Paul M O'Neill

Summary

Affiliation: University of Liverpool
Country: UK

Publications

  1. doi request reprint Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics
    Victoria Barton
    Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L697ZD, UK
    J Med Chem 53:4555-9. 2010
  2. ncbi request reprint Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether
    P M O'Neill
    Department of Chemistry, The University of Liverpool, P O Box 147, Liverpool L69 7ZD, U K
    J Med Chem 42:5487-93. 1999
  3. ncbi request reprint Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK
    Bioorg Med Chem Lett 16:2991-5. 2006
  4. ncbi request reprint Enantiomeric 1,2,4-trioxanes display equivalent in vitro antimalarial activity versus Plasmodium falciparum malaria parasites: implications for the molecular mechanism of action of the artemisinins
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, The Robert Robinson Laboratories, Oxford Street, Liverpool, L69 7ZD, UK
    Chembiochem 6:2048-54. 2005
  5. ncbi request reprint The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
    Expert Opin Investig Drugs 14:1117-28. 2005
  6. doi request reprint The molecular mechanism of action of artemisinin--the debate continues
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L697ZD, UK
    Molecules 15:1705-21. 2010
  7. ncbi request reprint Application of thiol-olefin co-oxygenation methodology to a new synthesis of the 1,2,4-trioxane pharmacophore
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, P O Box 147, Liverpool L69 3BX, UK
    Org Lett 6:3035-8. 2004
  8. ncbi request reprint Design and synthesis of endoperoxide antimalarial prodrug models
    Paul M O'Neill
    Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
    Angew Chem Int Ed Engl 43:4193-7. 2004
  9. ncbi request reprint A medicinal chemistry perspective on 4-aminoquinoline antimalarial drugs
    Paul M O'Neill
    Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L67 7ZD UK
    Curr Top Med Chem 6:479-507. 2006
  10. doi request reprint Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, Liverpool, United Kingdom
    J Med Chem 52:1408-15. 2009

Collaborators

Detail Information

Publications78

  1. doi request reprint Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics
    Victoria Barton
    Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L697ZD, UK
    J Med Chem 53:4555-9. 2010
    ..We also describe the synthesis of chemically cleavable linked conjugates designed to enable mild elution of labeled proteins during target protein identification...
  2. ncbi request reprint Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether
    P M O'Neill
    Department of Chemistry, The University of Liverpool, P O Box 147, Liverpool L69 7ZD, U K
    J Med Chem 42:5487-93. 1999
    ..On the basis of the products obtained from the in vitro biomimetic Fe(II)-mediated decomposition of 8, the radical mediator of biological activity of this series may be different from that of the parent drug, artemisinin (2)...
  3. ncbi request reprint Diels-Alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK
    Bioorg Med Chem Lett 16:2991-5. 2006
    ..Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides...
  4. ncbi request reprint Enantiomeric 1,2,4-trioxanes display equivalent in vitro antimalarial activity versus Plasmodium falciparum malaria parasites: implications for the molecular mechanism of action of the artemisinins
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, The Robert Robinson Laboratories, Oxford Street, Liverpool, L69 7ZD, UK
    Chembiochem 6:2048-54. 2005
    ..In five different P. falciparum isolates, however, the trioxane enantiomers (+)-7 a, (-)-7 a and (+)-7 b, (-)-7 b, showed the same level of in vitro antiparasitic activity...
  5. ncbi request reprint The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
    Expert Opin Investig Drugs 14:1117-28. 2005
    ..However, very recent progress with synthetic 1,2,4-trioxolanes provides a new benchmark for future medicinal chemistry efforts in this area...
  6. doi request reprint The molecular mechanism of action of artemisinin--the debate continues
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L697ZD, UK
    Molecules 15:1705-21. 2010
    ..In this review we will discuss the recent evidence explaining bioactivation and potential molecular targets in the chemotherapy of malaria and cancer...
  7. ncbi request reprint Application of thiol-olefin co-oxygenation methodology to a new synthesis of the 1,2,4-trioxane pharmacophore
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, P O Box 147, Liverpool L69 3BX, UK
    Org Lett 6:3035-8. 2004
    ..Manipulation of the phenylsulfenyl group in 4a allows for convenient modification to the spiro-trioxane substituents, and we describe, for the first time, the preparation of a new class of antimalarial prodrug...
  8. ncbi request reprint Design and synthesis of endoperoxide antimalarial prodrug models
    Paul M O'Neill
    Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
    Angew Chem Int Ed Engl 43:4193-7. 2004
  9. ncbi request reprint A medicinal chemistry perspective on 4-aminoquinoline antimalarial drugs
    Paul M O'Neill
    Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L67 7ZD UK
    Curr Top Med Chem 6:479-507. 2006
    ..Promising new lead compounds undergoing development are described and an overview of physicochemical properties of chloroquine and amodiaquine analogues is also included...
  10. doi request reprint Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, Liverpool, United Kingdom
    J Med Chem 52:1408-15. 2009
    ..This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class...
  11. ncbi request reprint A medicinal chemistry perspective on artemisinin and related endoperoxides
    Paul M O'Neill
    Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, U K
    J Med Chem 47:2945-64. 2004
  12. ncbi request reprint Synthesis, antimalarial activity, biomimetic iron(II) chemistry, and in vivo metabolism of novel, potent C-10-phenoxy derivatives of dihydroartemisinin
    P M O'Neill
    Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, England
    J Med Chem 44:58-68. 2001
    ....
  13. doi request reprint Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols
    Richard Amewu
    Department of Chemistry, University of Liverpool, P O Box 147, Liverpool, UK L69 3BX
    Org Biomol Chem 8:2068-77. 2010
    ..Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria...
  14. doi request reprint Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4'-fluoro and 4'-chloro analogues of amodiaquine. Identification of a suitable "back-up" compound for N-tert-butyl isoquine
    Paul M O'Neill
    Department of Chemistry, University of Liverpool, Liverpool, UK
    J Med Chem 52:1828-44. 2009
    ....
  15. ncbi request reprint Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10beta-(2-hydroxyethyl)deoxoartemisinin
    J Prince Jeyadevan
    Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
    J Med Chem 47:1290-8. 2004
    ..This observation emphasizes the importance of two trioxane units for high antiproliferative activity, and we propose that the nature of the linker in dimers of this type plays a crucial role in imparting potent anticancer activity...
  16. pmc Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2)
    Suet C Leung
    Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
    J Med Chem 55:1844-57. 2012
    ..falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies...
  17. doi request reprint Comparison of the reactivity of antimalarial 1,2,4,5-tetraoxanes with 1,2,4-trioxolanes in the presence of ferrous iron salts, heme, and ferrous iron salts/phosphatidylcholine
    Fatima Bousejra-El Garah
    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U K
    J Med Chem 54:6443-55. 2011
    ..The efficient process of heme alkylation and extensive lipid peroxidation observed here may play a role in the mechanism of action of these two important classes of synthetic endoperoxide antimalarial...
  18. ncbi request reprint Synthesis of 1,2,4-trioxepanes via application of thiol-olefin co-oxygenation methodology
    Richard Amewu
    Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK
    Bioorg Med Chem Lett 16:6124-30. 2006
    ..FMO calculations clearly show that the sigma* orbital of the peroxide moiety of 1,2,4-trioxane derivatives 4a and 14b are lower in energy and more accessible to attack by Fe(II) compared to their trioxepane analogues 8b and 9b...
  19. pmc Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria
    Giancarlo A Biagini
    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom
    Proc Natl Acad Sci U S A 109:8298-303. 2012
    ....
  20. doi request reprint Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity
    Peter Gibbons
    Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
    J Med Chem 53:8202-6. 2010
    ..Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells...
  21. ncbi request reprint Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues
    Stephen Hindley
    Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
    J Med Chem 45:1052-63. 2002
    ....
  22. pmc Identification, design and biological evaluation of bisaryl quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2)
    Chandrakala Pidathala
    Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
    J Med Chem 55:1831-43. 2012
    ..Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress...
  23. ncbi request reprint Design and synthesis of orally active dispiro 1,2,4,5-tetraoxanes; synthetic antimalarials with superior activity to artemisinin
    Richard Amewu
    Department of Chemistry, University of Liverpool, PO Box 147, Liverpool, UK L69 3BX
    Org Biomol Chem 4:4431-6. 2006
    ..Several analogues display an unprecedented level of oral antimalarial activity for this class of endoperoxide drug...
  24. doi request reprint Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles
    Gemma L Ellis
    Department of Chemistry, University of Liverpool, Liverpool, U K
    J Med Chem 51:2170-7. 2008
    ....
  25. ncbi request reprint Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials
    Paul M O'Neill
    Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
    J Med Chem 46:4933-45. 2003
    ..On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine...
  26. doi request reprint Design, synthesis and antimalarial/anticancer evaluation of spermidine linked artemisinin conjugates designed to exploit polyamine transporters in Plasmodium falciparum and HL-60 cancer cell lines
    James Chadwick
    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
    Bioorg Med Chem 18:2586-97. 2010
    ..Although some limitations in this vector-based approach are apparent, a number of high potency Boc-protected analogues were identified with activity against malaria parasites as low as 0.21nM...
  27. doi request reprint Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex
    Giancarlo A Biagini
    Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK
    Mol Pharmacol 73:1347-55. 2008
    ..falciparum bc(1) Q(o). Dihydroacridinediones represent an entirely new class of bc(1) inhibitors and the potential of these compounds as novel antimalarial drugs is discussed...
  28. doi request reprint Antitumour and antimalarial activity of artemisinin-acridine hybrids
    Michael Jones
    Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK
    Bioorg Med Chem Lett 19:2033-7. 2009
    ..Strong evidence that the compounds induce apoptosis in HL60 cells was obtained by flow cytometry, which indicated accumulation of cells in the G1 phase of the cell cycle...
  29. doi request reprint Modular synthesis and in vitro and in vivo antimalarial assessment of C-10 pyrrole mannich base derivatives of artemisinin
    Bénédicte Pacorel
    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
    J Med Chem 53:633-40. 2010
    ....
  30. ncbi request reprint Novel short chain chloroquine analogues retain activity against chloroquine resistant K1 Plasmodium falciparum
    Paul A Stocks
    Department of Chemistry, The University of Liverpool, United Kingdom
    J Med Chem 45:4975-83. 2002
    ..We conclude that the ability to accumulate at higher concentrations within the food vacuole of the parasite is an important parameter that dictates their potency against CQ sensitive and the chloroquine resistant K1 P. falciparum...
  31. pmc Examination of the cytotoxic and embryotoxic potential and underlying mechanisms of next-generation synthetic trioxolane and tetraoxane antimalarials
    Ian M Copple
    MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, United Kingdom
    Mol Med 18:1045-55. 2012
    ....
  32. doi request reprint Artemisinin-polypyrrole conjugates: synthesis, DNA binding studies and preliminary antiproliferative evaluation
    Louise La Pensée
    Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK
    ChemMedChem 8:709-18. 2013
    ..DNA binding/modelling studies and preliminary biological evaluation give insights into their mechanism of action and the potential of this strategy...
  33. doi request reprint Synthesis and biological evaluation of extraordinarily potent C-10 carba artemisinin dimers against P. falciparum malaria parasites and HL-60 cancer cells
    James Chadwick
    Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
    Bioorg Med Chem 17:1325-38. 2009
    ....
  34. pmc The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials
    Amy E Mercer
    Medical Research Council Centre for Drug Safety Science, The University of Liverpool, Liverpool L69 3GE, United Kingdom
    J Biol Chem 286:987-96. 2011
    ..36 ± 0.20 μM and 11 ± 5%; and with succinylacetone, >100 μM and 2 ± 5%)...
  35. pmc Identification of novel antimalarial chemotypes via chemoinformatic compound selection methods for a high-throughput screening program against the novel malarial target, PfNDH2: increasing hit rate via virtual screening methods
    Raman Sharma
    Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom
    J Med Chem 55:3144-54. 2012
    ..This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria...
  36. doi request reprint Targeting the mitochondrial electron transport chain of Plasmodium falciparum: new strategies towards the development of improved antimalarials for the elimination era
    Gemma L Nixon
    Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK
    Future Med Chem 5:1573-91. 2013
    ..Common barriers to progress and opportunities for novel chemistry and potential additional electron transport chain targets are discussed in the context of the target candidate profiles for uncomplicated malaria. ..
  37. doi request reprint Synthesis and antimalarial activities of a diverse set of triazole-containing furamidine analogues
    Olivier Berger
    Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 3BX UK
    ChemMedChem 6:2094-108. 2011
    ..vinckei...
  38. doi request reprint Inhibiting Plasmodium cytochrome bc1: a complex issue
    Victoria Barton
    Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L69 7ZD, UK
    Curr Opin Chem Biol 14:440-6. 2010
    ..Significantly, many of these developmental compounds demonstrate little cross resistance with atovaquone-resistant parasite strains, and selected classes have excellent oral activity profiles in rodent models of malaria...
  39. ncbi request reprint Evidence for the involvement of carbon-centered radicals in the induction of apoptotic cell death by artemisinin compounds
    Amy E Mercer
    Department of Pharmacology and Therapeutics, University of Liverpool, UK
    J Biol Chem 282:9372-82. 2007
    ..Overall, these results indicate that endoperoxide-induced cell death is a consequence of activation of the endoperoxide bridge to radical species, which triggers caspase-dependent apoptosis...
  40. doi request reprint Convenient syntheses of benzo-fluorinated dibenz[b,f]azepines: rearrangements of isatins, acridines, and indoles
    Emma Claire Elliott
    Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
    Org Lett 13:5592-5. 2011
    ..A range of mono- and difluorinated analogues is accessible, and the syntheses can deliver gram quantities of the final products, which are precursors of fluoro analogues of the important anticonvulsant carbamazepine...
  41. doi request reprint An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity
    Gemma L Ellis
    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
    Bioorg Med Chem Lett 18:1720-4. 2008
    ..Using this methodology a range of bridged tetraoxanes which display good in vitro antimalarial activity were synthesized...
  42. ncbi request reprint Hepatocellular bioactivation and cytotoxicity of the synthetic endoperoxide antimalarial arteflene
    James L Maggs
    Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK
    Chem Biol Interact 147:173-84. 2004
    ..Cellular glutathione was depleted under these conditions. Therefore arteflene was acutely cytotoxic, though only at relatively high concentrations, when it was metabolized via a pathway which generates carbon-centered radicals...
  43. doi request reprint Convenient syntheses of halo-dibenz[b,f]azepines and carbamazepine analogues via N-arylindoles
    Emma Claire Elliott
    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
    Org Biomol Chem 11:8426-34. 2013
    ..The 5-(carboxamido) side chain of carbamazepine may be added in various ways, affording overall a convenient access to drug molecules. ..
  44. pmc PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX
    Patrick G Bray
    Department of Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
    Mol Microbiol 62:238-51. 2006
    ..The efflux of CQ in CQR lines is not directly coupled to the energy supply, consistent with a model in which mutant PfCRT functions as a gated channel or pore, allowing charged CQ species to leak out of the DV...
  45. doi request reprint Synthesis and evaluation of the antimalarial, anticancer, and caspase 3 activities of tetraoxane dimers
    Richard K Amewu
    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK Electronic address
    Bioorg Med Chem 21:7392-7. 2013
    ..Our studies reveal that several molecules possess potent nanomolar antimalarial and single digit micromolar antiproliferative IC(50)s versus colon (HT29-AK and leukemia (HL60) cell lines...
  46. doi request reprint Metabolic and chemical origins of cross-reactive immunological reactions to arylamine benzenesulfonamides: T-cell responses to hydroxylamine and nitroso derivatives
    J Luis Castrejon
    MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool L69 3GE, United Kingdom
    Chem Res Toxicol 23:184-92. 2010
    ..1 h. T-cell cross-reactivity with nitroso sulfonamides provides a mechanistic explanation as to why structurally related arylamine benzenesulfonamides are contraindicated in hypersensitive patients...
  47. ncbi request reprint Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents
    Gary H Posner
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 N Charles Street, Baltimore, Maryland 21218 2685, USA
    J Med Chem 47:1299-301. 2004
    ..In the transgenic adenocarcinoma of mouse prostate model, some of the trioxane dimers had potent anticancer activity...
  48. ncbi request reprint Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity
    Ik Hyeon Paik
    Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218 2685, USA
    J Med Chem 49:2731-4. 2006
    ....
  49. ncbi request reprint Mild, fast, and stereoselective epoxide opening by ketone enolate anions. Application to synthesis of the norlignan curculigine
    Gary H Posner
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA
    J Org Chem 68:3049-54. 2003
    ....
  50. ncbi request reprint Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy
    Gary H Posner
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218 2685, USA
    J Med Chem 46:1060-5. 2003
    ....
  51. ncbi request reprint A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic beta-sulfonyl-endoperoxides
    Mario D Bachi
    Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
    J Med Chem 46:2516-33. 2003
    ..NS. In view of the nontoxicity of beta-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates...
  52. pmc Electronically stabilized versions of the antimalarial acetal trioxanes artemether and artesunate
    Gary H Posner
    Department of Chemistry, The Johns Hopkins University, 3400 N Charles Street, Baltimore, MD 21218, USA
    Bioorg Med Chem 16:5247-53. 2008
    ..The very strong inductive electron-withdrawing C-9 substituent is shown to retard considerably C-10 ionization (acid-promoted etherification) of 9-fluoro-DHA and 9-sulfonyl-DHA...
  53. ncbi request reprint Antimalarial chemotherapeutic peroxides: artemisinin, yingzhaosu A and related compounds
    Kristina Borstnik
    Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218 2685, USA
    Int J Parasitol 32:1661-7. 2002
    ..This review summarises recent achievements in this area of peroxide drug development for malaria chemotherapy...
  54. pmc In vitro inhibition of Toxoplasma gondii by four new derivatives of artemisinin
    Lorraine Jones-Brando
    Stanley Division of Developmental Neurovirology, Dept of Pediatrics, Johns Hopkins University School of Medicine, 600 N Wolfe St, Baltimore, MD 21287 4988, USA
    Antimicrob Agents Chemother 50:4206-8. 2006
    ..We synthesized novel, nonacetal, hydrolytically stable derivatives of artemisinin and showed that they inhibit the replication of Toxoplasma gondii in cell culture...
  55. ncbi request reprint New chemical and biological aspects of artemisinin-derived trioxane dimers
    Gary H Posner
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA
    Bioorg Med Chem 10:227-32. 2002
    ..Each dimer was evaluated in vitro for antimalarial, antiproliferative, and antitumor activities; ketone dimers and, more than fluorinated dimers and, are promising for chemotherapy of both malaria and cancer...
  56. ncbi request reprint Malaria-infected mice are cured by a single dose of novel artemisinin derivatives
    Gary H Posner
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins Malaria Research Institute, Johns Hopkins University, Baltimore, Maryland 21218, USA
    J Med Chem 50:2516-9. 2007
    ..Four of these trioxane dimers cure malaria-infected mice after only a single subcutaneous dose, and two other dimers cure after three oral doses...
  57. ncbi request reprint Orally active, water-soluble antimalarial 3-aryltrioxanes: short synthesis and preclinical efficacy testing in rodents
    Gary H Posner
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 N Charles Street, Baltimore, Maryland 21218 2685, USA
    J Med Chem 45:3824-8. 2002
    ..4 than is artelinic acid (1), a leading semisynthetic, herb-derived antimalarial trioxane drug candidate...
  58. doi request reprint Malaria-infected mice are cured by oral administration of new artemisinin derivatives
    Gary H Posner
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218 2685, USA
    J Med Chem 51:1035-42. 2008
    ..7-13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials...
  59. ncbi request reprint Malaria: new chemotherapeutic peroxide drugs
    Kristina Borstnik
    Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
    Mini Rev Med Chem 2:573-83. 2002
    ..This review summarizes recent achievements in this area of peroxide drug development for malaria chemotherapy...
  60. ncbi request reprint Knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides
    Gary H Posner
    Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
    Acc Chem Res 37:397-404. 2004
    ..Incorporating metabolism-blocking substituents also provides some new, potent, semi-synthetic artemisinin derivatives...
  61. ncbi request reprint Conceptually new low-calcemic oxime analogues of the hormone 1 alpha,25-dihydroxyvitamin D(3): synthesis and biological testing
    Gary H Posner
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, Maryland 21218, USA
    J Med Chem 45:1723-30. 2002
    ..In terms of in vivo toxicity (hypercalcemia), ketone 2b is strongly calcemic in rats, whereas oxime 3b and oxime ether 4b are considerably less calcemic (i.e., safer) than calcitriol (1)...
  62. ncbi request reprint Vitamin D analogs as modulators of vitamin D receptor action
    Sara Peleg
    Department of Endocrine Neoplasia and Hormonal Disorders, Box 435, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Curr Top Med Chem 3:1555-72. 2003
    ..Finally, we will describe the current and potential use of these selective modulators of the VDR for treatment of human diseases such as osteoporosis, cancer, and secondary hyperparathyroidism...
  63. ncbi request reprint Low-calcemic vitamin D analogs (deltanoids) for human cancer prevention
    Gary H Posner
    Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
    J Nutr 132:3802S-3803S. 2002
    ..A short summary is provided of leading chemopreventive analogs of vitamin D3...
  64. ncbi request reprint Low-calcemic, efficacious, 1alpha,25-dihydroxyvitamin D3 analog QW-1624F2-2: calcemic dose-response determination, preclinical genotoxicity testing, and revision of A-ring stereochemistry
    Gary H Posner
    Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA
    Steroids 69:757-62. 2004
    ..This analog is shown to be approximately 80-100 times less calciuric than the natural hormone 1alpha,25-dihydoxyvitamin D3. This analog is shown also to be non-genotoxic in three different standard assays...
  65. ncbi request reprint Low-calcemic, highly antiproliferative, 1-difluoromethyl hybrid analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation
    Sara Peleg
    Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas, M D Anderson Cancer Center, Houston, Texas 77030, USA
    J Med Chem 49:7513-7. 2006
    ..Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferative in vitro but are low-calcemic in vivo...
  66. ncbi request reprint Unexpected steric effects of "remote" alkyl groups on the rate of conjugate additions to alkyl alpha,beta-ethylenic sulfones, sulfoxides, and esters
    Aimee R Usera
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, Maryland 21218, USA
    J Org Chem 72:2329-34. 2007
    ..Competition experiments establish the relative rates of Michael additions to be in the following order: Et>i-Pr>t-Bu...
  67. pmc Antiproliferative, low-calcemic, fluorinated sulfone analogs of 1alpha,25-dihydroxyvitamin D3: chemical synthesis and biological evaluation
    Aimee R Usera
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA
    Bioorg Med Chem 15:5509-18. 2007
    ..Incorporation of additional fluorines, as in a perfluorobutyl analog, results in a loss of antiproliferative activity...
  68. ncbi request reprint Low-calcemic, highly antiproliferative, 23-oxa ether analogs of the natural hormone 1 alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation
    Kimberly S Petersen
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA
    J Med Chem 50:5824-32. 2007
    ..One of these three 23-oxa analogs has transcriptional potency almost as high as that of calcitriol, even though it binds to the human vitamin D receptor only about 1% as well as calcitriol...
  69. ncbi request reprint Biological mechanisms of action of novel C-10 non-acetal trioxane dimers in prostate cancer cell lines
    Adebusola A Alagbala
    Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
    J Med Chem 49:7836-42. 2006
    ..TDs also promoted apoptosis in LNCaP cells with increased expression of proapoptotic bax. These results demonstrate that TDs are potentially useful agents that warrant further preclinical development for treatment of prostate cancer...
  70. ncbi request reprint Less calcemic Vitamin D analogs enhance creatine kinase specific activity and modulate responsiveness to gonadal steroids in the vasculature
    Dalia Somjen
    Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    J Steroid Biochem Mol Biol 101:232-8. 2006
    ..These results corroborate our previous in vitro studies in human vascular cells and further suggest that the Vitamin D system plays an important physiological role in maintaining normal cell energy reservoir in the vasculature...
  71. pmc Effect of artemisinins and other endoperoxides on nitric oxide-related signaling pathway in RAW 264.7 mouse macrophage cells
    V Badireenath Konkimalla
    German Cancer Research Center, Pharmaceutical Biology C015, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
    Nitric Oxide 19:184-91. 2008
    ..In addition, other signaling pathways also contribute to the inhibitory effect of artesunate towards RAW 264.7 cells pointing to a multi-factorial mode of action of artesunate...
  72. ncbi request reprint Highly antiproliferative, low-calcemic, side-chain amide and hydroxamate analogs of the hormone 1alpha,25-dihydroxyvitamin D3
    Sandra Sinishtaj
    Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
    Bioorg Med Chem 14:6341-8. 2006
    ..Even though lacking the 25-OH group characteristic of natural calcitriol (1), analogs 2-4 are as antiproliferative in vitro as calcitriol (1) but are 20-40 times less calciuric in vivo than calcitriol (1)...
  73. ncbi request reprint Inhibition of prostate cancer-meditated osteoblastic bone lesions by the low-calcemic analog 1alpha-hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy vitamin D3
    Sara Peleg
    Department of Endocrine Neoplasia and Hormonal Disorders, Unit 435, The University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA
    J Steroid Biochem Mol Biol 97:203-11. 2005
    ..These experiments led to the hypothesis that, in vivo, JK-1626-2 prevented the metastatic bone lesions by inhibiting the mitogenic response of osteoblasts to growth factors produced by MDA-PCa 2b cells...
  74. ncbi request reprint Highly antiproliferative, low-calcemic, side-chain ketone analogs of the hormone 1alpha,25-dihydroxyvitamin D3
    Gary H Posner
    Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
    Bioorg Med Chem 13:5569-80. 2005
    ..In addition, ketone analog 19-nor-2a is not significantly less calcemic in vivo than 19-methylene analog 2a...
  75. ncbi request reprint A-ring hydroxymethyl 19-nor analogs of the natural hormone 1alpha,25-dihydroxyvitamin D(3): synthesis and preliminary biological evaluation
    Mark A Hatcher
    Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
    Bioorg Med Chem 13:3964-76. 2005
    ....
  76. ncbi request reprint Novel A-ring analogs of the hormone 1alpha,25-dihydroxyvitamin D3: synthesis and preliminary biological evaluation
    Gary H Posner
    Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
    Bioorg Med Chem 13:2959-66. 2005
    ....
  77. ncbi request reprint Potent, selective and low-calcemic inhibitors of CYP24 hydroxylase: 24-sulfoximine analogues of the hormone 1alpha,25-dihydroxyvitamin D(3)
    Mehmet Kahraman
    Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA
    J Med Chem 47:6854-63. 2004
    ..4 nM) having low calcemic activity. In addition, this compound shows high selectivity toward the CYP24 enzyme in comparison to CYP27A1 (IC(50) > 1000 nM) and CYP27B (IC(50) = 554 nM)...
  78. pmc Difluoromethyl analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation
    Gary H Posner
    Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA
    J Steroid Biochem Mol Biol 103:213-21. 2007
    ..The transcriptional activity of the 25-CHF(2) analog 3 is higher than that of the 1-CHF(2) analog 4...