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1	Re-engineering of the Duocarmycin Structural Architecture Enables Bioprecursor Development Targeting CYP1A1 and CYP2W1 for Biological Activity Sheldrake, Helen M., Travica, S., Johansson, I., Loadman, Paul, Sutherland, Mark, Elsalem, Lina M.I., Illingworth, Nicola A., Cresswell, Alexander J., Reuillon, Tristan, Shnyder, Steven, Mkrtchian, S., Searcey, M., Ingelman-Sundberg, M., Patterson, Laurence H., Pors, Klaus 11 July 2013 (has links) Yes / A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM–nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors. Bioprecursor development CYP1A1 CYP2W1 Duocarmycin
2	Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds Ortuzar, N., Karu, K., Presa, Daniela, Morais, Goreti R., Sheldrake, Helen M., Shnyder, Steven D., Barnieh, Francis M., Loadman, Paul, Patterson, Laurence H., Pors, Klaus, Searcey, M. 05 October 2023 (has links) Yes / The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation. / The authors would like to thank Yorkshire Cancer Research (Program grant B381PA) for supporting our work focused on exploring CYPs as targets for prodrug development. The human recombinant CYP1A1 was a gift from Prof Emily E. Scott, University of Michigan; the enzyme was produced via NIH funded grant (R37 GM076343). Cytochrome P450 Duocarmycin Bioactivation Bioprecursor Cytotoxicity
3	Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds Ortuzar, N., Karu, K., Presa, Daniela, Morais, Goreti R., Sheldrake, Helen M., Shnyder, Steven, Barnieh, Francis M., Loadman, Paul, Patterson, Laurence H., Pors, Klaus, Searcey, M. 06 July 2021 (has links) Yes / The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation. Cytochrome P450 Duocarmycin Bioactivation Bioprecursor Cytotoxicity
4	Development of prodrugs to deliver super-potent drugs to prostate tumours Twum, Elvis Asare January 2013 (has links) Conventional treatments for prostate cancer have significant limitations making it difficult to control the disease. Cyclopropabenzindoles (CBI) are more biologically potent, stable and synthetically accessible analogues of cyclopropapyrroloindole (CPI) anti-tumour antibiotics, such as duocarmycin-SA and CC1065. A polymeric prodrug carrying a CBI drug attached to the polymeric backbone through a PSA cleavable linker peptide has two modes of selectivity: activation by PSA and the EPR effect. To synthesise a 5-amino-seco-CBI analogue, 2,4-dinitronaphthalen- 1-ol gave di-Boc-1-iodonaphthalene-2,4-diamine in five steps (triflation, SNAr displacement with iodide, reduction (loss of iodine), protection and restoration of the iodine. For the amino-seco-CBI, it was important to discriminate between N2 and N4. Acidic removal of the Boc-group(s) resulted in deiodination. NMR investigations showed an unexpected Wheland-like cationic intermediate. N3 of naphthalene-1,3-diamine was selectively trifluoroacetylated and N1 was masked with Boc. Electrophilic iodination gave an orthogonally protected 1-iodonaphthalene-2,4-diamine. Allylation at the trifluoroacetamide was followed by free radical cyclisation with TEMPO trap. Removal of the trifluoroacetyl group allowed coupling to 5-(2-(dimethylamino)ethoxy)-1H-indole-2-carboxylic acid. Reductive removal of 2,2,6,6-tetramethylpiperidine, substitution of the exposed hydroxy group with chloride and removal of the Boc-group gave the amino-seco-CBI drug, 5-amino-1-chloromethyl-3-(5-(2-dimethylaminoethoxy)indole-2-carbonyl)-2,3-dihydro-1H-benz[e]indole. A DNA-melting assay confirmed that it binds very strongly to dsDNA causing a 13 deg. C increase in melting temperature. The drug was a highly potent cytotoxin in vitro, with IC50 = 18 nM against LNCaP prostate cancer cells. The polymeric prodrug system involved the synthesis of the pentapeptide SSKLQ. The amide side chain of glutamine can be masked as the nitrile and this can be quantitatively hydrated to the γ-carboxamide of L-Gln with hydroperoxide. The pentapeptide was coupled to 4-methoxynaphthalen-1-amine and to poly(ethylene glycol) as a model polymeric prodrug system. Efficient release of the model drug from the polymeric prodrug by PSA will allow this polymeric prodrug system to be adopted for the synthesised amino-seco-CBI drug. 616.99463061
5	Synthese und biologische Evaluierung neuartiger Acronycin-Duocarmycin-Hybride / Synthesis and Biological Evaluation of Novel Acronycine-Duocarmycin Hybrid Heins, Arne 15 December 2011 (has links) No description available. 000 Allgemeines Wissenschaft Chemistry Acronycin Duocarmycin Hybrid-Naturstoff acronycine duocarmycine hybrids natural product 35.52
6	Investigation of cytochrome p450 isoforms 1A1, 1B1 and 2W1 as targets for therapeutic intervention in head and neck cancer. Probing CYP1A1, 1B1 and 2W1 activity with duocarmycin bioprecursors Presa, Daniela January 2018 (has links) The full text will be available at the end of the embargo: 30th July 2026 Cytochrome P450 (CYP) CYP1A1 CYP1B1 CYP2W1 Head and Neck Cancer (HNC) Duocarmycin Prodrug Bioprecursor DNA damage Therapeutic intervention
7	Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products. Ghosh, Nandita, Sheldrake, Helen M., Searcey, M., Pors, Klaus 10 1900 (has links) Yes / CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products. / EPSRC, Yorkshire Cancer Research, Big C Cancer Research, UCB Pharma Duocarmycin Anti-tumour antibiotics CC-1065 Aadozelesin CBI CPI DNA minor groove binders (MGBs) Adenine N3 alkylation Prodrugs Anti-cancer therapeutics Natural products
8	Synthese und biologische Evaluierung von fluorezenzmarkierten Duocarmycin-Analoga / Synthesis and biological evaluation of fluorescence labeled Duocarmycin analogues Behrendt, Frank 25 November 2011 (has links) No description available. 540 Chemie Chemistry ADEPT Tumortherapie Prodrug CC-1065 Duocarmycine DNA Fluoreszenz Live Cell Imaging Zelluläre Aufnahme Wirkmechanismus ADEPT tumor therapy prodrug CC-1065 duocarmycin DNA fluorescence Live Cell Imaging Cellular Uptake mechanism of action 35.26 35.29 35.33 35.59 35.71 35.75 35.52 44.33
9	Synthese, biologische Evaluation und Untersuchung des Wirkmechanismus neuartiger Duocarmycin-Analoga für eine selektive Krebstherapie / Synthesis, Biological Evaluation and Investigation of the Mode of Action of Novel Anti-Tumour Agents for a Selective Cancer Therapy Krewer, Birgit 22 January 2009 (has links) No description available. 540 Chemie Mathematics and Computer Science ADEPT Tumortherapie Prodrug CC-1065 Duocarmycine DNA Massenspektrometrie Chromatographie Circular Dichroismus Wirkmechanismus ADEPT tumor therapy prodrug CC-1065 duocarmycin DNA mass spectrometry chromatography Circular Dichroism mechanism of action 35.26 35.29 35.33 35.59 35.71 35.75 35.52 44.33

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