Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti-inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F17%3A00476739" target="_blank" >RIV/68081707:_____/17:00476739 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/17:73583749

Výsledek na webu

<a href="http://dx.doi.org/10.1021/acs.inorgchem.6b02553" target="_blank" >http://dx.doi.org/10.1021/acs.inorgchem.6b02553</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.inorgchem.6b02553" target="_blank" >10.1021/acs.inorgchem.6b02553</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti-inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects

Popis výsledku v původním jazyce

One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than parental conventional Pt(II) drug cisplatin, free DCF and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affect distribution of cells in individual phases of the cell cycle, inhibit glycolysis and lactate transport, collapse mitochondrial membrane potential, and suppress the cellular properties characteristic of metastatic progression.

Název v anglickém jazyce

Novel Antitumor Platinum(II) Conjugates Containing the Nonsteroidal Anti-inflammatory Agent Diclofenac: Synthesis and Dual Mechanisms of Antiproliferative Effects

Popis výsledku anglicky

One concept how to improve anticancer effects of conventional metallodrugs consists in conjugation of these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, biological effects, and mechanisms of action of new Pt(II) derivatives containing one or two nonsteroidal anti-inflammatory diclofenac (DCF) ligands also known for their antitumor effects. The antiproliferative properties of these metallic conjugates show that these compounds are potent and cancer cell selective cytotoxic agents exhibiting activity in cisplatin resistant and the COX-2 positive tumor cell lines. One of these compounds, compound 3, in which DCF molecules are coordinated to Pt(II) through their carboxylic group, is more potent than parental conventional Pt(II) drug cisplatin, free DCF and the congeners of 3 in which DCF ligands are conjugated to Pt(II) via a diamine. The potency of 3 is due to several factors including enhanced internalization that correlates with enhanced DNA binding and cytotoxicity. Mechanistic studies show that 3 combines multiple effects. After its accumulation in cells, it releases Pt(II) drug capable of binding/damaging DNA and DCF ligands, which affect distribution of cells in individual phases of the cell cycle, inhibit glycolysis and lactate transport, collapse mitochondrial membrane potential, and suppress the cellular properties characteristic of metastatic progression.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10402 - Inorganic and nuclear chemistry

Projekt

<a href="/cs/project/GA17-05302S" target="_blank" >GA17-05302S: Protinádorově účinná metalofarmaka cílená na rakovinné kmenové buňky. Studie mechanismu působení</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Inorganic Chemistry

ISSN

0020-1669

e-ISSN

—

Svazek periodika

56

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

1483-1497

Kód UT WoS článku

000393630300052

EID výsledku v databázi Scopus

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