Bioorganometallic Chemistry

A series of new γ-aminobutyric acid (GABA) derivatives was obtained from 4-(1,3-dioxoisoindolin-2-yl)butanoic acid by coupling it with various substituted amines by using DCC as coupling reagent. The compound 3 was synthesized by treating GABA and phthalimide at high temperature under anhydrous conditions. All the synthesized compounds were confirmed and characterized by using various spectral technique like (IR, 1H NMR, 13C NMR, and mass spectroscopy) studies. Anticonvulsant evaluations of all the synthesized compounds were done by using various seizures models like maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and intraperitoneal picrotoxin (ipPIC)-induced seizure threshold tests at a dose of 30, 100, and 300 mg/kg body weight and anticonvulsant activity was noted at 0.5 and 4 h time intervals after the drug administration. The compound 4a 4-(1,3-dioxoisoindolin-2-yl)-N-phenylbutanamide displayed weak anticonvulsant activity in MES test at a dose of 300 mg/kg. Analogs 4d, 4h, and 4m displayed promising activity in scPTZ seizures model. Most of the synthesized compounds were found to be effective in the scSTY and ipPIC models and very few compounds showed protection in the scPTZ model. Among all the tested compounds, 4h 4-(1,3-dioxoisoindolin-2-yl)-N-(4-ethylphenyl)butanamide showed protection in various seizures model except in the scSTY model, while analog 4d was found to be the most potent compound in scPTZ model showing protection at a dose of 30 mg/kg. Further all the compounds exhibited lesser neurotoxicity compared with standard drug. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.

This study confirms previous reports of the antiproliferative effect of OH–ferrocifen on both hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell models. Contrastive analysis of the proliferative effects of classical agonists (including estradiol and ethynylestradiol) and selective estrogen receptor modulators (SERMs) such as tamoxifen and its active metabolite, 4-hydroxy-tamoxifen, was also performed. Previous studies have attributed the effects of OH–ferrocifen on hormoneindependent cells to an underlying mechanism based on intracellular oxidation, production of hydroxyl radicals and oxidative damage of DNA. Here we report that the chemically generated OH–ferrocifen cation (as well as the decamethylferrocenium cation) is less cytotoxic to both cell lines than the neutral parent complex. Moreover, fluorescence activated cell sorting (FACS) analysis of 8-oxo-guanine production indicates that, even at relatively high concentrations, OH–ferrocifen produces negligible oxidative DNA damage as compared to other SERMs, namely tamoxifen and 4-hydroxy- amoxifen. Alternative pathways to explain the remarkable activity of OH–ferrocifen must therefore be sought.

In this work, we prepared for the first time triphenylantimony(V) catecholate complexes containing gallic acid derivatives and assessed their radical-scavenging activity in reaction with 2,2-diphenyl-picrylhydrazyl (DPPH) radical and in the non-enzymatic peroxidation of oleic (cis-9-octadecenoic) acid. The compounds were shown to display antiradical activity in the test with DPPH radical. Taking into account the EC50 value, we believe that the activity of complex (CH3O(O)C–Cat)SbPh3 (1) compares well with that of the known antioxidant L-ascorbyl palmitate. Compounds 1–3 are not only efficient inhibitors of oleic acid autooxidation but also behave as hydroperoxide destructors. Compounds of such a kind can be considered as potential antioxidants containing an organo
metallic fragment.

Ferrociphenols have been found to have high antiproliferative activity against estrogen-independent breast cancer cells. The rat and human liver microsome-mediated metabolism of three compounds of the ferrocifen (FC) family, 1,1-bis(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC1), 1-(4-hydroxyphenyl)-1-(phenyl)-2-ferrocenyl-but-1-ene (FC2), and 1-[4-(3-dimethylaminopropoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC3), was studied. Three main metabolite classes were identified: quinone methides (QMs) deriving from two-electron oxidation of FCs, cyclic indene products (CPs) deriving from acid-catalyzed cyclization of QMs, and allylic alcohols (AAs) deriving from hydroxylation of FCs. These metabolites are generated by cytochromes P450 (P450s), as shown by experiments with either N-benzylimidazole as a P450 inhibitor or recombinant human P450s. Such P450-dependent oxidation of the phenol function and hydroxylation of the allylic CH2 group of FCs leads to the formation of QM a...

The synthesis and evaluation of benzetimide derivatives showing potent CXCR3 antagonism are described. Optimization of the screening hits led to the identification of more potent CXCR3 antagonists devoid of anti-cholinergic activity and identification of the key pharmacophore moieties of the series.

It is well known that metal ions play an important role in the biological and biomedical processes. Many processes such as breathing, metabolism, photosynthesis, growth, reproduction, muscle contraction cannot be imagined without the presence of some metal ions. Bioinorganic chemistry, among other thing, is focused on mechanism of biological processes in the organism that occur during applications of essential and non-essential element’s compounds in medicine. Many metal-based coordination compounds are widely used in medicine for the treatment of many diseases, including various cancers, Alzheimer's disease, diabetes, rheumatoid arthritis, etc. 
In this monograph, the influence of HSAB principle on preference of central metal ions to biologically relevant molecule has been discussed. Taking into account the author’s scientific work on investigations the kinetics and mechanism of interaction between transition metal-based compounds with potential  antitumor activity, such as Pt(II), Pd(II) (soft acids) and Zn(II) and Cu(II) (intermediate acids) and biomolecules, a review of the scientific results in this field has been made. Author for more than  two decades, investigate substitution processes of monofunctional, bifunctional and dinuclear complexes  of platinum(II), palladium(II), lately, zinc(II) and copper(II) with biologically relevant nucleophiles.
In this monograph selected results from this field have been reported, considering the high velocity of developments. I hope this monograph will help the researchers and will be catalytic for the students to join research groups which are motivated and engaged in discovery of new knowledges which contribute to expansion of bioinorganic chemistry fields.

The aim of this work was to investigate the mechanism of action of 2-ferrocenyl-1,1-diphenylbut-1-ene (1) on HL-60 human leukemia cells. While inactive against noncancerous cells, 1 provoked a concentration-dependent decrease in viable tumor cells, primarily via apoptosis, as evidenced by analysis of cell morphology, activation of caspases 3 and 7, increased DNA fragmentation, and externalization of phosphatidylserine. Necrosis was observed only at the highest tested concentration (4 μM). Compound 1 interfered with the cell cycle, causing an accumulation of cells in the G1 /G0 phase. Interaction of 1 with dsDNA and ssDNA was observed by differential pulse voltammetry and confirmed by hyperchromicity in the UV/Vis spectra of dsDNA, with an interaction constant of 2×10(4) M(-1). Both the organic analogue 1,1,2-triphenylbut-1-ene (2) and ferrocene were inactive against cancer and noncancer cell lines and did not react with DNA. These results reinforce the idea that the hybrid strategy of conjugating ferrocene to the structure of tamoxifen derivatives is advantageous in finding new substances with antineoplastic activity.

Los bioelementos primarios son los elementos indispensables para formar las biomoléculas orgánicas (glúcidos,lípidos, proteínas y ácidos nucleicos); constituyen el 96% de la materia viva seca. Son el carbono, el hidrógeno, el oxígeno, el nitrógeno, el fósforo y el azufre (C, H, O, N, P, S, respectivamente). Carbono: forman largas cadenas carbono-carbono (macromoléculas) mediante enlaces simples (-CH2-CH2) o dobles (-CH=CH-), así como estructuras cíclicas. Los enlaces que forma son lo suficientemente fuertes como para formar compuestos estables, y a la vez son susceptibles de romperse sin excesiva dificultad. Por esto, la vida está constituida por carbono y no por silicio, un átomo con la configuración electrónica de su capa de valencia igual a la del carbono Hidrógeno: además de ser uno de los componentes de la molécula de agua, indispensable para la vida y muy abundante en los seres vivos, forma parte de los esqueletos de carbono de las moléculas orgánicas. Puede enlazarse con cualquier bioelemento. Oxígeno: es un elemento muy electronegativo que permite la obtención de energía mediante la respiración aeróbica. Nitrógeno: principalmente como grupo amino (-NH2.) presente en las proteínas ya que forma parte de todos los aminoácidos. También se halla en las bases nitrogenadas de los ácidos nucleicos. Prácticamente todo el nitrógeno es incorporado al mundo vivo como ion nitrato, por las plantas. El gas nitrógeno solo es aprovechado por algunas bacterias del suelo y algunas cianobacterias. Fósforo. Se halla principalmente como grupo fosfato (PO43-) formando parte de los nucleótidos. Forma enlaces ricos en energía que permiten su fácil intercambio (ATP). Azufre. Se encuentra sobre todo como radical sulfhidrilo (-SH) formando parte de muchas proteínas, donde crean enlaces disulfuro esenciales para la estabilidad de la estructura terciaria y cuaternaria.

... DdH hydrogenase, a second one being the bridging (Cp I) or essentially terminal (DdH) mode of coordination of the CO beneath the Fe–Fe vector. ... The high efficiency of dihydrogen production by the [FeFe]H 2 ases [4], the need for new energy sources as an alternative to fossil ...

Pyrone scaffolds are often present in natural products and many derivatives therefore exhibit favorable biocompatibility and toxicity profiles. Hydroxypyrones are obtained from natural sources or can be synthesized by different well established approaches and may easily be converted into the analogous thiopyrones and hydroxypyridones. These features make them well suited to drug development and other biological applications. Herein, we summarize

Bioorganometallic iron-aryl and iron-alkyl adducts of hemoproteins are known to contain an S = 1/2 ferric center σ-bonded to a carbon atom. Here, DFT geometry optimization results are reported for models of the known phenyl and methyl adducts of heme-thiolate and heme-histidine enzyme active sites. Differences among thiolate and imidazole ligated models are examined, and parallels are drawn between these complexes (where the trans effect of thiolate and imidazole axial ligands shows virtually no π component) and heme-peroxo or-superoxo complexes of hemoproteins (where a well-defined π component is expected to exist). A novel, entirely mechanical, component of the " thiolate push " effect in cytochrome P450 monooxygenase is discussed.

Hydroxyferrocifen compounds are a new and promising class of ferrocifen-type breast-cancer drug candidates. They possess both endocrine-modulating properties and cytotoxic activity, which come from the tamoxifen skeleton and the presence of a ferrocene moiety, respectively. However, they suffer from reduced solubility in water, which presents a problem for their eventual therapeutic use. Herein, we examined the interactions of hydroxyferrocifen compounds with cyclodextrins (CDs) to evaluate whether or not their electron-transfer oxidation pathways were affected by their inclusion. It has been demonstrated that these inclusion complexes are soluble in pure water, which shows that CDs can be used to deliver these biologically active molecules. Therefore, a series of these compounds has been investigated by cyclic voltametry in various media in the presence of CDs (beta-CD and Me-beta-CD). In methanol, the hydroxyferrocifen compounds exhibited a weak interaction with the CD cavity. These interactions became stronger as the amount of added water increased. The complexation effect between the hydroxyferrocifen compounds and beta-CD was found to be stronger if the CD was partially methylated, which is probably due to hydrophobic effects between the cyclopentadienyl ring and/or the aromatic rings and the methoxy groups. Moreover, it appears that the structure of the hydroxyferrocifen compounds affects both their solubility and their complexation dynamics. Investigations in the presence of pyridine show that the base kinetically favors the dissociation of the ferrocifen-CD complex during the electron transfer step, but does not affect the follow-up reactivity of the electrogenerated ferrocenium cation, which leads eventually to the corresponding quinone methide, as reported in the absence of CD. Accordingly, the cytotoxicity of these beta-CD-encapsulated organometallic complexes in hormone-independent breast-cancer cells (MDA-MB231) were confirmed to be similar to those obtained in the absence of cyclodextrin.