Exploring Chemical Space with Organometallics: Ruthenium Complexes as Protein Kinase Inhibitors

Meggers, Eric; Atilla‐Gokcumen, G. Ekin; Bregman, Howard; Maksimoska, Jasna; Mulcahy, Seann P.; Pagano, Nicholas; Williams, Douglas S.

doi:10.1002/chin.200731205

Cited by 16 publications

(36 citation statements)

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“…The kinetic inertness of the coordination/organometallic bonds make these compounds in principle behave like organic compounds. This approach immensely expands our ability to chart biologically relevant chemical space [36 ]. The group of Meggers has pioneered this approach in their development of organometallic ruthenium complexes that mimic organic enzyme inhibitors.…”

mentioning

confidence: 99%

New trends for metal complexes with anticancer activity

Bruijnincx

Sadler

2008

Current Opinion in Chemical Biology

1,198

718

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Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side-effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selective delivery and/or activation of cisplatin-related prodrugs and the discovery of new non-covalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in 'metals in medicine'. DOI 10.1016DOI 10. /j.cbpa.2007 Introduction Medicinal inorganic chemistry [1 ,2,3] is a field of increasing prominence as metal-based compounds offer possibilities for the design of therapeutic agents not readily available to organic compounds. The wide range of coordination numbers and geometries, accessible redox states, thermodynamic and kinetic characteristics, and the intrinsic properties of the cationic metal ion and ligand itself offer the medicinal chemist a wide spectrum of reactivities that can be exploited. Although metals have long been used for medicinal purposes in a more or less empirical fashion [4], the potential of metal-based anticancer agents has only been fully realised and explored since the landmark discovery of the biological activity of cisplatin [5]. To date, this prototypical anticancer drug remains one of the most effective chemotherapeutic agents in clinical use. It is particularly active against testicular cancer and, if tumours are discovered early, an impressive cure rate of nearly 100% is achieved. The clinical use of cisplatin against this and other malignancies is, however, severely limited by dose-limiting side-effects such as neuro-, hepato-and nephrotoxicity [5]. In addition to the high systemic toxicity, inherent or acquired resistance is a second problem often associated with platinum-based drugs, which further limits their clinical use. Much effort has been devoted to the development of new platinum drugs and the elucidation of cellular responses to them to alleviate these limitations [5,6]. These problems have also prompted chemists to develop alternative strategies based on different metals and aimed at different targets. We summarize here recent activities in the field of metal-based anticancer drugs. This overview highlights some significant recent advances and illustrates emerging trends. New modes of interaction with the classical target, DNAIn classical chemotherapy, anticancer agents target DNA ...

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mentioning

confidence: 99%

New trends for metal complexes with anticancer activity

Bruijnincx

Sadler

2008

Current Opinion in Chemical Biology

1,198

718

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“…2 Kao što je ranije navedeno, Meggers i sur. 13 proučavali su komplekse rutenija s izoindolinskim ligandom kao potencijalne inhibitore protein-kinaze. Na temelju saznanja o aktiv- Sistematski je ispitan utjecaj različitih supstituenata na prstenovima A, B i C. Supstitucija na prstenovima A i B nije dala značajne rezultate, za razliku od supstitucije na prstenu C, gdje su priređeni derivati 23a-n (slika 21) pokazali bolju aktivnost.…”

Section: Biološko Djelovanje Derivata Izoindolinaunclassified

Derivati izoindolina, sinteza i biološka aktivnost. II. Biološka aktivnost derivata izoindolina

Karminski‐Zamola¹

2014

Kem. Ind.

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S l i k a 2 -Triciklički keto derivat izoindolina 2 F i g. 2 -Tricyclic keto-derivative of isoindoline 2 Linden i sur. 3 opisali su 1997. godine derivat izoindolina pazinaklon 3 (DN-2327, slika 3) s anksiolitičkim, antiagresivnim i antikonvulzijskim djelovanjem. Istodobno pazinaklon 3 ne pokazuje sedativni učinak i znakove ovisnosti. U odnosu na poznate psihoaktivne lijekove benzodiazepinskog reda, pazinaklon ima veći afinitet prema GABA-receptorima u mozgu koji sudjeluju u inhibiciji neurotransmisije.Derivati izoindolina, sinteza i biološka aktivnost. II. Biološka aktivnost derivata izoindolinaDerivati izoindolina pokazuju vrlo različita biološka djelovanja in vitro, a neki djeluju i u uvjetima in vivo. Stoga se može očekivati da će istraživanja u budućnosti dovesti i do učinkovitih lijekova za različite vrste bolesti. Pokazuju nesteroidnu protuupalnu aktivnost, antihipertenzivno djelovanje, anksiolitičko, antipsihotičko i antikonvulzivno djelovanje. Djeluju kao lokalni anestetici, vazodilatatori te se vežu na dopaminske i serotononske receptore. Ubrajaju se također u skupinu antidijabetika inhibirajući dipeptidil-peptidaze. Metalni kompleksi izoindolina i njegovih derivata djeluju poput enzima katalaze koji štiti stanice od štetnog djelovanja vodikova peroksida te djeluju i kao inhibitori protein-kinaza. Osim ostalih značajno je njihovo antitumorsko djelovanje na stanice leukemije, karcinoma debelog crijeva, epidermalnog karcinoma te karcinoma jajnika. Oni također inhibiraju enzime koji potiču rast tumorskih stanica kao što su histon deacetilaza te receptori tirozin-kinaze i krvožilnog endotelnog čimbenika rasta (VEGF-R2).Ključne riječi: Biološko djelovanje izoindolina, antitumorsko djelovanje, inhibicija enzima

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“…[40] There is great interest in biomedicine and bio-nanotechnology in studies involving supported metal complexes as enzyme inhibitors. [41] Metals such as ruthenium, osmium, and iridium are capable of forming stable complexes which are not involved in biological environments, thereby expanding the coordination modes limited to carbon. This provides new opportunities for the construction of small molecular structures that cannot be occupied by purely organic compounds.…”

Section: Metallopolymersmentioning

confidence: 99%

From Ruthenium Complexes to Novel Functional Nanocomposites: Development and Perspectives

Segala¹,

Pereira²

2012

New Polymers for Special Applications

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Exploring Chemical Space with Organometallics: Ruthenium Complexes as Protein Kinase Inhibitors

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 16 publications

References 1 publication

New trends for metal complexes with anticancer activity

New trends for metal complexes with anticancer activity

Derivati izoindolina, sinteza i biološka aktivnost. II. Biološka aktivnost derivata izoindolina

From Ruthenium Complexes to Novel Functional Nanocomposites: Development and Perspectives

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