Bioorganometallic Chemistry:  Structural Diversity of Organometallic Complexes with Bioligands and Molecular Recognition Studies of Several Supramolecular Hosts with Biomolecules, Alkali-Metal Ions, and Organometallic Pharmaceuticals

Fish, Richard H.; Jaouen, Gérard

doi:10.1021/om0300777

Cited by 334 publications

(155 citation statements)

References 40 publications

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confidence: 99%

“…Applications in biology and medicine are in their infancy, but the potential for exciting developments is clear (2). In the field of cancer chemotherapy, the cyclopentadienyl complex [Cp 2 TiCl 2 ] has been in clinical trials (3,4), and a ferrocene derivative of Tamoxifen is a candidate for trials for breast cancer therapy (5). The successful design of second-and thirdgeneration platinum anticancer drugs, now widely used in the clinic, has demonstrated that detailed knowledge of the factors that control ligand substitution and redox reactions is very valuable in drug design.…”

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confidence: 99%

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Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

Wang

Habtemariam

Geer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

296

298

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Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional ''piano-stool'' ruthenium(II) arene complexes of the type [( 6 -arene)Ru(ethylenediamine)(X)] n؉ . A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X ‫؍‬ halide [arene ‫؍‬ hexamethylbenzene (hmb)]} or moderately slowly [e.g., X ‫؍‬ azide, dichloropyridine (arene ‫؍‬ hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X ‫؍‬ py) are inactive. An intriguing exception is the X ‫؍‬ thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.anticancer ͉ bioorganometallic ͉ hydrolysis ͉ kinetics ͉ ruthenium complexes O rganometallic chemistry has evolved rapidly during the last 50 years, notably in areas related to catalysis and materials (1). Applications in biology and medicine are in their infancy, but the potential for exciting developments is clear (2). In the field of cancer chemotherapy, the cyclopentadienyl complex [Cp 2 TiCl 2 ] has been in clinical trials (3, 4), and a ferrocene derivative of Tamoxifen is a candidate for trials for breast cancer therapy (5). The successful design of second-and thirdgeneration platinum anticancer drugs, now widely used in the clinic, has demonstrated that detailed knowledge of the factors that control ligand substitution and redox reactions is very valuable in drug design. The chemical reactivity of the complexes can be chosen so as to balance the inertness required for the drug to reach its target site (e.g., DNA) and minimize attack on other sites (side effects) yet allow activation necessary for binding to the target. Thus, cis-[PtCl 2 (NH 3 ) 2 ], cisplatin, is relatively unreactive in high-chloride media (e.g., blood plasma) and is activated by hydrolysis near DNA in the nucleus (6). In contrast, carboplatin and oxaliplatin are relatively inert to hydrolysis, have a milder spectrum of side effects, and probably attack DNA by means of chelate ...

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confidence: 99%

mentioning

confidence: 99%

Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

Wang

Habtemariam

Geer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

296

298

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“…rganometallic chemistry can provide novel concepts in structural diversity and molecular recognition that can be applied to the design of pharmaceutics (1). For example, Jaouen et al (2) have designed antiestrogenic cyclopentadienyl complexes that recognize the estrogen receptor and have potential for treatment of breast cancer, and other workers have also carried out pioneering studies on the recognition of nucleobases, amino acids, and peptides by organometallic centers (1,(3)(4)(5).…”

mentioning

confidence: 99%

“…For example, Jaouen et al (2) have designed antiestrogenic cyclopentadienyl complexes that recognize the estrogen receptor and have potential for treatment of breast cancer, and other workers have also carried out pioneering studies on the recognition of nucleobases, amino acids, and peptides by organometallic centers (1,(3)(4)(5). However, as far as we are aware, there are few investigations of specific interactions of organometallic arene complexes with natural DNA (6).…”

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confidence: 99%

Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers

Chen

Parkinson

Nováková

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

119

112

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Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by 6 -arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [(( 6 -biphenyl)RuCl(en)) 2 -(CH2)6] 2؉ (3, en ‫؍‬ ethylenediamine) was elucidated by studies of the half unit [( 6 -biphenyl)RuCl(Et-en)] ؉ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated R* RuR * N and S* RuR * N diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t1/2 Ϸ 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the R* RuR * N configurations are more stable than S* RuR * N (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to S* RuR * N diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31°) of plasmid DNA, twice that of mononuclear 2 (14°), and effectively inhibited DNA-directed RNA synthesis in vitro. This dinuclear complex gave rise to interstrand cross-links on a 213-bp plasmid fragment with efficiency similar to bifunctional cisplatin, and to 1,3-GG interstrand and 1,2-GG and 1,3-GTG intrastrand cross-links on site-specifically ruthenated 20-mers. Complex 3 blocked intercalation of ethidium considerably more than mononuclear 2. The concept of induced-fit recognition of DNA by organometallic complexes containing dynamic stereogenic centers via dynamic epimerization, intercalation, and cross-linking may be useful in the design of anticancer drugs.

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“…Stability is the major requirement for the biological evaluation of DNA/BSA binding interaction study, so checking the stability of the complexes in solution is very important. 30 DMSO is the most widely preferred solvent to prepare stock solutions for biophysical and biological testing. For many transition metal complexes, DMSO acts as a good ligand, coordinating with the metal center through either the sulfur or oxygen atom.…”

Section: Synthesis Of Ruthenium(ii) Schiff Base Complexesmentioning

confidence: 99%

Catechol Oxidase, Phosphatase-Like Activity, DNA/BSA Binding Studies of RuII Complexes of S-Allyldithiocarbazate: Synthesis and Spectral Studies

Ponnusamy¹,

Rajendiran²,

Nanjundan³

et al. 2016

J. Braz. Chem. Soc.

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New ruthenium(II) complexes with formulae [RuCl(CO)(PPh 3 ) 2 L 1 ] and [RuCl(CO)(PPh 3 ) 2 L 2 ] (L 1 = S-allyl-4-methoxy benzylidene hydrazine carbodithioate, L 2 = S-allyl-1-naphthylidene hydrazine carbodithioate) have been synthesized and characterized by elemental analysis, Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR), UV-Vis, electrospray ionization (ESI)-mass spectral studies. Both the Schiff base ligands are coordinated to ruthenium through azomethine nitrogen (C=N) and thiolato sulfur donor atoms in the thiolate form. On the basis of spectral data obtained, an octahedral structure has been assigned to all the new complexes, satisfied by coordination of donor atoms N and S. The stability of complexes in solution was determined by molar conductivity measurements. The interaction of the two complexes with calf thymus (CT) DNA was investigated by fluorescence spectroscopic and viscometric methods. Bovine serum albumin (BSA) protein was examined by fluorescence spectroscopic methods. These techniques indicate that the two metal complexes bind to DNA via intercalation mode and BSA bind with static interaction. Catecholase and phosphatase like activities promoted by these two complexes under physiological conditions have been studied. In vitro anticancer activities have been demonstrated by 3,4,5-dimethylthiazolyl-2-2,5-diphenyltetrazolium bromide (MTT) assay, acridine orange/ethidium bromide (AO/EB) and diamidino-2-phenylindole (DAPI) staining against HeLa cancer cell line.

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Bioorganometallic Chemistry: Structural Diversity of Organometallic Complexes with Bioligands and Molecular Recognition Studies of Several Supramolecular Hosts with Biomolecules, Alkali-Metal Ions, and Organometallic Pharmaceuticals

Cited by 334 publications

References 40 publications

Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers

Catechol Oxidase, Phosphatase-Like Activity, DNA/BSA Binding Studies of RuII Complexes of S-Allyldithiocarbazate: Synthesis and Spectral Studies

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