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Conjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand FunctionalizationConjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand Functionalization

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Biancalana Lorenzo, Gruchała Martyna, Batchelor Lucinda K., Błauż Andrzej, Monti Andrea, Pampaloni Guido, Rychlik Błażej, Dyson Paul J., Marchetti Fabio,
Project Modulation of the site specificity of binding of metal-based drugs to chromatin
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Original article (peer-reviewed)

Journal European Journal of Inorganic Chemistry
Volume (Issue) 2020(11-12)
Page(s) 1061 - 1072
Title of proceedings European Journal of Inorganic Chemistry
DOI 10.1002/ejic.201900922

Open Access

Abstract

Two-step functionalization of 4-diphenylphosphino benzoic acid with biotin afforded 2-(biotinyloxy)ethyl 4-(diphenylphosphanyl) benzoate (LP), that was subsequently used to synthesize the Ru(II) arene complexes [RuCl2(η6-p-cymene)- (LP)] (1), [Ru(C2O4)(η6-p-cymene)(LP)] (2) and [Ru(curc)(η6-pcymene)( LP)]NO3 ([3]NO3), the latter incorporating curcumin (curcH) as an additional bioactive fragment. [Ru(curc)(η6-pcymene)( PPh3)]NO3 ([4]NO3) was also prepared as a reference compound. Compounds 2 and [3]NO3 exhibited excellent sta- Introduction The development of metal-based anticancer drugs that overcome the limitations of platinum compounds currently used in chemotherapy continues to receive considerable attention.[1] In this respect, ruthenium compounds have emerged as promising alternatives, with [indazoleH][trans-Ru(N-indazole)2Cl4] (KP1019) and [imidazoleH][trans-Ru(N-imidazole)(S-DMSO)Cl4] (NAMI-A), having undergone clinical evaluation.[2] These Ru(III) compounds exhibit lower toxicities and side-effects than the clinically approved Pt(II) drugs, attributed to in situ reduction and activation of Ru(III) to Ru(II) species in the tumour environment. 2,[3] However, a key limitation of all of these drugs is that they do not efficiently target tumours. Consequently, efforts have been devoted to attaching targeting groups to metalbased drugs to enhance their uptake into cancer cells, by exploiting the different characteristics of cancerous and normal cells.[4] Therefore, various small molecule targeting groups have been investigated, including folic acid,[5] riboflavin[6] and sugars.[ 4a,c],[7] In this regard, biotin (see Figure 1) is a vitamin whose uptake into cancer cells is related to sodium-dependent multi- [a] Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy E-mail: fabio.marchetti1974@unipi.it http://www.dcci.unipi.it/fabio-marchetti.html [b] Cytometry Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, ul. Pomorska 141/143, 90-236 Łódź, Poland [c] Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under https://doi.org/10.1002/ejic.201900922. Eur. J. Inorg. Chem. 2020, 1061–1072 1061 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim bility in water/DMSO solution while being slowly activated in the cell culture medium over 72 hours. Together with LP, they were therefore assessed for their antiproliferative activity towards a panel of cancer cell lines, with different levels of biotin transporter expression. The apparent affinity of the compounds towards avidin varies, and their antiproliferative activity does not correlate with biotin transporter expression, although it is systematically enhanced when biotin-free cell culture medium is used. vitamin
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