John A Hartley

Summary

Affiliation: University College London
Country: UK

Publications

  1. pmc Evidence for different mechanisms of 'unhooking' for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples
    Victoria J Spanswick
    CR UK Drug DNA Interactions Research Group, UCL Cancer Institute, London, WC1E 6BT, UK
    BMC Cancer 12:436. 2012
  2. pmc Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses
    D Alan Anthoney
    St James Institute of Oncology, University of Leeds and Leeds Teaching Hospitals Trust, Leeds LS9 7TF, United Kingdom
    BMC Cancer 12:536. 2012
  3. doi request reprint Small molecule drugs - optimizing DNA damaging agent-based therapeutics
    John A Hartley
    Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, London WC1E 6BT, UK
    Curr Opin Pharmacol 12:398-402. 2012
  4. doi request reprint DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057
    John A Hartley
    Spirogen Ltd, UCL Cancer Institute, Paul O Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
    Invest New Drugs 30:950-8. 2012
  5. pmc SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug that cross-links DNA and exerts highly potent antitumor activity
    John A Hartley
    Spirogen Ltd, UCL Cancer Institute, UK
    Cancer Res 70:6849-58. 2010
  6. ncbi request reprint SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity
    John A Hartley
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, London, United Kingdom
    Cancer Res 64:6693-9. 2004
  7. doi request reprint The development of pyrrolobenzodiazepines as antitumour agents
    John A Hartley
    UCL Cancer Institute, 72 Huntley St, London, WC1E 6BT, UK
    Expert Opin Investig Drugs 20:733-44. 2011
  8. pmc The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136
    Peter H Clingen
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, UCL 91 Riding House Street, London, W1W 7BS, UK
    Nucleic Acids Res 33:3283-91. 2005
  9. doi request reprint Synthesis of a novel C2/C2'-aryl-substituted pyrrolo[2,1-c][1,4]benzodiazepine dimer prodrug with improved water solubility and reduced DNA reaction rate
    Philip W Howard
    Spirogen Ltd, The School of Pharmacy, 29 39 Brunswick Square, London WC1N1AX, UK
    Bioorg Med Chem Lett 19:6463-6. 2009
  10. doi request reprint An asymmetric C8/C8'-tripyrrole-linked sequence-selective pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer DNA interstrand cross-linking agent spanning 11 DNA base pairs
    Arnaud C Tiberghien
    Spirogen Ltd, 29 39 Brunswick Square, London WC1N 1AX, UK
    Bioorg Med Chem Lett 18:2073-7. 2008

Collaborators

Detail Information

Publications82

  1. pmc Evidence for different mechanisms of 'unhooking' for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples
    Victoria J Spanswick
    CR UK Drug DNA Interactions Research Group, UCL Cancer Institute, London, WC1E 6BT, UK
    BMC Cancer 12:436. 2012
    ..Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the 'unhooking' step is common to all ICLs...
  2. pmc Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses
    D Alan Anthoney
    St James Institute of Oncology, University of Leeds and Leeds Teaching Hospitals Trust, Leeds LS9 7TF, United Kingdom
    BMC Cancer 12:536. 2012
    ..A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011...
  3. doi request reprint Small molecule drugs - optimizing DNA damaging agent-based therapeutics
    John A Hartley
    Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, London WC1E 6BT, UK
    Curr Opin Pharmacol 12:398-402. 2012
    ..Understanding the mechanistic basis for interactions of these novel targeted agents with DNA-interactive drugs will inform design of optimal combinations for future studies and is critical to maximize benefit in the clinic...
  4. doi request reprint DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057
    John A Hartley
    Spirogen Ltd, UCL Cancer Institute, Paul O Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
    Invest New Drugs 30:950-8. 2012
    ..SG2057 is therefore a highly active antitumor agent, with more potent in vitro activity and superior in vivo activity to SG2000, warranting further development...
  5. pmc SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug that cross-links DNA and exerts highly potent antitumor activity
    John A Hartley
    Spirogen Ltd, UCL Cancer Institute, UK
    Cancer Res 70:6849-58. 2010
    ..Our findings define SG2285 as a highly active cytotoxic compound with antitumor properties desirable for further development...
  6. ncbi request reprint SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity
    John A Hartley
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, London, United Kingdom
    Cancer Res 64:6693-9. 2004
    ..v. administration. The level of cross-linking persists over a 24-hour period in this tumor in contrast to cross-links produced by conventional cross-linking agents observed over the same time period...
  7. doi request reprint The development of pyrrolobenzodiazepines as antitumour agents
    John A Hartley
    UCL Cancer Institute, 72 Huntley St, London, WC1E 6BT, UK
    Expert Opin Investig Drugs 20:733-44. 2011
    ..The search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues...
  8. pmc The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136
    Peter H Clingen
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, UCL 91 Riding House Street, London, W1W 7BS, UK
    Nucleic Acids Res 33:3283-91. 2005
    ..SJG-136 cytotoxicity is likely to result from the poor recognition of DNA damage by repair proteins resulting in the slow repair of both mono-adducts and more importantly crosslinks in the minor groove...
  9. doi request reprint Synthesis of a novel C2/C2'-aryl-substituted pyrrolo[2,1-c][1,4]benzodiazepine dimer prodrug with improved water solubility and reduced DNA reaction rate
    Philip W Howard
    Spirogen Ltd, The School of Pharmacy, 29 39 Brunswick Square, London WC1N1AX, UK
    Bioorg Med Chem Lett 19:6463-6. 2009
    ..The prodrug form is highly water soluble, stable in aqueous conditions, and the rate of DNA cross-link formation is much slower compared to the parent bis-imine...
  10. doi request reprint An asymmetric C8/C8'-tripyrrole-linked sequence-selective pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer DNA interstrand cross-linking agent spanning 11 DNA base pairs
    Arnaud C Tiberghien
    Spirogen Ltd, 29 39 Brunswick Square, London WC1N 1AX, UK
    Bioorg Med Chem Lett 18:2073-7. 2008
    ....
  11. doi request reprint Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78
    Minal Kotecha
    Cancer Research UK Drug DNA Interac Research Group, UCL Cancer Institute, University College London, London, United Kingdom
    Mol Cancer Ther 7:1319-28. 2008
    ..Treatment of NIH3T3 cells with GWL-78 resulted in a block of cell cycle progression, which did not involve activation of p53. Thus, agents such as GWL-78 may be useful in modulating transcription and blocking cellular proliferation...
  12. ncbi request reprint DNA sequence selective adenine alkylation, mechanism of adduct repair, and in vivo antitumor activity of the novel achiral seco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145
    Konstantinos Kiakos
    Cancer Research Drug DNA Interactions Research Group, Department of Oncology, University College London, London, United Kingdom
    Mol Cancer Ther 6:2708-18. 2007
    ..v. or p.o. Its novel structure and in vivo activity renders AS-I-145 a new paradigm in the design of novel achiral analogues of CC-1065 and the duocarmycins...
  13. doi request reprint γ-H2AX foci formation as a pharmacodynamic marker of DNA damage produced by DNA cross-linking agents: results from 2 phase I clinical trials of SJG-136 (SG2000)
    Jenny Wu
    CR UK Drug DNA Interactions Research Group, UCL Cancer Institute, Paul O Gorman Building, Huntley Street, London, United Kingdom
    Clin Cancer Res 19:721-30. 2013
    ..To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand cross-linking drugs...
  14. pmc Characterization of the human SNM1A and SNM1B/Apollo DNA repair exonucleases
    Blanka Sengerová
    Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
    J Biol Chem 287:26254-67. 2012
    ..Together, our work establishes differences in the substrate selectivities of SNM1A and SNM1B that are likely to be relevant to their in vivo roles and which might be exploited in the development of selective inhibitors...
  15. ncbi request reprint Human SNM1A suppresses the DNA repair defects of yeast pso2 mutants
    Ali Hazrati
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, UCL Medical School, London, UK
    DNA Repair (Amst) 7:230-8. 2008
    ..Finally, we show that recombinant hSNM1A is a 5'-exonuclease, as also recently reported for the yeast Pso2 protein. Together our data suggest that hSnm1A is a functional homologue of yeast Pso2/Snm1...
  16. doi request reprint Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents
    Julien J M Boone
    Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK
    Mol Cancer Ther 8:3015-23. 2009
    ..Understanding the mechanisms of interaction between DNA-interacting agents and HER2 inhibitors will inform the design of clinical trials and optimize the therapeutic effects of these combinations...
  17. ncbi request reprint Sequence recognition in the minor groove of DNA by covalently linked formamido imidazole-pyrrole-imidazole polyamides: effect of H-pin linkage and linker length on selectivity and affinity
    Peter Uthe
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, University College London, 91 Riding House Street, London W1W 7BS, United Kingdom
    Biochemistry 46:11661-70. 2007
    ..This study demonstrates that the high-affinity cooperative binding of f-ImPyIm can be enhanced significantly by suitable covalent linkage, while maintaining its strict cognate site selectivity...
  18. ncbi request reprint Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma
    Victoria J Spanswick
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, London, United Kingdom
    Blood 100:224-9. 2002
    ..These findings suggest that ICL repair may be an important mechanism by which melphalan resistance emerges after autologous SCT or oral therapy. This mechanism may have implications for MM patients undergoing melphalan therapy...
  19. pmc Defects in interstrand cross-link uncoupling do not account for the extreme sensitivity of ERCC1 and XPF cells to cisplatin
    Inusha U De Silva
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, 91 Riding House Street, London W1W 7BS, UK
    Nucleic Acids Res 30:3848-56. 2002
    ..Surprisingly, XRCC2 and XRCC3 cells are defective in the uncoupling step of cisplatin interstrand cross-link repair, suggesting that homologous recombination might be initiated prior to excision of this type of cross-link...
  20. doi request reprint Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors
    Daniel Hochhauser
    Drug Development Office, Cancer Research UK, Cancer Research UK Drug DNA Interactions Research Group, and University College London Cancer Institute, London, United Kingdom
    Clin Cancer Res 15:2140-7. 2009
    ..The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data...
  21. ncbi request reprint Modulation of DNA repair in vitro after treatment with chemotherapeutic agents by the epidermal growth factor receptor inhibitor gefitinib (ZD1839)
    Benjamin Friedmann
    Department of Oncology, Royal Free and University College Medical School, University College London, London, United Kingdom
    Clin Cancer Res 10:6476-86. 2004
    ..We investigated mechanisms for this modulation...
  22. doi request reprint Measurement of DNA interstrand crosslinking in individual cells using the Single Cell Gel Electrophoresis (Comet) assay
    Victoria J Spanswick
    Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, University College London, Paul O Gorman Building, London, UK
    Methods Mol Biol 613:267-82. 2010
    ..The method has also become invaluable in studies using human tissue and can be used as a method for pharmacodynamic analysis in early clinical trials...
  23. ncbi request reprint Chemosensitivity of primary human fibroblasts with defective unhooking of DNA interstrand cross-links
    Peter H Clingen
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, 91 Riding House Street, London, W1W 7BS, UK
    Exp Cell Res 313:753-60. 2007
    ..Since cellular sensitivity of primary human fibroblasts usually reflects clinical sensitivity such patients with cancer would be at risk of increased toxicity...
  24. doi request reprint Novel C8-linked pyrrolobenzodiazepine (PBD)-heterocycle conjugates that recognize DNA sequences containing an inverted CCAAT box
    Federico Brucoli
    The School of Pharmacy, University of London, London, UK
    Bioorg Med Chem Lett 21:3780-3. 2011
    ..One conjugate (2d) has a greater selectivity and DNA binding affinity for inverted CCAAT sequences within the Topoisomerase IIα promoter than the known C8-bis-pyrrole PBD conjugate GWL-78 (1b)...
  25. doi request reprint Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer
    Jonathan A Ledermann
    UCL Hospitals, UCL Cancer Institute, London, United Kingdom
    Clin Cancer Res 16:4899-905. 2010
    ..Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair...
  26. ncbi request reprint Saccharomyces cerevisiae RAD5 influences the excision repair of DNA minor groove adducts
    Konstantinos Kiakos
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, University College London, 91 Riding House Street, United Kingdom
    J Biol Chem 277:44576-81. 2002
    ..Our results indicate that the RAD5 subpathway may interact with NER factors during the repair of certain DNA adducts...
  27. doi request reprint Measurement of DNA damage in individual cells using the Single Cell Gel Electrophoresis (Comet) assay
    Janet M Hartley
    Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK
    Methods Mol Biol 731:309-20. 2011
    ..It can be further adapted to, for example, study specific DNA repair mechanisms, be combined with fluorescent in situ hybridisation, or incorporate lesion specific enzymes...
  28. pmc EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment
    Gianmaria Liccardi
    Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, University College London, London, United Kingdom
    Cancer Res 71:1103-14. 2011
    ..Our findings show that EGFR subcellular distribution can modulate DNA repair kinetics, with implications for design of EGFR-targeted combinational therapies...
  29. ncbi request reprint Modulation of topoisomerase IIalpha expression by a DNA sequence-specific polyamide
    Daniel Hochhauser
    Department of Oncology, Royal Free and University College Medical School, University College London, 91 Riding House Street, London W1W 7BS, United Kingdom
    Mol Cancer Ther 6:346-54. 2007
    ..This correlated both with increased DNA double-strand breaks as shown by comet assay and decreased cell viability following exposure to etoposide. Polyamides can modulate gene expression and chemosensitivity of cancer cells...
  30. ncbi request reprint Regulation of DNA repair gene expression in human cancer cell lines
    Claire J McGurk
    Prostate Cancer Research Centre, Institute of Urology, UCL, 3rd Floor Research Laboratories, London, W1W 7EJ, United Kingdom
    J Cell Biochem 97:1121-36. 2006
    ..Taken together, these results suggest that constitutive levels of these DNA repair proteins are controlled at the level of translation...
  31. doi request reprint Measurement of DNA interstrand crosslinking in naked DNA using gel-based methods
    Konstantinos Kiakos
    Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, University College London, Paul O Gorman Building, London, UK
    Methods Mol Biol 613:283-302. 2010
    ....
  32. ncbi request reprint Assessment of the significance of mitochondrial DNA damage by chemotherapeutic agents
    Soo Lo
    Department of Oncology, Royal Free and University College Medical School, University College London, London W1P 8BT, UK
    Int J Oncol 27:337-44. 2005
    ..Mitochondrial DNA is a critical target for MKT-077 and daunorubicin, and is a potential target for novel chemotherapeutic agents...
  33. pmc A 96-well DNase I footprinting screen for drug-DNA interactions
    Tom Ellis
    Spirogen Ltd, London Bioscience Innovation Centre, London, UK
    Nucleic Acids Res 35:e89. 2007
    ..The dramatic increase in throughput, quantified data and decreased handling time allow, for the first time, DNase I footprinting to be used as a screening tool to assess DNA-binding agents...
  34. pmc DNA interstrand cross-link repair in the Saccharomyces cerevisiae cell cycle: overlapping roles for PSO2 (SNM1) with MutS factors and EXO1 during S phase
    Louise J Barber
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, University College London, London
    Mol Cell Biol 25:2297-309. 2005
    ..These findings have led to considerable clarification of the complex genetic relationship between various ICL repair pathways...
  35. doi request reprint Evodiamine, a dual catalytic inhibitor of type I and II topoisomerases, exhibits enhanced inhibition against camptothecin resistant cells
    Xiaobei Pan
    Institute for Health Research and Policy, London Metropolitan University, London, UK
    Phytomedicine 19:618-24. 2012
    ..74 and 78.81 μM, respectively. The improved toxicity towards camptothecin resistant cells further supports its inhibitory mechanism which is different from camptothecin, and its therapeutic potential...
  36. ncbi request reprint Sequence-selective recognition of duplex DNA through covalent interstrand cross-linking: kinetic and molecular modeling studies with pyrrolobenzodiazepine dimers
    Melissa Smellie
    Cancer Research UK Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, UCL, 91 Riding House Street, London W1W 7BS, UK
    Biochemistry 42:8232-9. 2003
    ..Molecular modeling confirms the order of cross-linking reactivity, and highlights the role of linker length in dictating sequence recognition for this class of DNA-reactive agent...
  37. ncbi request reprint A phase I study of single administration of antibody-directed enzyme prodrug therapy with the recombinant anti-carcinoembryonic antigen antibody-enzyme fusion protein MFECP1 and a bis-iodo phenol mustard prodrug
    Astrid Mayer
    Department of Oncology, Hampstead Campus, University College London, UK
    Clin Cancer Res 12:6509-16. 2006
    ..MFECP1 is manufactured in mannosylated form to facilitate normal tissue elimination...
  38. doi request reprint Antibody-drug conjugates - a perfect synergy
    John R Adair
    UCL Cancer Institute, Spirogen Ltd, Paul O Gorman Building, London, UK
    Expert Opin Biol Ther 12:1191-206. 2012
    ..There is increasing interest in ADCs by major pharmaceutical companies and a growing pipeline of candidates for clinical use. This review summarises progress with development of this new class of drugs...
  39. doi request reprint Circulating tumor cells as prognostic markers in neuroendocrine tumors
    Mohid S Khan
    University College London UCL Cancer Institute, London, United Kingdom
    J Clin Oncol 31:365-72. 2013
    ..To determine the prognostic significance of circulating tumor cells (CTCs) in patients with neuroendocrine cancer...
  40. pmc DNA sequence recognition in the minor groove by crosslinked polyamides: The effect of N-terminal head group and linker length on binding affinity and specificity
    C Caroline O'Hare
    Cancer Research Campaign Drug DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, UCL, 91 Riding House Street, London, W1W 7BS, United Kingdom
    Proc Natl Acad Sci U S A 99:72-7. 2002
    ..Moreover, the leading head group and methylene linker length significantly influences the binding characteristics of crosslinked polyamides...
  41. pmc Schizosaccharomyces pombe checkpoint response to DNA interstrand cross-links
    Sarah Lambert
    Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom
    Mol Cell Biol 23:4728-37. 2003
    ..Disruption of cds1 confers increased resistance to ICLs, suggesting that this second-cycle S-phase arrest might be a lethal event...
  42. ncbi request reprint Synthesis of novel DNA cross-linking antitumour agents based on polyazamacrocycles
    Laurie L Parker
    Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
    Bioorg Med Chem 13:2389-95. 2005
    ..In particular the cyclen derivative 2a was more than 10(4) times more effective at cross-linking DNA (2a XL(50)<<10nM) than chlorambucil (XL(50) 100microM), and showed significant cytotoxicity in human tumour cells in vitro...
  43. ncbi request reprint Novel furano analogues of duocarmycin C1 and C2: design, synthesis, and biological evaluation of seco-iso-cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco-cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) analogues
    Tiffany T Howard
    Department of Chemistry, Furman University, Greenville, SC 29613, USA
    Bioorg Med Chem 10:2941-52. 2002
    ....
  44. ncbi request reprint Targeting the inverted CCAAT Box-2 of the topoisomerase IIalpha gene: DNA sequence selective recognition by a polyamide-intercalator as a staggered dimer
    Hilary Mackay
    Department of Chemistry, Furman University, Greenville, SC 29613, USA
    Bioorg Med Chem 16:2093-102. 2008
    ..These results suggest that the conjugate can enter the nucleus, bind to its target site, presumably as a stacked dimer, and up-regulate the expression of topoIIalpha by blocking the binding of NF-Y...
  45. ncbi request reprint Design, synthesis, and biological evaluation of achiral analogs of duocarmycin SA
    Kristen Daniell
    Department of Chemistry, Furman University, Greenville, SC 29613, USA
    Bioorg Med Chem Lett 15:177-80. 2005
    ....
  46. ncbi request reprint A novel class of achiral seco-analogs of CC-1065 and the duocarmycins: design, synthesis, DNA binding, and anticancer properties
    Stanley Kupchinsky
    Department of Chemistry, Furman University, 3300 Poinsett Highway, Greenville, SC 29613, USA
    Bioorg Med Chem 12:6221-36. 2004
    ..Furthermore, compound 5c was not toxic to murine bone marrow cell growth in culture, at a dose that was toxic for the previously reported seco-CBI (cyclopropylbenzoindoline)-TMI (4)...
  47. ncbi request reprint Linker length modulates DNA cross-linking reactivity and cytotoxic potency of C8/C8' ether-linked C2-exo-unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers
    Stephen J Gregson
    Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, 29 39 Brunswick Square, London WC1N 1AX, UK
    J Med Chem 47:1161-74. 2004
    ..A novel synthesis of core synthetic building blocks for PBD dimers via stepwise Mitsunobu reaction and nitration with Cu(NO3)2 is also reported...
  48. doi request reprint Fluorescent 7-diethylaminocoumarin pyrrolobenzodiazepine conjugates: synthesis, DNA interaction, cytotoxicity and differential cellular localization
    Geoffrey Wells
    Cancer Research UK Gene Targeted Drug Design Research Group, School of Pharmacy, University of London, 29 39 Brunswick Square, London WC1N 1AX, UK
    Bioorg Med Chem Lett 18:2147-51. 2008
    ..The results show that the linker structure plays a critical role for all three parameters...
  49. ncbi request reprint Targeting the inverted CCAAT box 2 in the topoisomerase IIalpha promoter by JH-37, an imidazole-pyrrole polyamide hairpin: design, synthesis, molecular biology, and biophysical studies
    James A Henry
    Department of Chemistry, Furman University, Greenville, South Carolina 29613, USA
    Biochemistry 43:12249-57. 2004
    ..This approach is in contrast to the traditional strategy of targeting 15-16 base pairs, which has not been successful in actual biological systems due to poor cell uptake and distribution...
  50. ncbi request reprint SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 2: efficacy evaluations
    Michael C Alley
    Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda and Frederick, Maryland 21701 8527, USA
    Cancer Res 64:6700-6. 2004
    ....
  51. ncbi request reprint Cinnamoyl nitrogen mustard derivatives of pyrazole analogues of tallimustine modified at the amidino moiety: design, synthesis, molecular modeling and antitumor activity studies
    Pier Giovanni Baraldi
    Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, 44100 Ferrara, Italy
    Bioorg Med Chem 12:3911-21. 2004
    ..Our preliminary results indicated that the compounds of this series have a pattern of alkylation similar to that of tallimustine, but they seem to be less reactive overall in alkylating naked DNA...
  52. ncbi request reprint Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A
    Pier Giovanni Baraldi
    Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, 44100 Ferrara, Italy
    J Med Chem 45:3630-8. 2002
    ....
  53. ncbi request reprint Synthesis and biological evaluation of novel chloroethylaminoanthraquinones with potent cytotoxic activity against cisplatin-resistant tumor cells
    Klaus Pors
    Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, 29 39 Brunswick Square, University of London, London WC1N 1AX, UK
    J Med Chem 47:1856-9. 2004
    ..All the 1,4-disubstituted chloroethylaminoanthraquinones were potently cytotoxic (nM IC(50)s) against cisplatin-resistant ovarian cancer cell lines...
  54. pmc Energetic basis for selective recognition of T*G mismatched base pairs in DNA by imidazole-rich polyamides
    Eilyn R Lacy
    Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
    Nucleic Acids Res 32:2000-7. 2004
    ..DNase I footprinting analysis in a long DNA sequence provided supporting evidence that f-ImImIm binds selectively to T.G mismatch sites...
  55. ncbi request reprint Novel nitrogen mustard-armed combi-molecules for the selective targeting of epidermal growth factor receptor overexperessing solid tumors: discovery of an unusual structure-activity relationship
    Zakaria Rachid
    Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center Royal Victoria Hospital, Montreal, H3A 1A1, Quebec, Canada
    J Med Chem 50:2605-8. 2007
    ..Combi-molecule 6a blocked EGFR phosphorylation in an irreversible manner, induced DNA-cross-links, and arrested the cells in mid-S...
  56. ncbi request reprint Sequence specific recognition of DNA by tailor-made hairpin conjugates of achiral seco-cyclopropaneindoline-2-benzofurancarboxamide and pyrrole-imidazole polyamides
    Carly A Price
    Department of Chemistry, Furman University, Greenville, SC 29613, United States
    Bioorg Med Chem Lett 15:3151-6. 2005
    ..Models for the binding of hairpin conjugates 1-3 with sequences 5'-TCA(888)G-3', 5'-CAA(857)C-3', and 5'-TTA(843)C-3' are proposed...
  57. ncbi request reprint A novel achiral seco-amino-cyclopropylindoline (CI) analog of CC-1065 and the duocarmycins: design, synthesis and biological studies
    James L Toth
    Department of Chemistry, Furman University, 3300 Poinsett Highway, Greenville, SC 29613, USA
    Med Chem 1:13-9. 2005
    ..The novel aminophenethyl halide moiety is, therefore, a useful template from which to develop future achiral analogs of CC-1065 and the duocarmycins...
  58. ncbi request reprint Novel (S)-(-)- and R-(+)-seco-iso-cyclopropylfurano[e]indoline-5,6,7-trimethoxyindole-2-carboxamide (iso-CFI) analogs of duocarmycin C2: synthesis and biological evaluation
    Bethany Purnell
    Department of Chemistry, Furman University, Greenville, SC 29613, USA
    Med Chem 2:139-46. 2006
    ..The natural (S)-(-)-enantiomer of 1 is more reactive with DNA and more cytotoxic than its unnatural mirror image and the racemic mixture...
  59. ncbi request reprint Interaction of the epidermal growth factor receptor and the DNA-dependent protein kinase pathway following gefitinib treatment
    Benjamin J Friedmann
    Cancer Research UK Drug DNA Interactions Research Group, Royal Free and University College Medical School, University College London
    Mol Cancer Ther 5:209-18. 2006
    ..This is correlated with decreased function of DNA-PK(CS). Inhibition of DNA-PK(CS) may be an important factor in sensitization to chemotherapy and radiation following treatment with inhibitors of the EGFR pathway...
  60. ncbi request reprint Design, synthesis, and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates
    Geoff Wells
    Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, 29 39 Brunswick Square, London WC1N 1AX, UK
    J Med Chem 49:5442-61. 2006
    ..50a-f were shown to have good cellular/nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed...
  61. ncbi request reprint Azinomycin inspired bisepoxides: influence of linker structure on in vitro cytotoxicity and DNA interstrand cross-linking
    Rachel C LePla
    Department of Chemistry, University of Warwick, Coventry, UK
    Bioorg Med Chem Lett 15:2861-4. 2005
    ..The incorporation of an aminomethyl group into the linker between the two alkylating epoxide units is shown to significantly enhance in vitro cytotoxicity against human tumour cell lines and DNA interstand cross-linking efficiency...
  62. ncbi request reprint Synthesis and biological evaluation of novel pyrrolo[2,1-c][1,4]benzodiazepine prodrugs for use in antibody-directed enzyme prodrug therapy
    Luke A Masterson
    CR UK Gene Targeting Drug Design Research Group, School of Pharmacy, University of London, 29 39 Brunswick Square, London WC1 1AX, UK
    Bioorg Med Chem Lett 16:252-6. 2006
    ....
  63. ncbi request reprint Design of a hairpin polyamide, ZT65B, for targeting the inverted CCAAT box (ICB) site in the multidrug resistant (MDR1) gene
    Karen L Buchmueller
    Department of Chemistry, Furman University, Greenville, SC 29613, USA
    Chembiochem 6:2305-11. 2005
    ..These can be used to specifically target the subset of ubiquitous gene elements known as ICBs, and thereby affect the expression of one or a few proteins...
  64. ncbi request reprint Design and synthesis of a DNA-crosslinking azinomycin analogue
    Maxwell A Casely-Hayford
    Dept of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, 29 39 Brunswick Square, London, UK WC1N 1AX
    Org Biomol Chem 3:3585-9. 2005
    ..These observations will be important in the design of further azinomycin analogues with antitumour activity...
  65. ncbi request reprint A novel class of in vivo active anticancer agents: achiral seco-amino- and seco-hydroxycyclopropylbenz[e]indolone (seco-CBI) analogues of the duocarmycins and CC-1065
    Atsushi Sato
    Department of Chemistry, Furman University, 3300 Poinsett Highway, Greenville, South Carolina 29613, USA
    J Med Chem 48:3903-18. 2005
    ..Finally, compound 11a was not toxic to murine bone marrow cell growth in culture at a dose that was toxic for the previously reported compound 4...
  66. ncbi request reprint DNA interstrand crosslinking agents: synthesis, DNA interactions, and cytotoxicity of dimeric achiral seco-amino-CBI and conjugates of achiral seco-amino-CBI with pyrrolobenzodiazepine (PBD)
    Bethany Purnell
    Department of Chemistry, Furman University, 3300 Pointsett Highway, Greenville, SC 29613, USA
    Bioorg Med Chem Lett 16:5677-81. 2006
    ..Both compounds were found to induce apoptosis in P815 cells. Due to its poor water solubility, dimer 13 did not give any appreciable DNA binding or cytotoxicity...
  67. ncbi request reprint Synthesis and biophysical evaluation of minor-groove binding C-terminus modified pyrrole and imidazole triamide analogs of distamycin
    Toni Brown
    Division of Natural Sciences and Department of Chemistry, Hope College, Holland, MI 49423, USA
    Bioorg Med Chem 15:474-83. 2007
    ..However, the number of cationic centers within the molecule may also play a role. The alkyldiamino-containing compounds (7 and 8) warrant further investigation in the field of polyamide research...
  68. ncbi request reprint Time-dependent cytotoxicity induced by SJG-136 (NSC 694501): influence of the rate of interstrand cross-link formation on DNA damage signaling
    Stephanie Arnould
    Cancer Research UK Centre, The University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom
    Mol Cancer Ther 5:1602-9. 2006
    ....
  69. ncbi request reprint Sequence-selective interaction of the minor-groove interstrand cross-linking agent SJG-136 with naked and cellular DNA: footprinting and enzyme inhibition studies
    Chris Martin
    Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom
    Biochemistry 44:4135-47. 2005
    ..Finally, SJG-136 efficiently inhibits the action of restriction endonuclease BglII, which has a 5'-A-GATC-T-3' motif at its cleavage site...
  70. ncbi request reprint Synthesis of DNA-directed pyrrolidinyl and piperidinyl confined alkylating chloroalkylaminoanthraquinones: potential for development of tumor-selective N-oxides
    Klaus Pors
    Institute of Cancer Therapeutics, University of Bradford, West Yorkshire, BD7 1DP, United Kingdom
    J Med Chem 49:7013-23. 2006
    ..Derivatization of the potent DNA cross-linking agent 15 to an N-oxide resulted in loss of the DNA unwinding, DNA interstrand cross-linking and cytotoxic activity of the parent molecule...
  71. ncbi request reprint Physical and structural basis for the strong interactions of the -ImPy- central pairing motif in the polyamide f-ImPyIm
    Karen L Buchmueller
    Department of Chemistry, Furman University, Greenville, South Carolina 29613, USA
    Biochemistry 45:13551-65. 2006
    ..Collectively, the NMR and ITC experiments show that formation of the 2:1 f-ImPyIm-CGCG complex achieves a structure more ordered and more thermodynamically favored than the structure of the 2:1 f-PyImIm-CCGG complex...
  72. ncbi request reprint PCR-based methods for detecting DNA damage and its repair at the sub-gene and single nucleotide levels in cells
    Keith A Grimaldi
    Mol Biotechnol 20:181-96. 2002
    ..If antibodies to the DNA adducts of interest are available, these can be used to capture and isolate adducted DNA for use in single-strand ligation PCR increasing the sensitivity of the assay...
  73. ncbi request reprint Benzoyl and cinnamoyl nitrogen mustard derivatives of benzoheterocyclic analogues of the tallimustine: synthesis and antitumour activity
    Pier Giovanni Baraldi
    Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, Via Fossato di Mortara 17 19, 44100 Ferrara, Italy
    Bioorg Med Chem 10:1611-8. 2002
    ..Our preliminary results indicate that these derivatives preferentially bind to AT-rich sequence with a sequence selectivity similar to tallimustine...
  74. ncbi request reprint Relationships between DNA strand breakage and apoptotic progression upon treatment of HL-60 leukemia cells with tafluposide or etoposide
    Jerome Kluza
    INSERM U524, Institut de Recherche sur le Cancer de Lille, Lille, France
    Anticancer Drugs 17:155-64. 2006
    ..We suggest that drug-induced mitochondrial alterations can be divided into three successive steps: (i) hyperpolarization, (ii) depolarization and (iii) increase of the mitochondrial mass...
  75. doi request reprint Modifying the N-terminus of polyamides: PyImPyIm has improved sequence specificity over f-ImPyIm
    Toni Brown
    Department of Chemistry, Furman University, Greenville, SC 29613, USA
    Bioorg Med Chem 16:5266-76. 2008
    ..PyImPyIm (4) is an especially interesting molecule, because although the binding affinity is slightly reduced, the specificity with respect to f-ImPyIm (1) is significantly improved...
  76. ncbi request reprint Chemical synthesis and cytotoxicity of dihydroxylated cyclopentenone analogues of neocarzinostatin chromophore
    Michael D Urbaniak
    Center for Biomolecular Design and Drug Development, School of Chemistry, University of Sussex, Falmer, Brighton, BN1 9QJ, UK
    Bioorg Med Chem Lett 13:2025-7. 2003
    ..Those compounds containing a cyclopentenone moiety were active, with the carbonyl group being essential for biological activity...
  77. ncbi request reprint A novel design strategy for stable metal complexes of nitrogen mustards as bioreductive prodrugs
    Laurie L Parker
    Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
    J Med Chem 47:5683-9. 2004
    ..The use of macrocyclic nitrogen mustard complexes represents a promising new strategy in the design of hypoxia-selective cytotoxins...
  78. ncbi request reprint Delineating noncovalent interactions between the azinomycins and double-stranded DNA: importance of the naphthalene substitution pattern on interstrand cross-linking efficiency
    Cyrille A S Landreau
    Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U K, School of Chemistry, University of St Andrews, Purdie Building, St Andrews, Fife KY16 9ST, UK
    Org Lett 6:3505-7. 2004
    ....
  79. ncbi request reprint Binding of f-PIP, a pyrrole- and imidazole-containing triamide, to the inverted CCAAT box-2 of the topoisomerase IIalpha promoter and modulation of gene expression in cells
    N Minh Le
    Department of Chemistry, Furman University, 3300 Pointsett Highway, Greenville, SC 29613, USA
    Bioorg Med Chem Lett 16:6161-4. 2006
    ..The results suggested that the triamide was able to enter the nucleus, interacted with the target site within ICB2, inhibited NF-Y binding, and activated gene expression...
  80. ncbi request reprint Synthesis and evaluation of an intercalator-polyamide hairpin designed to target the inverted CCAAT box 2 in the topoisomerase IIalpha promoter
    Lloyd V Flores
    Department of Chemistry, Furman University, Greenville, SC 29613, USA
    Chembiochem 7:1722-9. 2006
    ....
  81. ncbi request reprint Design and synthesis of a nitrogen mustard derivative stabilized by apo-neocarzinostatin
    Michael D Urbaniak
    Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK
    J Med Chem 47:4710-5. 2004
    ..This novel approach demonstrates for the first time that an enediyne apo-protein can be used to improve the stability of substances that are of potential interest in cancer chemotherapy...
  82. ncbi request reprint Sequence selective recognition of DNA by hairpin conjugates of a racemic seco-cyclopropaneindoline-2-benzofurancarboxamide and polyamides
    James L Toth
    Department of Chemistry, Furman University, Greenville, SC 29613, USA
    Bioorg Med Chem Lett 12:2245-8. 2002
    ..A model for the binding of hairpin conjugates 1 and 2 with the 3'-GACT-5' sequence is proposed...