem 51:5823-32. 2008
    ..Lack of cross-resistance against a broad variety of mutant HCMV strains points to an antiviral target that is different from those drugs that are currently approved for clinical use...
  18. ncbi request reprint Synthesis and structural characterization of pyrimidine bi- and tricyclic nucleosides with sugar puckers conformationally locked into the eastern region of the pseudorotational cycle
    Cristina Chamorro
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    J Org Chem 68:6695-704. 2003
    ..The bicyclic nucleosides described herein present an interesting potential for diverse and selective chemical treatments on the 2'-hydroxyl and/or the functionalities incorporated at the bridge between C-3' and C-5'...
  19. ncbi request reprint Improving the selectivity of acyclic nucleoside analogues as inhibitors of human mitochondrial thymidine kinase: replacement of a triphenylmethoxy moiety with substituted amines and carboxamides
    Ana Isabel Hernández
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, E 28006 Madrid, Spain
    Bioorg Med Chem Lett 13:3027-30. 2003
    ..A molecular model was built that can account for the observed selectivities...
  20. ncbi request reprint Synthesis of novel Bi-, Tri-, and tetracyclic nucleosides by reaction of a common cyclic enamine derived from TSAO-T with nucleophiles
    Maria Cruz Bonache
    Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    J Org Chem 69:8758-66. 2004
    ..Some of these polycyclic nucleosides may be useful intermediates for a second series of reactions that may lead to the generation of structurally new nucleosides...
  21. doi request reprint Dipeptidyl peptidase IV-activated prodrugs of anti-varicella zoster virus bicyclic nucleoside analogues containing different self-cleavage spacer systems
    Alberto Diez-Torrubia
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    ChemMedChem 7:1612-22. 2012
    ....
  22. ncbi request reprint Recent advances in thymidine kinase 2 (TK2) inhibitors and new perspectives for potential applications
    Eva Maria Priego
    Instituto de Química Médica C S I C, c Juan de la Cierva, 3, E 28006 Madrid, Spain
    Curr Pharm Des 18:2981-94. 2012
    ..Moreover, the last section will be focused on several recent investigations that suggest that depletion of mtDNA can take place both in tumorigenesis and during cancer treatment with certain nucleoside analogues...
  23. doi request reprint Dipeptidyl peptidase IV (DPPIV/CD26)-based prodrugs of hydroxy-containing drugs
    Alberto Diez-Torrubia
    Instituto de Química Médica C S I C, Juan de la Cierva 3, 28006 Madrid, Spain
    ChemMedChem 7:618-28. 2012
    ..In contrast, a tertiary hydroxy group was much less susceptible to conversion into its parent drug by DPPIV/CD26 or serum. A number of the prodrugs showed remarkable increases in water solubility relative to their parent drugs...
  24. ncbi request reprint Novel non-nucleoside human cytomegalovirus inhibitors based upon TSAO nucleoside derivatives: structure-activity relationships
    Sonia de Castro
    Instituto de Quimica Medica CSIC, Madrid, Spain
    Nucleosides Nucleotides Nucleic Acids 26:625-8. 2007
    ..Interestingly, these studies revealed that the compounds may inhibit HCMV at the DNA polymerase step via a non-nucleoside mechanism...
  25. ncbi request reprint A cyclic enamine derived from 1,2-O-isopropylidene-alpha-D-xylofuranose as a novel carbohydrate intermediate to achieve skeletal diversity
    Alessandra Cordeiro
    Instituto de Química Médica C S I C, Juan de la Cierva 3, 28006 Madrid, Spain
    J Org Chem 71:7224-35. 2006
    ..The constrained structures and dense functionalization of the polycyclic sugar derivatives generated from 8 make these compounds promising candidates for use as starting agents for the production of new analogues and as drugs...
  26. doi request reprint Efficient synthesis and anti-enteroviral activity of 9-arylpurines
    Leire Aguado
    Instituto de Química Médica IQM CSIC, Madrid, Spain
    Eur J Med Chem 49:279-88. 2012
    ..The cross-resistance studies performed with different 9-aryl-6-chloropurines indicate that they all belong to the same pharmacological family and differ from other CVB3 drugs such as enviroxime...
  27. doi request reprint Design, synthesis and inhibitory activity against Mycobacterium tuberculosis thymidine monophosphate kinase of acyclic nucleoside analogues with a distal imidazoquinolinone
    Olga Familiar
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, E 28006 Madrid, Spain
    Eur J Med Chem 45:5910-8. 2010
    ....
  28. doi request reprint From β-amino-γ-sultone to unusual bicyclic pyridine and pyrazine heterocyclic systems: synthesis and cytostatic and antiviral activities
    Sonia de Castro
    Instituto de Química Médica C S I C, Juan de la Cierva 3, 28006 Madrid, Spain
    ChemMedChem 6:686-97. 2011
    ..Compounds 3 a, 15 a, and 21 a inhibited HIV-1-induced cytopathicity. Compound 7 showed remarkable cytostatic activity, and can be regarded as a potential antitumor candidate for further exploration...
  29. doi request reprint Application of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to different amine-containing drugs
    Alberto Diez-Torrubia
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 53:559-72. 2010
    ..This DPPIV/CD26-directed prodrug technology can be useful to increase solubility of the parent drug molecules and/or to allow better formulation properties...
  30. doi request reprint 9-Arylpurines as a novel class of enterovirus inhibitors
    Leire Aguado
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 53:316-24. 2010
    ..No toxicity on different cell lines was observed at concentrations up to 250 microM. Moreover, no cross-resistance to TBZE-029 and TTP-8307 CVB3 resistant strains was detected...
  31. doi request reprint Novel N-3 substituted TSAO-T derivatives: synthesis and anti-HIV-evaluation
    Maria Cruz Bonache
    Instituto de Química Médica C S I C, Madrid, Spain
    Nucleosides Nucleotides Nucleic Acids 27:351-67. 2008
    ..These compounds have been useful to study how the conformational restriction of the linker affects in the interaction between the N-3 substituent and the HIV-1 RT enzyme...
  32. ncbi request reprint Unprecedented lability of the 5'-O-tert-butyldimethylsilyl group from 3'-spiro-5''-(4''-acylamino-1'',2''-oxathiole-2'',2''-dioxide) nucleoside derivatives via neighboring group participation of the 4''-acylamino residue
    Sonia de Castro
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Org Chem 71:1407-15. 2006
    ..A silyl hydrolysis mechanism involving neighboring group participation of the 4' '-acylamino group is proposed...
  33. ncbi request reprint Hybrids of [TSAO-T]-[foscarnet]: The first conjugate of foscarnet with a non-nucleoside reverse transcriptase inhibitor through a labile covalent ester bond
    Sonsoles Velazquez
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 47:3418-26. 2004
    ..Moreover, stability studies of the [TSAO-T]-[PFA] conjugates demonstrated that the compounds were stable in PBS whereas some of the conjugates regenerated the parent inhibitors in extracts from CEM cells...
  34. ncbi request reprint 5'-O-tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase
    Elena Casanova
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 49:5562-70. 2006
    ..The here reported results further substantiate that 5'-O-trityl nucleosides represent a new class of TPase inhibitors that should be further explored in those biological systems where TPase plays an instrumental role (i.e. angiogenesis)...
  35. ncbi request reprint Mitochondrial thymidine kinase inhibitors
    María Jesús Pérez-Pérez
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, E 28006 Madrid, Spain
    Curr Top Med Chem 5:1205-19. 2005
    ....
  36. ncbi request reprint Role of histidine-85 in the catalytic mechanism of thymidine phosphorylase as assessed by targeted molecular dynamics simulations and quantum mechanical calculations
    Jesús Mendieta
    Departamento de Farmacologia, Universidad de Alcala, E 28871 Alcala de Henares, Madrid, Spain, Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    Biochemistry 43:405-14. 2004
    ..These results highlight a previously unreported role for His-85 in the catalytic mechanism of TPase and can have important implications for the design of novel TPase inhibitors...
  37. doi request reprint Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides
    Maria Cruz Bonache
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    Antiviral Res 92:37-44. 2011
    ..The tricyclic nucleosides here described represent a novel type of selective anti HIV-1 inhibitors, targeted at the HIV-1-encoded reverse transcriptase...
  38. doi request reprint One-pot synthesis of polycyclic nucleosides with unusual molecular skeletons
    Maria Cruz Bonache
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    J Org Chem 74:9071-81. 2009
    ..The scope of the reaction is briefly studied concluding that the nature of the ketone (R(1)COR(2)) is critical for the initial attack of the NH to the carbonyl group...
  39. ncbi request reprint Thymidine phosphorylase inhibitors: recent developments and potential therapeutic applications
    María Jesús Pérez-Pérez
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, E 28006 Madrid, Spain
    Mini Rev Med Chem 5:1113-23. 2005
    ..Here we have summarized the most recent approaches in the search for novel TPase inhibitors together with the potential therapeutic applications of such inhibitors...
  40. ncbi request reprint Efficient conversion of tetrapeptide-based TSAO prodrugs to the parent drug by dipeptidyl-peptidase IV (DPPIV/CD26)
    Carlos García-Aparicio
    Instituto de Química Médica C S I C, Juan de la Cierva 3, E 28006 Madrid, Spain
    Antiviral Res 76:130-9. 2007
    ..The antiviral activity of the prototype NAP-TSAO could also be modulated by introducing different tetrapeptide moieties on the molecule resulting, in some cases, in a superior antiviral potential in cell culture than the parent drug...
  41. ncbi request reprint 7,5'-O-dibenzylinosines: synthesis and studies on their conformational properties
    Elena Casanova
    Instituto de Quimica Medica CSIC, Madrid, Spain
    Nucleosides Nucleotides Nucleic Acids 26:695-9. 2007
    ....
  42. ncbi request reprint Synthesis of highly condensed polycyclic carbohydrates by reaction of a spirocyclic enamino sulfonate derived from d-xylofuranose with bifunctional reagents
    Alessandra Cordeiro
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    J Org Chem 72:9713-21. 2007
    ..X-ray diffraction analysis and intensive NMR studies with one of these carbohydrates were performed to highlight the strained nature of these compounds...
  43. doi request reprint Targeting HIV entry through interaction with envelope glycoprotein 120 (gp120): synthesis and antiviral evaluation of 1,3,5-triazines with aromatic amino acids
    Virginia Lozano
    Instituto de Química Médica IQM CSIC, Madrid, Spain
    J Med Chem 54:5335-48. 2011
    ..The collected data support the interest of this novel family of anti-HIV agents and qualify them as potential novel microbicide lead compounds...
  44. ncbi request reprint Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A(3) adenosine receptor antagonists
    Eva Maria Priego
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    J Med Chem 45:3337-44. 2002
    ..Because xanthine derivatives have traditionally been considered poor A(3) antagonists, the described pyrido[2,1-f]purine-2,4-dione derivatives represent a new family of adenosine receptor antagonists which deserves further exploration...
  45. doi request reprint Probing the dimerization interface of Leishmania infantum trypanothione reductase with site-directed mutagenesis and short peptides
    Miguel A Toro
    Departamento de Biología de Sistemas, Unidad Asociada de I D I al CSIC, Universidad de Alcala, 28871 Alcala de Henares, Madrid, Spain
    Chembiochem 14:1212-7. 2013
    ..Replacement of a glutamic acid residue with a lysine promoted monomer dissociation and enzyme inhibition. ..
  46. doi request reprint 5'-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target
    Elena Casanova
    Instituto de Química Médica IQM CSIC, Juan de la Cierva 3, 28006, Madrid Spain
    ChemMedChem 8:1161-74. 2013
    ..Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds. ..
  47. doi request reprint Exploring acyclic nucleoside analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase
    Olga Familiar
    Instituto de Quimica Medica CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
    ChemMedChem 3:1083-93. 2008
    ..The fact that these inhibitors are more easily synthesizable than previously identified TMPKmt inhibitors, together with their potency against the target enzyme, makes them attractive lead compounds for further optimization...
  48. doi request reprint 4-Benzyloxy-gamma-sultone derivatives: discovery of a novel family of non-nucleoside inhibitors of human cytomegalovirus and varicella zoster virus
    Sonia de Castro
    Instituto de Quimica Medica CSIC, C Juan de la Cierva 3, E 28006 Madrid, Spain
    J Med Chem 52:1582-91. 2009
    ..The novel compounds do not show cross-resistance against a wide variety of mutant drug-resistant HCMV strains, pointing to a novel mechanism of antiviral action...