Towards (99m)Tc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study.
Doxorubicin is a clinical benchmark drug, which is applied in the treatment of numerous cancers. Known for its accumulation in the nucleus and ability to intercalate into DNA, it targets quickly dividing i.e. hypermitotic cells. Through this mechanism, it could be an ideal structural motif for a new class of imaging agents, given that the new entity approximates the in vitro profile of the parent drug. Here we describe design, synthesis and biological activity of a small array of Doxorubicin-metalloconjugates (M = (99m)Tc, Re). We demonstrate that the conjugates preferably accumulate in the nuclear compartment, tightly bind to DNA and retain an appreciable cytotoxicity. Moreover, the Re conjugates effectively act as inhibitors of the human Topoisomerase II enzyme, which is the widely accepted mechanism of action of the parent drug. Since the conjugates effectively mimic the in vitro behavior of native Doxorubicin, the (99m)Tc compounds are prospective imaging agents.
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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Imstepf
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland and Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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Pierroz
Centro de Ciências e Tecnologias Nucleares, Universidade de Lisboa, Estrada Nacional 10, PT-2695-066 Bobadela LRS, Portugal.
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Raposinho
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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Felber
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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Fox
Centro de Ciências e Tecnologias Nucleares, Universidade de Lisboa, Estrada Nacional 10, PT-2695-066 Bobadela LRS, Portugal.
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Fernandes
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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Gasser
Centro de Ciências e Tecnologias Nucleares, Universidade de Lisboa, Estrada Nacional 10, PT-2695-066 Bobadela LRS, Portugal.
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Santos
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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Alberto
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003952:Diagnostic Imaging; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D013667:Technetium / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D007364:Intercalating Agents; D009942:Organometallic Compounds; D059005:Topoisomerase II Inhibitors; D013667:Technetium; D004317:Doxorubicin