取代基对有机金属铼化合物中分子内α-氢转移反应势垒的影响

使用B3LYP方法研究了有机铼化合物R³R⁵(NHR⁴)Re(＝CHR¹)(＝NR²)中分子内α-氢转移反应, 探讨了不同取代基对α-氢转移反应势垒的影响. 研究发现, 可以通过改变取代基来影响过渡金属Re有机化合物中的α-氢转移反应. R¹位置的取代基为Me或CMe₃时, 可以较大程度降低α-氢转移反应的势垒. R²为H时, α-氢转移反应势垒最低. R³和R⁵位置为SiH₃时的反应势垒最低. R⁴为CMe₃时, α-氢转移反应势垒最低. 研究结果还表明, 取代基对于反应势垒的影响有加和性.     

Light-Activated Rhenium Complexes with Dual Mode of Action against Bacteria

New antibiotics and innovative approaches to kill drug-resistant bacteria are urgently needed. Metal complexes offer access to alternative modes of action but have only sparingly been investigated in antibacterial drug discovery. We have developed a light-activated rhenium complex with activity against drug-resistant S. aureus and E. coli. The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.     

薄层色谱法在金属有机合成中的应用

This paper describes a simple thin-layer chromatographic methed for monitoring the reaction process,separation and purity of the organometallic compounds.     

Highlights of New Strategies to Increase the Efficacy of Transition Metal Complexes for Cancer Treatments

Although important progress has been made, cancer still remains a complex disease to treat. Serious side effects, the insurgence of resistance and poor selectivity are some of the problems associated with the classical metal-based anti-cancer therapies currently in clinical use. New treatment approaches are still needed to increase cancer patient survival without cancer recurrence. Herein, we reviewed two promising—at least in our opinion—new strategies to increase the efficacy of transition metal-based complexes. First, we considered the possibility of assembling two biologically active fragments containing different metal centres into the same molecule, thus obtaining a heterobimetallic complex. A critical comparison with the monometallic counterparts was done. The reviewed literature has been divided into two groups: the case of platinum; the case of gold. Secondly, the conjugation of metal-based complexes to a targeting moiety was discussed. Particularly, we highlighted some interesting examples of compounds targeting cancer cell organelles according to a third-order targeting approach, and complexes targeting the whole cancer cell, according to a second-order targeting strategy.     

稀土金属有机配合物化学60年

60年来稀土金属有机配合物化学取得重要发展. 辅助配体从环戊二烯基,五甲基环戊二烯基,茚基发展到各种非茂配体,如双酚,β-二亚胺,胍基,脒基等. 配合物的种类从简单的三茂稀土配合物发展到各种形式的二茂稀土配合物和单茂稀土配合物. 非茂配体的应用不仅拓展了稀土金属有机配合物的结构种类,还极大推动稀土金属有机配合物在高分子和有机合成中的应用. 稀土金属有机配合物可有效催化烯烃均聚与共聚,共轭双烯烃以及极性单体的选择性聚合. 稀土金属有机配合物还能催化氢化,氢胺化和膦氢化等重要有机反应. 本文对稀土金属有机配合物化学过去60年的发展进行综述.     

Decomposition of Organometallic Complexes in the Mass Spectrometer

The reliable interpretation of mass spectra for the determination of molecular constitutions requires systematic studies on the fragmentation behavior of classes of compounds, since the large number of kinetic and energy parameters that determine the decomposition of excited polyatomic ions makes ab-initio predictions of spectra almost impossible. In this progress report, a number of general rules for the decomposition of organometallic complexes upon electron impact are discussed; a classification into decomposition types is also presented, and is illustrated by selected examples.     

茂型稀土金属有机配合物催化甲基丙烯酸酯类聚合研究进展

综述了茂型稀土金属有机配合物催化甲基丙烯酸酯类聚合的研究现状和最新进展。系统地介绍了不同的茂型稀土金属有机催化体系中温度、反应时间、溶剂等条件对催化甲基丙烯酸酯类聚合的影响规律,并研究其催化反应机理,最后展望茂型稀土金属有机化学今后的研究方向及前景。     

Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes

Rhenium tricarbonyl complexes have been recently investigated as novel anticancer agents. However, little is understood about their mechanisms of action, as well as the means by which cancer cells respond to chronic exposure to these compounds. To gain a deeper mechanistic insight into these rhenium anticancer agents, we developed and characterized an ovarian cancer cell line that is resistant to a previously studied compound [Re(CO)₃(dmphen)(ptolICN)]⁺, where dmphen=2,9‐dimethyl‐1,10‐phenanthroline and ptolICN=para‐tolyl isonitrile, called TRIP. This TRIP‐resistant ovarian cancer cell line, A2780TR, was found to be 9 times less sensitive to TRIP compared to the wild‐type A2780 ovarian cancer cell line. Furthermore, the cytotoxicities of established drugs and other rhenium anticancer agents in the TRIP‐resistant cell line were determined. Notably, the drug taxol was found to exhibit a 184‐fold decrease in activity in the A2780TR cell line, suggesting that mechanisms of resistance towards TRIP and this drug are similar. Accordingly, expression levels of the ATP‐binding cassette transporter P‐glycoprotein, an efflux transporter known to detoxify taxol, were found to be elevated in the A2780TR cell line. Additionally, a gene expression analysis using the National Cancer Institute 60 cell line panel identified the MT1E gene to be overexpressed in cells that are less sensitive to TRIP. Because this gene encodes for metallothioneins, this result suggests that detoxification by this class of proteins is another mechanism for resistance to TRIP. The importance of this gene in the A2780TR cell line was assessed, confirming that its expression is elevated in this cell line as well. As the first study to investigate and identify the cancer cell resistance pathways in response to a rhenium complex, this report highlights important similarities and differences in the resistance responses of ovarian cancer cells to TRIP and conventional drugs.     

Preparation of Organometallic Ruthenium–Arene–Diaminotriazine Complexes as Binding Agents to DNA

The reactions of two diaminotriazine ligands 2,4‐diamino‐6‐(2‐pyridyl)‐1,3,5‐triazine (2‐pydaT) and 6‐phenyl‐2,4‐diamino‐1,3,5‐triazine (PhdaT) with ruthenium–arene precursors led to a new family of ruthenium(II) compounds that were spectroscopically characterized. Four of the complexes were cationic, with the general formula [(η⁶‐arene)Ru(κ²‐N,N‐2‐pydaT)Cl]X (X=BF₄, TsO; arene=p‐cymene: 1.BF4 , 1.TsO arene=benzene: 2.BF4 , 2.TsO ). The neutral cyclometalated complex [(η⁶‐p‐cymene)Ru(κ²‐C,N‐PhdaT*)Cl] ( 3 ) was also isolated. The structures of complexes 2.BF4 and 3.H2O were determined by X‐ray diffraction. Complex 1.BF4 underwent a partial reversible‐aquation process in water. UV/Vis and NMR spectroscopic measurements showed that the reaction was hindered by the addition of NaCl and was pH‐controlled in acidic solution. At pH 7.0 (sodium cacodylate) Ru–Cl complex 1.BF4 was the only species present in solution, even at low ionic strength. However, in alkaline medium (KOH), complex 1.BF4 underwent basic hydrolysis to afford a Ru–OH complex ( 5 ). Fluorimetric studies revealed that the interaction of complex 1.BF4 with DNA was not straightforward; instead, its main features were closely linked to ionic strength and to the [DNA]/complex ratio. The bifunctional complex 1.BF4 was capable of interacting concurrently through both its p‐cymene and 2‐pydaT groups. Cytotoxicity and genotoxicity studies showed that, contrary to the expected behavior, the complex species was biologically inactive; the formation of a Ru–OH complex could be responsible for such behavior.     

pH and Reduction Dual-Responsive Nanogels as Smart Nanocarriers to Resist Doxorubicin Aggregation

The use of smart nanocarriers that can modulate therapeutic release aided by biological cues can prevent undesirable cytotoxicity caused by the premature release of cytotoxic drugs during nanocarrier circulation. In this report, degradable nanocarriers based on pH/reduction dual-responsive nanogels were synthesized to encapsulate doxorubicin hydrochloride (DOX) and specifically boost the release of DOX in conditions characteristic of the cancer microenvironment. Nanogels containing anionic monomer 2-carboxyethyl acrylate (CEA) and N,N′-bis(acryloyl)cystamine (CBA) as a degradable crosslinker have been successfully synthesized via photoinitiated free radical polymerization. The loading process was conducted after polymerization by taking advantage of the electrostatic interaction between the negatively charged nanogels and the positively charged DOX. In this case, a high drug loading capacity (DLC) of up to 27.89% was achieved. The entrapment of DOX into a nanogel network could prevent DOX from aggregating in biological media at DOX concentrations up to ~160 µg/mL. Anionic nanogels had an average hydrodynamic diameter (d_H) of around 90 nm with a negative zeta (ζ) potential of around −25 mV, making them suitable for targeting cancer tissue via the enhanced permeation effect. DOX-loaded nanogels formed a stable dispersion in different biological media, including serum-enriched cell media. In the presence of glutathione (GSH) and reduced pH, drug release was enhanced, which proves dual responsivity. An in vitro study using the HCT 116 colon cancer cell line demonstrated the enhanced cytotoxic effect of the NG-CBA/DOX-1 nanogel compared to free DOX. Taken together, pH/reduction dual-responsive nanogels show promise as drug delivery systems for anticancer therapy.     

Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides

The synthesis and chemical oxidation profile of a new generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular, the hydroxypropyl derivative HO(CH₂)₃C(Fc)=C(C₆H₄OH)₂ ( 3 b ) exhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA‐MB‐231 TNBC, with IC₅₀ values of 0.07 and 0.11 μM , respectively. Chemical oxidation of 3 b yielded an unprecedented tetrahydrofuran‐substituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH₃CH₂‐C(Fc)=C(C₆H₄OH)₂ merely formed a vinyl QM. The ferrocenyl group in 3 b plays a key role, not only as an intramolecular reversible redox “antenna”, but also as a stabilized carbenium ion “modulator”. The presence of the oxygen heterocycle in 3 b‐QM enhances its stability and leads to a unique chemical oxidation profile, thus revealing crucial clues for deciphering its mechanism of action in vivo.     

Synthesis of HPMA Copolymers Containing Doxorubicin Bound via a Hydrazone Linkage. Effect of Spacer on Drug Release and in vitro Cytotoxicity

The aim of this study was the synthesis, physico‐chemical characterization and preliminary evaluation of biological activity of novel polymer drugs based on conjugates of anti‐cancer drug doxorubicin (Dox) with water‐soluble polymer drug carriers based on N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymers. In the conjugates, Dox is attached to the polymer via a pH‐sensitive linkage susceptible to hydrolysis at pH ≈ 5–6, thus enabling intracellular Dox release. Seven Dox‐containing polymer conjugates differing in the length and structure of the single‐amino‐acid or oligopeptide spacer were synthesized (Gly, β‐Ala, 6‐aminohexanoyl, 4‐aminobenzoyl, GlyGly, GlyLeuGly, Gly‐DL ‐PheLeuGly) and the relationship between the spacer structure and the rate of in vitro Dox release was studied at various pH. The rate of Dox release at pH 5 (close to lysosomal pH) ranged from 70 to 96% of total Dox/48 h, depending on the spacer structure and being the highest for the conjugate containing the 6‐aminohexanoyl spacer. The rate of Dox release from most conjugates incubated at pH 7.4 (blood pH) was more than 10 times slower, ca. 4–10% of total Dox/48 h. Molecular weight of the polymer (25 000–115 000 g/mol) did not significantly influence the rate. The presence of lysosomal enzyme cathepsin B in incubation media increased the rate of Dox release from the conjugates with oligopeptide GlyLeuGly and Gly‐DL ‐PheLeuGly spacers by 15–30%, whereas the release from conjugates with other spacers remained unchanged. Cytotoxicity of all hydrazone conjugates for mouse EL‐4 T cell lymphoma cells was much higher and close to that of free Dox (IC₅₀ ≈ 0.1–0.34 μg Dox/mL), in contrast to cytotoxicity of similar classic conjugates bearing Dox attached via an amide bond (IC₅₀ ≈ 19 μg Dox/mL).     

Arene Control over Thiolate to Sulfinate Oxidation in Albumin by Organometallic Ruthenium Anticancer Complexes

Arene control : Anticancer complexes [Ru(arene)Cl(en)]⁺ (arene=p‐cymene or biphenyl; en=ethylenediamine) bind to surface histidine (His128, His247, His510) and methionine (Met298) residues in human albumin, but only the p‐cymene complex can gain entry to the crevice containing the free cysteine thiolate (Cys34) and induce oxidation to sulfinate.

     

茂型稀土金属有机配合物的合成与表征研究进展

本文综述了茂型稀土金属有机配合物的研究现状和最新进展。系统地介绍了茂型稀土金属有机配合物的特征、合成、以及结构表征方法,并着重介绍了典型三茂型、二茂型、含茚基、含芴基稀土金属有机配合物的晶体结构。最后,展望其发展趋势和研究方向。     

Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review

The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases and deaths are increasing at a rapid rate worldwide. Doxorubicin, an anticancer agent, is currently used to treat several types of cancer. It disrupts myriad processes such as histone eviction, ceramide overproduction, DNA-adduct formation, reactive oxygen species generation, Ca²⁺, and iron hemostasis regulation. However, its use is limited by factors such as drug resistance, toxicity, and congestive heart failure reported in some patients. The combination of doxorubicin with other chemotherapeutic agents has been reported as an effective treatment option for cancer with few side effects. Thus, the hybridization of doxorubicin and other chemotherapeutic drugs is regarded as a promising approach that can lead to effective anticancer agents. This review gives an update on hybrid compounds containing the scaffolds of doxorubicin and its derivatives with potent chemotherapeutic effects.     

From Composition to Cure: A Systems Engineering Approach to Anticancer Drug Carriers

The molecular complexity and heterogeneity of cancer has led to a persistent, and as yet unsolved, challenge to develop cures for this disease. The pharmaceutical industry focuses the bulk of its efforts on the development of new drugs, but an alternative approach is to improve the delivery of existing drugs with drug carriers that can manipulate when, where, and how a drug exerts its therapeutic effect. For the treatment of solid tumors, systemically delivered drug carriers face significant challenges that are imposed by the pathophysiological barriers that lie between their site of administration and their site of therapeutic action in the tumor. Furthermore, drug carriers face additional challenges in their translation from preclinical validation to clinical approval and adoption. Addressing this diverse network of challenges requires a systems engineering approach for the rational design of optimized carriers that have a realistic prospect for translation from the laboratory to the patient.     

Coupling of SPME and GC-AED for the Determination of Organometallic Compounds

 The solid-phase microextraction (SPME) technique coupled with gas chromatography and atomic emission detection was successfully applied for the determination of selected organometallic species of Pb, As and Hg in aqueous samples. To obtain a high extraction yield, the SPME conditions were optimised for each element by fibre selection and varying the exposure time, stirring rate, pH range and desorption time. All the organometallic compounds tested were extracted from the aqueous phase using SPME. The preconcentration factors attained ranged between 40 and 150, depending on the compound. Detection limits in the pg/L and ng/L ranges were achieved. Received January 18, 2000. Revision April 11, 2000.     

Ligand‐Modification Effects on the Reactivity,Solubility, and Stability of Organometallic Tantalum Complexes in Water

Tantalum complexes [TaCp*Me{κ⁴‐C,N,O,O‐(OCH₂)(OCHC(CH₂NMe₂)?CH)py}] ( 4 ) and [TaCp*Me{κ⁴‐C,N,O,O‐(OCH₂)(OCHC(CH₂NH₂)?CH)py}] ( 5 ), which contain modified alkoxide pincer ligands, were synthesized from the reactions of [TaCp*Me{κ³‐N,O,O‐(OCH₂)(OCH)py}] (Cp*=η⁵‐C₅Me₅) with HC?CCH₂NMe₂ and HC?CCH₂NH₂, respectively. The reactions of [TaCp*Me{κ⁴‐C,N,O,O‐(OCH₂)(OCHC(Ph)?CH)py}] ( 2 ) and [TaCp*Me{κ⁴‐C,N,O,O‐(OCH₂)(OCHC(SiMe₃)?CH)py}] ( 3 ) with triflic acid (1:2 molar ratio) rendered the corresponding bis‐triflate derivatives [TaCp*(OTf)₂{κ³‐N,O,O‐(OCH₂)(OCHC(Ph)?CH₂)py}] ( 6 ) and [TaCp*(OTf)₂{κ³‐N,O,O‐(OCH₂)(OCHC(SiMe₃)?CH₂)py}] ( 7 ), respectively. Complex 4 reacted with triflic acid in a 1:2 molar ratio to selectively yield the water‐soluble cationic complex [TaCp*(OTf){κ⁴‐C,N,O,O‐(OCH₂)(OCHC(CH₂NHMe₂)?CH)py}]OTf ( 8 ). Compound 8 reacted with water to afford the hydrolyzed complex [TaCp*(OH)(H₂O){κ³‐N,O,O‐(OCH₂)(OCHC(CH₂NHMe₂)?CH₂)py}](OTf)₂ ( 9 ). Protonation of compound 8 with triflic acid gave the new tantalum compound [TaCp*(OTf){κ⁴‐C,N,O,O‐(OCH₂)(HOCHC(CH₂NHMe₂)?CH)py}](OTf)₂ ( 10 ), which afforded the corresponding protonolysis derivative [TaCp*(OTf)₂{κ³‐N,O,O‐(OCH₂)(HOCHC(CH₂NHMe₂)?CH₂)py}](OTf) ( 11 ) in solution. Complex 8 reacted with CNtBu and potassium 2‐isocyanoacetate to give the corresponding iminoacyl derivatives 12 and 13 , respectively. The molecular structures of complexes 5 , 7 , and 10 were established by single‐crystal X‐ray diffraction studies.