The discovery of cisplatin and its later approved derivatives started a new era in the bioinorganic medicinal chemistry field but the persistence of severe side-effects along with the emerging of drug resistance evoke the need of a new generation of transition metal-based chemotherapeutics. The starting point of this journey was the preparation of diamine ligands derived from variously substituted N-methyl-2-aminomethyl imidazoles.1 By introducing differently-long saturated and unsaturated chains at N1, the lipophilicity and the consequent cytotoxicity of the corresponding Pt(II)-complexes was modulated whereas its substitution with the 1,2,5-oxadiazole moiety selectively introduced the ability to simultaneously interact with DNA and to interrupt STAT3 signalling pathway.2 Breaking the assumption that bifunctionality is necessary for antiproliferative activity, a series of monofunctional cationic platinum complexes were synthesised showing a potent cytotoxic effect toward triple-negative breast cancer cells and in cancer cell lines partially resistant to cisplatin. Moreover, the prominent stability of this class of platinum complexes suggested also a possible application for MSCs loading to use for advanced cell therapy.3 Moving forward in this field, the effect of the bidentate ligands on the biological activity was highlighted showing for the Pt-8-aminoquinoline series a different biological profile.4 In order to gain some mechanistic insights, the interaction of such platinum-based compounds with some model proteins was investigated through ESI-MS analysis. Since an increasing interest has recently arisen in the development of platinum based theranostic agents, indeed, a series of cyclometalated anionic Pt(II) complexes carrying tetrabromocatechol or alizarine as O^O chelating ligands was developed. This last series of platinum complexes displayed enhanced cytotoxicity toward triple-negative breast cancer (TNBC) and they furthermore resulted emissive in solution.5 Moreover, fluorescence confocal analysis showed their localization in the perinuclear region of MDA-MB231 cells proving their ability to serve as luminescent theranostic probes.

New platinum-based chemotherapeutics: a journey beyond cisplatin / G. Facchetti, I. Rimoldi. ((Intervento presentato al convegno DiSFarm Insights tenutosi a Milano nel 2021.

New platinum-based chemotherapeutics: a journey beyond cisplatin

G. Facchetti
;
I. Rimoldi
2021-09-13

Abstract

The discovery of cisplatin and its later approved derivatives started a new era in the bioinorganic medicinal chemistry field but the persistence of severe side-effects along with the emerging of drug resistance evoke the need of a new generation of transition metal-based chemotherapeutics. The starting point of this journey was the preparation of diamine ligands derived from variously substituted N-methyl-2-aminomethyl imidazoles.1 By introducing differently-long saturated and unsaturated chains at N1, the lipophilicity and the consequent cytotoxicity of the corresponding Pt(II)-complexes was modulated whereas its substitution with the 1,2,5-oxadiazole moiety selectively introduced the ability to simultaneously interact with DNA and to interrupt STAT3 signalling pathway.2 Breaking the assumption that bifunctionality is necessary for antiproliferative activity, a series of monofunctional cationic platinum complexes were synthesised showing a potent cytotoxic effect toward triple-negative breast cancer cells and in cancer cell lines partially resistant to cisplatin. Moreover, the prominent stability of this class of platinum complexes suggested also a possible application for MSCs loading to use for advanced cell therapy.3 Moving forward in this field, the effect of the bidentate ligands on the biological activity was highlighted showing for the Pt-8-aminoquinoline series a different biological profile.4 In order to gain some mechanistic insights, the interaction of such platinum-based compounds with some model proteins was investigated through ESI-MS analysis. Since an increasing interest has recently arisen in the development of platinum based theranostic agents, indeed, a series of cyclometalated anionic Pt(II) complexes carrying tetrabromocatechol or alizarine as O^O chelating ligands was developed. This last series of platinum complexes displayed enhanced cytotoxicity toward triple-negative breast cancer (TNBC) and they furthermore resulted emissive in solution.5 Moreover, fluorescence confocal analysis showed their localization in the perinuclear region of MDA-MB231 cells proving their ability to serve as luminescent theranostic probes.
Settore CHIM/03 - Chimica Generale e Inorganica
Dipartimento di Scienze Farmaceutiche-Università degli studi di Milano
New platinum-based chemotherapeutics: a journey beyond cisplatin / G. Facchetti, I. Rimoldi. ((Intervento presentato al convegno DiSFarm Insights tenutosi a Milano nel 2021.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/869321
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