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Towards99mTc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study


Imstepf, Sebastian; Pierroz, Vanessa; Raposinho, Paula; Felber, Michael; Fox, Thomas; Fernandes, Célia; Gasser, Gilles; Santos, Isabel R; Alberto, Roger (2016). Towards99mTc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study. Dalton Transactions, 45(33):13025-13033.

Abstract

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 = 99mTc, 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 99mTc compounds are prospective imaging agents.

Abstract

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 = 99mTc, 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 99mTc compounds are prospective imaging agents.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research

07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2016
Deposited On:04 Aug 2016 12:26
Last Modified:09 Feb 2017 09:40
Publisher:Royal Society of Chemistry
ISSN:1477-9226
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1039/C6DT00871B
PubMed ID:27097328

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