Nucleophilic Susceptibility Research Articles

Synthesis and Experimental Structure of a Multifunctional Catechol‐Azomethinebenzoic Acid, DFT/DMol3 Calculations, and Molecular Docking with Hsp90

AbstractThe multifunctional catechol‐azomethine‐benzoic acid derivative 4‐[(E)‐[(2,3‐dihydroxyphenyl)methylidene]amino]benzoic acid (1) was prepared and the structure were confirmed by EI‐MS and 1H and 13C NMR spectroscopy. A Single‐crystal X‐ray diffraction study revealed coplanarity of the two aromatic rings within the imine function, supported by intramolecular N−H⋯O hydrogen bonds. In the crystal structure intermolecular O−H⋯O hydrogen bonds form chains, propagating along [010]. FT‐IR and Hirshfeld surface analysis confirms the multiple hydrogen bonding. DFT/DMol3 calculations localized the highest occupied molecular orbital (HOMO) on the o‐catechol unit, while the lowest unoccupied molecular orbital (LUMO) is delocalized over the entire molecule. The calculated map of electrostatic potential (MEP) showed relatively low values for both electrophilic and nucleophilic susceptibility. A molecular docking study of 1 in comparison with the established inhibitor geldanamycin (G) using the protein structure of the heat shock protein 90 co‐crystallized with G (Hsp90⋅G) showed that 1 occupies the same binding pocket as G in the Hsp90⋅G structure, indicating that the title structure might be a suitable inhibitor. The Swiss ADME approach showed promising general drug‐likeness properties for 1 with a relatively high lipophilicity (logP=1.68) and a logS value of −2.99 which lies in the middle of the logS distribution of traded drugs.

Epigallocatechin Gallate (EGCG) – A Novel Covalent NF- κB Inhibitor: Structural and Molecular Characterization

Tea contains antioxidant catechins thought to exert health-promoting protective effects against conditions involving chronic inflammation, such as cardiovascular diseases. The most abundant catechin in tea is Epigallocatechin Gallate (EGCG), thought to be a key contributor to tea’s health-promoting actions. EGCG exerts protective cardiovascular effects via its antioxidant, antiinflammatory, hypolipidemic, anti-thrombogenic, and anti-hypertensive actions. Because EGCG inhibits the strong proinflammatory gene-inducing transcription factor NF-κB, we analyzed the chemical and molecular details of the mechanism by which EGCG mediates NF-κB inhibition. We quantified and mapped key parameters of its chemical reactivity including its electrophilic Fukui ƒ+ function, in silico covalent binding, and identified its frontier Molecular Orbitals (MOs) and nucleophilic susceptibility. These physical and chemical reactivity parameters revealed that the bond-forming MOs are distributed on the B ring of the EGCG oxidized state with nucleophilic susceptibility, and that this B ring has properties that favor participating in a Cys-alkylating 1,4-addition reaction. Molecular modeling and docking analysis further revealed that EGCG bonds covalently with Cys-38 of NF-κB-p65, and thereby inhibits its DNA binding ability. We also generated a model pharmacophore based on the EGCG-NF-κB complex. We conclude that EGCG covalently binds to NF-κB-p65 and inhibits it by abolishing its DNA binding, by chemical mechanisms that may inform design of EGCG derivatives as novel anti-inflammatory agents.

Hybridized Fe/Ru-SiMWCNT-ionic liquid nanofluid for CO2 conversion into carbamate using superoxide ion

Suppressing the nucleophilic susceptibility of ionic liquids based nanofluid is necessary for energy storage and superoxide ion (O2•−) utilization. This study reports the development of novel pseudocapacitive Fe/Ru-SiMWCNT nanofluid comprising of Fe3O4, RuO2, SiO2, and MWCNT hybridized phases. The Fe/Ru-SiMWCNT nanohybrid possessed CO2 and O2 sorption capability, as confirmed from the temperature-programmed desorption experiments. Detailed spectroscopy techniques characterize the Fe/Ru-SiMWCNT nanohybrid component's physicochemical and morphological properties. The novel ionic liquid (IL) based nanofluid index is Fe/Ru-SiMWCNT/1-(2-methoxyethyl)-1-methylpyrrolidinium tris(pentafluoroethyl) trifluorophosphate. Therefore, stable O2•− was generated therein at −0.445 V vs Ag/AgCl and recorded long-term stability for 2 days with 87.31 % efficiency. Moreover, the O2•− mediated CO2 conversion to C2O62− at −0.54 V vs Ag/AgCl with 97.90 % energy efficiency. Also, the normalized exchange current density in the nanofluid was 2.20 mA/cm2, which is higher than 1.94 mA/cm2 observed in the IL counterpart. The high normalized exchange current density is due to Fe/Ru-SiMWCNT nanohybrid phase's pseudocapacitance. Accordingly, this pseudocapacitive capability enables converting O2 and CO2 in the nanofluid with lower activation overpotential of −0.305 and −0.460 V vs Ag/AgCl, respectively. In contrast, the conversion of O2 and CO2 in the IL required higher activation overpotential of −0.826 and −1.013 V vs Ag/AgCl, respectively. The electrolysis of O2/CO2 in the nanofluid containing diethanolamine at −1.564 V vs Ag/AgCl, 60 °C and 1.0 h produced methyl 2-hydroxyethyl (methyl) carbamate as the primary product. The heteronuclear multiple bond correlation spectroscopy analysis finally elucidated the carbamate structure by two strong correlations between the protons and carbons in the vicinity of three and four bonds apart. Therefore, this study highlights the control design of electrochemically stable IL-based nanofluids robust for reactive oxygen species, energy storage and conversion.

Синтез 1,1'-оксалилдибензотриазола, изучение кинетических и термодинамических особенностей его гидролиза и прогнозирование биологической активности

The article describes a two-step method for the synthesis of 1,1'-oxalyl dibenzotriazole (bis(1H-benzotriazol-1-yl)ethane-1,2-dione) from benzotriazole via 1-trimethylsilylbenzotriazole, followed by reaction with oxalyl chloride; the yield of the final product is 87%. The kinetics of hydrolysis, alcoholysis and aminolysis of 1,1'-oxalyldibenzotriazole was studied in the systems acetonitrile – water (9 : 1), acetonitrile – methanol (9 : 1), acetonitrile – diethylamine (9 : 1) at 25 °C, and also by the equation Arrhenius values of the activation energy in the reactions of hydrolysis, alcoholysis, and aminolysis of 1,1'-oxalyl dibenzotriazole were calculated. To study the thermodynamic features of the reactions of obtaining this compound in the Spartan’14 1.1.4 program, a number of thermodynamic characteristics were calculated, determining the spontaneous and exothermic nature of the process. For the 1,1'-oxalyl dibenzotriazole molecule, possible conformers were found in the Molecular Operating Environment 2014.0901 software, for which the surfaces of nucleophilic susceptibility were calculated in the SCIGRESS Modeling 3.1.4 software. The structure of 1,1'-oxalyl dibenzotriazole was confirmed by IR and 1H NMR spectroscopy. The program PASS Professional 2007 predicted the most likely types of biological activity of the studied compounds. The most significant types of biological activity are in relation to renal diseases, anti-neurotoxic, anti-acid, anti-inflammatory. The obtained data allow us to choose the optimal conditions for the synthesis of 1,1’-oxalyl dibenzotriazole and to conclude that it is low stability in nucleophilic-containing media.

Синтез, структура и реакционная способность оксалилди(4-метилимидазола)

The article describes a two-step method for the synthesis of oxalyl di(4-methylimidazole) from 4(5)-methylimidazole through 1-trimethyl-4-methylimidazole followed by interaction with oxalyl chloride; the yield of the final product is 89%. The kinetics of hydrolysis, alcoholysis, and aminolysis of oxalyl di(4-methylimidazole) in acetonitrile – water (9 : 1), acetonitrile – methanol (9 : 1), acetonitrile – diethylamine (9 : 1) at 25 °C was studied. To study the thermodynamic features of the reactions to obtain this compound in the Spartan’14 1.1.4 program, a number of thermodynamic characteristics were determined that determine the spontaneous and exothermic nature of the process. The data obtained make it possible to select the optimal conditions for the synthesis of oxalyl di(4-methylimidazole) and to draw a conclusion about its low stability in media containing nucleophiles. Possible conformers were found for the oxalyl di(4-methylimidazole) molecule in the Molecular Operating Environment 2014.0901 program, for which nucleophilic susceptibility surfaces were calculated in the SCIGRESS Modeling 3.1.4 program. It was shown that the most reactive conformers in which carbonyl groups are minimally screened by fragments of 4-methylimidazole. The structure of oxalyl di(4-methylimidazole) was confirmed by IR and 1H NMR spectroscopy. Characteristic absorption bands were found in the IR spectra, confirming the presence of the corresponding functional groups in the structure of the compound, and proton signals with characteristic chemical shifts for the corresponding functional groups were detected in 1H NMR spectra. In the PASS Professional 2007 program, the most probable types of biological activity of the test compound were predicted. The most significant types of biological activity are in relation to urological diseases, antiseborrheic effect, stimulator of renal function, stimulator of leukopoiesis.

Синтез малонилди(1,2,4-триазола), изучение кинетических и термодинамических особенностей его гидролиза и прогнозирование биологической активности

This article describes a two-step method for the synthesis of malondyl (1,2,4-triazole) (1,3-di (1H-1,2,4-triazol-1-yl)propane-1,3-dione) of 1,2,4-triazole through 1-trimethylsilyl-1,2,4-triazole, followed by reaction with malonyl chloride; the yield of the final product is 85%. The kinetics of hydrolysis of malonyldi(1,2,4-triazole) in the acetonitrile – water system (9:1) at 25 °C and 35 °C was studied, and the activation energy of the hydrolysis of malonyldi(1,2,4-triazole). To study the thermodynamic features of the reactions of obtaining this compound in the Spartan’14 1.1.4 program, a number of thermodynamic characteristics were calculated, which determine the spontaneous and exothermic nature of the process. For the molecule malonyldi(1,2,4-triazole), the most and least stable conformers were found in the program Molecular Operating Environment 2009.10, for which the surfaces of nucleophilic susceptibility were calculated in the program SCIGRESS Modeling 3.1.4. It was shown that the most stable conformer of the malonyldi(1,2,4-triazole) molecule should have the highest reactivity in reactions with different nucleophiles and the lowest value of the heat of formation. In this case, the nucleophilic susceptibility of carbonyl carbon atoms is different, despite the symmetry of the structure of the molecules malonyldi(1,2,4-triazole), which suggests a stepwise interaction of malonyldi(1,2,4-triazole) with nucleophiles. The structure of malonyldi(1,2,4-triazole) was confirmed by IR, 1H NMR spectroscopy, individuality – by thin-layer chromatography. The proposed mechanism for the hydrolysis of malonyldi(1,2,4-triazole) is described. The program PASS Professional 2007 predicted the most likely types of biological activity of the studied compounds. The most significant types of biological activity are anti-diabetic, anti-ulcer, anti-ischemic, anti-oxidant. The obtained data allow us to choose the optimal conditions for the synthesis of malonyldi(1,2,4-triazole) and to conclude that it is highly hydrolytically stable in an aqueous acetonitrile medium.

Total synthesis of Crotogossamide using an on-resin concomitant cyclization/cleavage reaction

Crotogossamide, a cyclic peptide isolated from the latex of Croton gossypifolius, has been synthesized by a rapid and efficient Boc solid-phase peptide synthesis. The strategy takes advantage of the oxime resin nucleophile susceptibility and comprises the synthesis of a linear precursor followed by on-resin head-to-tail concomitant cyclization/cleavage. In addition, we report the first antimicrobial and antibiofilm investigations on Crotogossamide.

Effect by Doping and Surface Termination on c-BN Surface Reactivity: A Theoretical DFT Approach

The cubic phase of boron nitride, c-BN, is a very promising material due to its very interesting and extreme properties, of which some are comparable or even superior to diamond. However, there are severe problems with the initial nucleation during vapor phase synthesis of c-BN thin films. Investigations of new possibilities for growth mechanisms are therefore of greatest importance to perform. It has experimentally been shown that the film quality will increase when a small amount of oxygen is added into the film during deposition. In the present study, the adsorption and abstraction energies of the surface terminating species, the geometrical structures, and the resulting electronic structures were studied for the situation when N (or B) was substituted by O (or C) atom in combination with different terminating species (H, F, or Cl) on the c-BN (100) surface. This theoretical study was performed by using first-principles functional theory (DFT) calculations under periodic boundary conditions. The results indicate that the reactivity of the B-rich c-BN (100)-2 × 1 surface is more pronounced when doping an H-terminated surface with O (or C). For a corresponding F-terminated surface, only the C-doped surface will result in a more exothermic adsorption process. Doping with O gives a slightly less exothermic adsorption process, when compared to the nondoped situation. The situation was completely different for the N-rich c-BN (100)-1 × 1 surface, where the H and F terminating species were found to chemisorb stronger for the nondoped situation than for the O (or C)-doped one. When Cl-terminating the surfaces, all the adsorption processes became endothermic and hence not possible to perform. The results from the DFT calculations also indicate that the extra electron density induced in the system by doping with O or C atoms will not stay in the nearest vicinity to the respective dopant, but will instead move closer to the nearest surface atoms. This overall increase in electron density was observed to either strengthen the surface-terminating bonds for the B-rich surface or weaken these bonds for the N-rich surface. The reactivity of the terminated surfaces, as obtained from the Fukui functions, revealed a much larger variation in electrophilic and nucleophilic susceptibility for the doped N-rich surfaces, as compared with the doped B-rich ones.

The rapid generation of isothiocyanates in flow

Isothiocyanates are versatile starting materials for a wide range of chemical reactions. However, their high nucleophilic susceptibility means they are best prepared and used immediately. We report here on a flow platform for the fast and efficient formation of isothiocyanates by the direct conversion of easily prepared chloroximes. To expedite this chemistry a flow insert cartridge containing two immobilised reagents is used to affect the chemical transformation which typically eliminates the requirements for any conventional work-up or purification of the reaction stream.

Curcumin Inhibits the Proteasome Activity in Human Colon Cancer Cells In vitro and In vivo

Curcumin (diferuloylmethane) is the major active ingredient of turmeric (Curcuma longa) used in South Asian cuisine for centuries. Curcumin has been shown to inhibit the growth of transformed cells and to have a number of potential molecular targets. However, the essential molecular targets of curcumin under physiologic conditions have not been completely defined. Herein, we report that the tumor cellular proteasome is most likely an important target of curcumin. Nucleophilic susceptibility and in silico docking studies show that both carbonyl carbons of the curcumin molecule are highly susceptible to a nucleophilic attack by the hydroxyl group of the NH(2)-terminal threonine of the proteasomal chymotrypsin-like (CT-like) subunit. Consistently, curcumin potently inhibits the CT-like activity of a purified rabbit 20S proteasome (IC(50) = 1.85 micromol/L) and cellular 26S proteasome. Furthermore, inhibition of proteasome activity by curcumin in human colon cancer HCT-116 and SW480 cell lines leads to accumulation of ubiquitinated proteins and several proteasome target proteins, and subsequent induction of apoptosis. Furthermore, treatment of HCT-116 colon tumor-bearing ICR SCID mice with curcumin resulted in decreased tumor growth, associated with proteasome inhibition, proliferation suppression, and apoptosis induction in tumor tissues. Our study shows that proteasome inhibition could be one of the mechanisms for the chemopreventive and/or therapeutic roles of curcumin in human colon cancer. Based on its ability to inhibit the proteasome and induce apoptosis in both HCT-116 and metastatic SW480 colon cancer cell lines, our study suggests that curcumin could potentially be used for treatment of both early-stage and late-stage/refractory colon cancer.

Pristimerin induces apoptosis by targeting the proteasome in prostate cancer cells

Pristimerin is a natural product derived from the Celastraceae and Hippocrateaceae families that were used as folk medicines for anti inflammation in ancient times. Although it has been shown that pristimerin induces apoptosis in breast cancer cells, the involved mechanism of action is unknown. The purpose of the current study is to investigate the primary target of pristimerin in human cancer cells, using prostate cancer cells as a working model. Nucleophilic susceptibility and in silico docking studies show that C6 of pristimerin is highly susceptible towards a nucleophilic attack by the hydroxyl group of N-terminal threonine of the proteasomal chymotrypsin subunit. Consistently, pristimerin potently inhibits the chymotrypsin-like activity of a purified rabbit 20S proteasome (IC50 2.2 micromol/L) and human prostate cancer 26S proteasome (IC50 3.0 micromol/L). The accumulation of ubiquitinated proteins and three proteasome target proteins, Bax, p27 and I kappa B-alpha, in androgen receptor (AR)-negative PC-3 prostate cancer cells supports the conclusion that proteasome inhibition by pristimerin is physiologically functional. This observed proteasome inhibition subsequently led to the induction of apoptotic cell death in a dose- and kinetic-dependent manner. Furthermore, in AR-positive, androgen-dependent LNCaP and AR-positive, androgen-independent C4-2B prostate cancer cells, proteasome inhibition by pristimerin results in suppression of AR protein prior to apoptosis. Our data demonstrate, for the first time, that the proteasome is a primary target of pristimerin in prostate cancer cells and inhibition of the proteasomal chymotrypsin-like activity by pristimerin is responsible for its cancer cell death-inducing property.

Methylation of green tea polyphenols affects their binding to and inhibitory poses of the proteasome β5 subunit

Previously, we showed that ester carbon-containing tea polyphenols, including (-)-epigallocatechin gallate [(-)-EGCG] and (-)-epicatechin-3-gallate [(-)-ECG], potently inhibit proteasomal chymotrypsin-like activity. In addition, our in silico docking study suggested that a particular pose of (-)-EGCG could lead to potential covalent modification of the N-terminal threonine (Thr 1) of the proteasome beta5 subunit in the chymotrypsin-like active site. It has been suggested that some major biotransformation reactions, such as methylation, could result in reduced biological activity of (-)-EGCG in vivo. We hypothesize that methylation reduces binding of (-)-EGCG to the beta5 subunit of the proteasome and, therefore, decreases its proteasomal chymotrypsin-like-inhibitory potency. Here, we report that, while methylation has no effect on nucleophilic susceptibility of (-)-EGCG and (-)-ECG, it may disrupt the ability of these polyphenols to interact with Thr 1 of the proteasome beta5 subunit. In silico docking shows that methylation results in the tea polyphenols' ester carbon being moved away or blocked entirely from Thr 1. Additionally, methylation impairs the ability of (-)-EGCG and (-)-ECG to dock in a consistent low energy pose. These observations, no change in nucleophilic susceptibility, moving or blocking the ester carbon from Thr 1, and lack of a consistent docking pose, suggest that methylation disrupts the ability of (-)-EGCG and (-)-ECG to bind to the proteasome beta5 subunit, which may then diminish their proteasomal chymotrypsin-inhibitory and, therefore, other biological activities.

Relation between molecular electrostatic potential, several electronic properties and antibacterial activity of some synthetic furane derivatives

The present work reports the preliminary evaluation of the antibacterial activity, molecular electrostatic potential (MEP) determination and relevant electronic properties for their behavior as one electron acceptor, of a serial of compounds, active and inactive analogues, derived form furan, that were previously synthesized within our investigation group, with the purpose of establishing the existence of a valid correlation between their antibacterial activity and those electrostatic and electronic properties. According to the balance between the positive and negative areas in combination with the size of the MEP’s area it was determined that these derivatives exhibit activity against Gram-positive and Gram-negative bacteria or only against Gram-positive ones. We found no valid correlation between the single point energy, the energy associated to the lowest unoccupied molecular orbital (LUMO); LUMO’s density, nucleophilic susceptibility, Log P and the dipole moment, with the experimental activity determined for them. This could be because this is an homologous serial where the properties derived from the electronic distribution just change between those molecules that have a nitro group (active) in contrast with those wherein this group is absent (inactive).

Kinetic Dissection of α1-Antitrypsin Inhibition Mechanism

Serpins (serine protease inhibitors) inhibit target proteases by forming a stable covalent complex in which the cleaved reactive site loop of the serpin is inserted into beta-sheet A of the serpin with concomitant translocation of the protease to the opposite of the initial binding site. Despite recent determination of the crystal structures of a Michaelis protease-serpin complex as well as a stable covalent complex, details on the kinetic mechanism remain unsolved mainly due to difficulties in measuring kinetic parameters of acylation, protease translocation, and deacylation steps. To address the problem, we applied a mathematical model developed on the basis of a suicide inhibition mechanism to the stopped-flow kinetics of fluorescence resonance energy transfer during complex formation between alpha(1)-antitrypsin, a prototype serpin, and proteases. Compared with the hydrolysis of a peptide substrate, acylation of the protease by alpha(1)-antitrypsin is facilitated, whereas deacylation of the acyl intermediate is strongly suppressed during the protease translocation. The results from nucleophile susceptibility of the acyl intermediate suggest strongly that the active site of the protease is already perturbed during translocation.

Structure-metabolism relationships of substituted anilines: prediction of N-acetylation and N-oxanilic acid formation using computational chemistry

1. The relationship between the in vivo metabolism of substituted anilines, in particular N-acetylation and subsequent formation of oxanilic acids, and their molecular physico-chemical properties has been investigated using computational chemistry and pattern-recognition methods. The methods revealed that the physico-chemical properties most important for N-acetylation and subsequent oxanilic acid formation were electronic descriptors based on partial atomic charges and the susceptibility of the molecules to nucleophilic attack at certain ring positions. 2. The calculated partial atom charge on the amine nitrogen was the parameter most important for predicting that an aniline would be N-acetylated. The calculated nucleophilic susceptibility of the aromatic carbon para to the amino group (NS4) was the most significant parameter for determining oxanilic acid formation following N-acetylation. Thus, highly electron-withdrawing groups substituted at this position gave higher nucleophilic susceptibilities that were related to the presence of an oxanilic acid metabolite. 3. If the parameters relating to N-acetylation were modified by other electron-withdrawing groups in the ring (particularly at the position ortho to the amino group), then acetylation and subsequent oxanilic acid formation did not occur. The introduction of groups that allow the possibility of competing oxidative metabolic pathways elsewhere in the molecule (e.g. CH3) also affected the production of oxanilic acids. 4. Using chemometric analysis of the computed physico-chemical properties, the result has been the generation of a model that classifies the metabolism of a number of anilines. This could be used to predict the acetylation and oxanilic formation propensity of a number of substituted anilines whose metabolism was unknown to the system, demonstrating that such techniques may be of use for predicting metabolism and hence could provide support for rational drug design.

Quantitative Structure-Toxicity Relationships for Chlorophenols to Bioluminescent Lux-Marked Bacteria Using Atom-Based Semi-Empirical Molecular-Orbital Descriptors

Literature data on the toxicity of chlorophenols for three luminescent bacteria (Vibrio fischeri, and the lux-marked Pseudomonas fluorescens 10586s pUCD607 and Burkholderia spp. RASC c2 (Tn4431)) have been analysed in relation to a set of computed molecular physico-chemical properties. The quantitative structure-toxicity relationships of the compounds in each species showed marked differences when based upon semi-empirical molecular-orbital molecular and atom based properties. For mono-, di- and tri-chlorophenols multiple linear regression analysis of V. fischeri toxicity showed a good correlation with the solvent accessible surface area and the charge on the oxygen atom. This correlation successfully predicted the toxicity of the heavily chlorinated phenols, suggesting in V. fischeri only one overall mechanism is present for all chlorophenols. Good correlations were also found for RASC c2 with molecular properties, such as the surface area and the nucleophilic superdelocalisability of the oxygen. In contrast the best QSTR for P. fluorescens contained the 2nd order connectivity index and ELUMO suggesting a different, more reactive mechanism. Cross-species correlations were examined, and between V. fischeri and RASC c2 the inclusion of the minimum value of the nucleophilic susceptibility on the ring carbons produced good results. Poorer correlations were found with P. fluorescens highlighting the relative similarity of V. fischeri and RASC c2, in contrast to that of P. fluorescens.

Quantitative structure-toxicity relationships for halogenated substituted-benzenes to Vibrio fischeri, using atom-based semi-empirical molecular-orbital descriptors

Quantitative structure-toxicity relationships (QSTR's) are derived for an extensive series of halogenated benzenes, anilines, phenols, nitrobenzenes, toluenes and other substituted benzenes against Vibrio fischeri using a wide range of whole molecule and atom-based descriptors derived from semi-empirical molecular-orbital calculations. In terms of direct statistical correlation with toxicity it was found that the molar refractivity was the most important parameter, closely followed by the solvent accessible surface area of the compound. The accuracy of these descriptors in fitting the numerous fluoro- and chloro-mono-aromatic compounds was compared with bromine and iodine analogues, where the ‘best’ descriptors for the former were found in general to be less accurate for the latter in the case of multi-halogen substitution. The equations obtained were also used to classify the compounds into narcosis-based mechanisms of toxicity and those with respiratory uncoupling potential. A combination of the molar refractivity and the nucleophilic susceptibility of one of the meta ring carbons predicted the toxicity of the halo-benzenes and toluenes, along with anisoles, benzonitriles, nitrobenzenes and most of the anilines. The relevance of these descriptors to developing coherent and more generally applicable models for QSTR's of mono-aromatic compounds to other species in environmental toxicology is discussed.

On the biogenesis of gliotoxin. Synthesis of 3-(β-aminoethyl)benzene oxide.

The synthesis of 3-(β-aminoethyl)benzene oxide ( 7 is described. The failure of 7 to ring close ( 7 → 8 ) is attributed to the low “nucleophilic susceptibility” of the arene oxide.