Oral Anticancer Heterobimetallic Pt IV -Au I Complexes Show High In Vivo Activity and Low Toxicity.

Autor: Babu T; Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel., Ghareeb H; Institute of Chemistry, The Center for Nanoscience and Nanotechnology, Casali Center for Applied Chemistry, The Hebrew University of Jerusalem, Jerusalem, 9190401, Israel., Basu U; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, 38106, Braunschweig, Germany., Schueffl H; Center for Cancer Research and Comprehensive Cancer Center, Austria., Theiner S; Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 38, 1090, Vienna, Austria., Heffeter P; Center for Cancer Research and Comprehensive Cancer Center, Austria., Koellensperger G; Center for Cancer Research and Comprehensive Cancer Center, Austria., Metanis N; Institute of Chemistry, The Center for Nanoscience and Nanotechnology, Casali Center for Applied Chemistry, The Hebrew University of Jerusalem, Jerusalem, 9190401, Israel., Gandin V; Dipartimento di Scienze del Farmaco, Universita di Padova, 35131, Padova, Italy., Ott I; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, 38106, Braunschweig, Germany., Schmidt C; Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel., Gibson D; Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2023 Mar 01; Vol. 62 (10), pp. e202217233. Date of Electronic Publication: 2023 Jan 31.
DOI: 10.1002/anie.202217233
Abstrakt: Au I -carbene and Pt IV -Au I -carbene prodrugs display low to sub-μM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt-derived Pt IV (phenylbutyrate) complex to a Au I -phenylimidazolylidene complex 2, yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug Pt IV (phenylbutyrate)-Au I -carbene (7) and the 1 : 1 : 1 co-administration of cisPt: phenylbutyrate:2 efficiently inhibited tumor growth (≈95 %), much better than 2 (75 %) or cisPt (84 %), 7 exhibited only 5 % body weight loss compared to 14 % for 2, 20 % for cisPt and >30 % for the co-administration. 7 was much more efficient than 2 at inhibiting TrxR activity in the isolated enzyme, in cells and in the tumor, even though it was much less efficient than 2 at binding to selenocysteine peptides modeling the active site of TrxR. Organ distribution and laser-ablation (LA)-ICP-TOFMS imaging suggest that 7 arrives intact at the tumor and is activated there.
(© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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