Nitrile Analogs Research Articles

Straightforward Access to Terminally Disubstituted Electron‐Deficient Alkylidene Cyclopent‐2‐en‐4‐ones through Olefination with α‐Carbonyl and α‐Cyano Secondary Alkyl Sulfones

AbstractHerein we report on a simplified synthesis of scarcely explored, terminally disubstituted electron‐poor alkylidene cyclopent‐2‐en‐4‐ones through uncommon olefination. Secondary sulfones, activated by electron‐withdrawing groups at the adjacent carbon atom, undergo K2CO3‐promoted coupling with 4‐acyloxy‐ and 4‐tert‐butyldimethylsilyloxycyclopent‐2‐en‐1‐ones giving directly, or after a separate dehydrosulfinylation step, alkylidene cyclopent‐2‐en‐4‐ones. A plausible mechanism for these transformations is proposed. Initially, β‐arylsulfonyl esters as well as their acetyl or nitrile analogues are allylated by cyclopentenone derivatives via a tandem Michael addition of α‐sulfonyl carbanions followed by proton migration and retro‐Michael‐type O‐nucleofuge elimination. The primary allylation products are formed as two diastereomers whose configuration and conformation were elucidated using single crystal X‐ray diffraction and NMR spectroscopy. Regardless of stereochemistry, both sets of diastereomers are subjected to Zaitsev‐type retro‐Michael vinylogous dehydrosulfinylation under either basic or thermal silica gel promoted conditions resulting in E/Z‐alkylidene cyclopent‐2‐en‐4‐ones. In these reactions activated sulfones serve as bearing electron‐withdrawing group alkylidene anion‐radical synthons, whereas 4‐oxy‐substituted cyclopentenones represent cyclopent‐2‐en‐4‐one cation‐radical surrogates.

Identification of a C3′-nitrile nucleoside analogue inhibitor of pancreatic cancer cell line growth

A synthetic strategy to access a novel family of nucleoside analogues bearing a C3′-nitrile substituted all-carbon quaternary center is presented herein. These purine bearing scaffolds were tested in two pancreatic cancer cell lines harboring either wild-type (BxPC3) or G12V KRAS (Capan2) mutations. A promising compound was shown to have significantly greater efficacy in the Capan2 cell line as compared to Gemcitabine, the clinical gold standard used to treat pancreatic cancer.

Synthesis and Biological Evaluation of 6-[(1R)-1-Hydroxyethyl]-2,4a(R),6(S),8a(R)-tetrahydropyrano-[3,2-b]-pyran-2-one and Structural Analogues of the Putative Structure of Diplopyrone

The phytotoxin diplopyrone is considered to be the main phytotoxin in a fungus that is responsible for cork oak decline. A carbohydrate-based synthesis of the enantiomer of the structure proposed for diplopyrone has been developed from a commercially available derivative of d-galactose. Key steps in the synthesis are a highly stereoselective pyranose chain-extension based on methyltitanium, preparation of a vinyl glycoside via Isobe C-alkynylation-rearrangement/reduction, and RCM-based pyranopyran construction. Crystallographic and NMR analysis confirms an earlier report that the structure originally proposed for diplopyrone may require revision. Structural analogues were prepared for biological evaluation, the most promising being a pyranopyran nitrile synthesized from tri- O-acetyl-d-galactal by Ferrier cyanoglycosidation, Wittig chain extension, and lactonization. Biological assays revealed potent antibacterial activity for the nitrile analogue against common bacterial pathogens Edwardsiella ictaluri and Flavobacterium columnare that cause enteric septicemia (ESC) and columnaris disease, respectively, in catfish. The IC50 value of 0.002 against E.ictaluri indicates approximately 100 times greater potency than the antibiotic florfenicol used commercially for this disease. Phytotoxic activity for all three target compounds against duckweed was also observed. The antibiotic and phytotoxic activities of the new pyranopyrans synthesized in this study demonstrate the potential of such compounds as antibiotics and herbicides.

Leveraging the cruzain S3 subsite to increase affinity for reversible covalent inhibitors

Cruzain is the major cysteine protease of Trypanosoma cruzi, the etiological agent of Chagas disease. Reversible covalent cruzain inhibitors can block the steps of cell differentiation in the parasite and kill the organism. To this end, the description of how inhibitors modified at the P2/P3 positions lead to analogs with greater cruzain affinity to the S2/S3 subsites is of fundamental importance. Albeit many efforts are being employed in the characterization of the interaction processes with S2 subsite, little is known about the cruzain S3 subsite. In this work, we show a brief but consistent study to identify favorable substitutions in P3 of dipeptidyl nitriles that increase cruzain affinity. Using molecular dynamics simulations, we have identified some dipeptidyl nitrile analogs with modifications at P3 position that had higher cruzain inhibition than the original unsubstituted compound. A matched molecular pair analysis shows the importance of including a chlorine atom in the P3-meta position. The modifications implemented in P3 are confirmed when profiling the thermodynamic parameters via isothermal titration calorimetry. The classical enthalpy-entropy compensation phenomenon, in which enthalpy changes are counterbalanced by entropy results in a small modification of ΔG. The inclusion of the chlorine atom in the P3-meta position results in the highest reduction of the detrimental entropic contribution observed in P3.

Cyanamide as an Infrared Reporter: Comparison of Vibrational Properties between Nitriles Bonded to N and C Atoms.

Infrared (IR) probes based on terminally blocked β-cyanamidoalanine (AlaNHCN) 1 and p-cyanamidophenylalanine (PheNHCN) 2 were synthesized, and the vibrational properties of their CN stretch modes were studied using Fourier transform infrared (FTIR) and femtosecond IR pump-probe spectroscopies in combination with quantum chemical calculations. From FTIR studies, it is found that the transition dipole strengths of the cyanamide (NHCN) group in 1 and 2 are much larger than those of the nitrile (CN) group but comparable to those of the isonitrile (NC) and azido (N3) groups in their previously studied analogs. The CN stretch frequencies in 1 and 2 are red-shifted from those in their nitrile analogs but more blue-shifted from the NC and N3 stretch frequencies in their isonitrile and azido analogs. The much larger transition dipole strength and the red-shifted frequency of the cyanamide relative to nitrile group originates from the n → π* interaction between the N atom's nonbonding (n) and CN group's antibonding (π*) orbitals of the NHCN group. Unlike aliphatic cyanamide 1, aromatic cyanamide 2 shows a complicated line shape of the CN stretch spectra. Such a complicated line shape arises from the Fermi resonance between the CN stretch mode of the NHCN group and one of the overtones of the phenyl ring vibrations and can be substantially simplified by deuteration of the NHCN into NDCN group. From IR pump-probe experiments, the vibrational lifetimes of the CN stretch mode in 1 were determined to be 0.58 ± 0.04 ps in D2O and 0.89 ± 0.09 ps in H2O and those in 2 were determined to be 1.64 ± 0.13 ps in CH3OD/dimethyl sulfoxide and 0.30 ± 0.05 and 2.62 ± 0.26 ps in CH3OH. The short time component (0.30 ± 0.05 ps) observed for 2 in CH3OH is attributed to the vibrational relaxation through Fermi resonance. These vibrational lifetimes are close to those of the nitrile and azido groups but shorter than those of the isonitrile group. Consequently, cyanamide behaves like an apparent vibrational hybrid of nitrile and isonitrile in that cyanamide is similar to nitrile in vibrational frequency and lifetime but to isonitrile in transition dipole strength. It is believed that cyanamide has the potential to be a strongly absorbing IR reporter of the conformational and environmental structure and dynamics of biomolecules in comparison to nitrile, a weak absorber.

Reaction of 6‐Methyl‐2‐Thiouracil and 6‐Phenyl‐2‐Thiouracil with Chloro‐β‐Dicarbonyl and Bromo‐β‐Dicarbonyl Compounds and Their Nitrile Analogs

Derivatives of 2‐methylidene‐1,3‐dihydropyrimidin‐4‐ones 2a, 2b, 2c, 2d, 2e, 2f, 2g were synthesized by interaction of 6‐methyl‐2‐thiouracil and 6‐phenyl‐2‐thiouracil 1a, 1b with some activated halogenides: diethyl bromomalonate, ethyl 2‐chloro‐3‐oxobutanoate, ethyl 2‐bromocyanoacetate, 2‐bromo‐5,5‐dimethylcyclohexan‐1,3‐dione, and bromomalononitrile. The boiling of 1a with ethyl 2‐bromocyanoacetate in mixture of ethanol and EtONa results in intramolecular cyclization and formation of thiazolo[3,2‐a]pyrimidin‐5‐one 3. Interaction of 1a with 3‐chloropentane‐2,4‐dione and 2‐bromo‐1,3‐diphenylpropane‐1,3‐dione yielded corresponding S‐substituted thiopyrimidines 4a,4b. In general, the products of 1b S‐alkylation are less prone to sulfur extrusion. Reaction of 1b with diethyl bromomalonate in the absence of EtONa stops at the S‐alkylation step, while in the presence of EtONa in ethanol or PPh3 in dioxane 2‐(ethoxycarbonylmethyl)thio‐6‐phenyl‐1,3‐dihydropyrimidin‐4(1H)‐one 6 is formed exclusively. Molecular structure and crystal structure of 2‐(1,1‐diethoxycarbonylmethyliden)‐6‐methyl‐1,3‐dihydropyrimidin‐4(1H)‐one 2a are discussed.

Practical Synthesis of N-(Diphenylmethyl)- and N-(1-Adamantyl)amides Directly from Aldehydes via a One-Pot Schmidt and Ritter Reaction Sequence

Nonoxidative and noncoupling reaction conditions have been developed for the synthesis of <i>N</i>-(diphenylmethyl)- and <i>N</i>-(1-adamantyl)amide derivatives directly from aldehydes by employing the concept of a Schmidt and Ritter reaction sequence in a one-pot operation. The reagent mixture consisting of sodium azide and HBF₄·OEt₂ in acetic acid converts the aldehydes into their respective nitrile analogues which in situ undergo the Ritter reaction with diphenylmethanol or 1-adamantanol to afford the corresponding <i>N</i>-(diphenylmethyl)- or <i>N</i>-(1-adamantyl)amide derivatives in very good yields. The method does not require column chromatographic purification for isolation of the products. With its simple reaction procedure and easy product purification technique, this method outshines earlier conventional two-step methods.

Dielectric Properties of Bisphenol A Polycarbonate and Its Tethered Nitrile Analogue

The relative permittivity and dielectric strength have been determined for a bisphenol A polycarbonate (BPA-PC), in which a cyanoethyl group has been substituted for one of the geminal dimethyl groups. The new material (CN-PC) has a glass transition temperature that is 19 K higher than that for BPA-PC. In addition, the dielectric strength of CN-PC, 405 V/μm, is somewhat smaller than that for BPA-PC, 620 V/μm. The relative permittivity was determined from 10 to 105 Hz over a wide temperature range and at pressures up to 0.25 GPa. While the real part of the relative permittivity at 103 Hz and room temperature for BPA-PC is about 3, that for CN-PC is found to be greater than 4. Correspondingly, the γ relaxation region in CN-PC is very strong. For the γ relaxation, a strong increase in peak height as temperature increases and a strong decrease in peak height as pressure increases are observed. A relaxation is found at temperatures higher than the γ relaxation. This process is labeled as the β relaxation becau...

Syntheses and X-Ray Crystal Structures of Cassiferaldehyde and Analogs

Cassiferaldehyde, a recently discovered naturally occurring tyrosinase inhibitor, and six of its analogs, in which the aldehyde group has been replaced by various other functionalities, have been synthesized by a short and simple sequence starting from 2,3-dihydroxybenzaldehyde. Single-crystal x-ray structures of cassiferaldehyde as well as its methyl ketone, nitrile, and carboxylic acid analogs are reported.

Sm(ii) reduction chemistry of heteroalkynes: stable adducts, reductive coupling, reductive C–C/C–N bond cleavage and trapping of the tert-butyl fragment with bulky nitriles, phosphaalkynes and isonitriles

Reactions of a dimetallated N,N'-dimethyl substituted porphyrinogen Sm(II) complex with a series of t-butyl substituted heteroalkynes affords a diverse range of reactivity. The phosphaalkyne t-BuC[triple bond]P gives a dinuclear Sm(III) P-P reductively coupled complex of (t-BuC=PP=C-t-Bu)(2-) featuring a new mu-eta(2)(1,2-C,P) binding mode. In contrast, the nitrile aza analogue t-BuC[triple bond]N forms Sm(II) adducts that undergo reductive C-C bond cleavage at elevated temperatures to afford a trimeric Sm(III) cyanide (mu-C[triple bond]N(-)) complex. The isomeric isonitrile t-BuN[triple bond]C undergoes the related reductive C-N bond cleavage reactivity at milder temperatures, allowing the trapping of the tert-butyl fragment as a Sm(III) eta(2)-iminoacyl (t-BuC=N-t-Bu)(-) complex.

Nitrile analogs of meperidine as high affinity and selective sigma-1 receptor ligands

A series of N-substituted-4-cyano-4-phenylpiperidine analogs were synthesized and evaluated for binding affinity at opioid receptors and showed no affinity. The series similarity to previously reported σ ligands prompted analysis at σ receptors to determine the SAR for affinity at σ receptors. Within the N-substituent series the saturated analogs showed increased affinity at both σ receptors. Optimal chain length in the N-arylalkyl series for σ 1 and σ 2 receptors proved to be N-propylphenyl; extension to a four carbon chain dramatically decreased affinity at both receptors. Substituents in the 4-position affect only σ 1 affinity; no change in affinity at σ 2 was shown. The N-isobutyl, N-phenylpropyl, and N-benzyl analogs are worth pursuing due to their good affinity and selectivity at the σ 1 receptor, whereas the N-benzyl analog exhibits the greatest selectivity for σ 1.

Use of the Novel Fluorescent Amino Acidp-Cyanophenylalanine Offers a Direct Probe of Hydrophobic Core Formation during the Folding of the N-Terminal Domain of the Ribosomal Protein L9 and Provides Evidence for Two-State Folding

Fluorescence-detected stopped flow measurements are the method of choice for studies of protein folding kinetics. However, the methodology suffers from the limitation that the protein of interest either must contain an intrinsic fluorophore or can tolerate its introduction by mutagenesis. Recently, the cyano (nitrile) analogue of phenylalanine has been proposed for use as a fluorescence analogue. Here we take advantage of this new methodology to monitor the formation of the hydrophobic core during the folding of the N-terminal domain of L9 (NTL9). Phenylalanine 5, which is completely buried in the folded state of NTL9, was replaced with p-cyanophenylalanine (p-cyano-Phe). This derivative reports on the formation of the hydrophobic core. The variant adopts the same fold as wild-type NTL9 and is slightly more stable. Refolding and unfolding were monitored using both guanidine HCl and urea jump experiments. In both cases, plots of the natural log of the observed relaxation rate versus denaturant concentration, so-called chevron plots, exhibited the characteristic V shape expected for two-state folding, and no hint of deviation from linearity was observed at low denaturant concentrations. The stability calculated from the measured folding and unfolding rates is in very good agreement with the value obtained from equilibrium measurements as is the m value. The relative compactness of the transition state for folding as defined by the Tanford beta parameter is identical to that of the wild type. The results illustrate the applicability of p-cyano-Phe analogues in protein folding studies and provide further evidence of two-state folding of NTL9.

Synthesis of N-alkyl substituted bioactive indolocarbazoles related to Gö6976

The syntheses of new nitrile and amide analogues of 7-keto Gö6976 are described. The amide analogue 22 was formed via the condensation with a new functionalized indoleacetic acid derivative 25 to overcome the solubility problem during the coupling reaction.

Chemoenzymatic preparation of the enantiomers of β-tryptophan ethyl ester and the β-amino nitrile analogue

Racemic α-tryptophan was chemoselectively transformed into the enantiomers of β-tryptophan ethyl ester. The key step in achieving enantiopurity was the N-acylation of the 3-amino-4-(3-indolyl)butanenitrile intermediate with Candida antarctica lipase A (CAL-A). The enzymatic N-acylation of racemic β-tryptophan ethyl ester was also studied. CAL-A was highly ( R)-enantioselective in the present kinetic resolutions, leading to a mixture of the butanamide product with an ( R)-configuration and the unreacted starting material with an ( S)-configuration at 50% conversion.

A Practical and Stereoselective Synthesis of Cinnamyl Alcohols Bearing α‐Cyano or α‐Ester Functional Group from Baylis—Hillman Adducts.

Cinnamyl alcohols bearing ester, acid, or nitrile functional group at the 2-position are very useful synthons for the synthesis of various biologically important compounds. Synthesis of cinnamyl alcohol derivatives from the BaylisHillman adducts has been reported by us and other groups. The conversion can be carried out directly by using 20% aqueous sulfuric acid (for the Baylis-Hillman adducts derived from acrylonitrile) or trifluoroacetic acid (for the Baylis-Hillman adducts derived from acrylates). Recently, Basavaiah and coworkers have reported the two-step, onepot conversion method: TMSOTf-assisted conversion of Baylis-Hillman alcohol into the corresponding primary acetate with acetic anhydride and the following partial hydrolysis with K2CO3 in methanol. In the above chemical transformation, the conversion of secondary acetate into the primary one is the key step. Rearrangement of secondary acetate into the primary one was conducted by following reaction conditions such as DABCO/THF/reflux, montmorillonite K10 clay/microwave, and TMSOTf (cat.)/CH2Cl2. Direct conversion of BaylisHillman alcohol into the corresponding primary acetate can be carried out by the Basavaiahs method: acetic anhydride in the presence of TMSOTf. However, TMSOTf is a moisturesensitive and somewhat expensive reagent. During the preparation of Baylis-Hillman acetate, we found that the use of acetic anhydride in the presence of a catalytic amount of sulfuric acid in CH2Cl2 afforded directly the corresponding primary acetate in excellent yield. In these regards we envisioned that we could develop the more convenient and practical method to convert the BaylisHillman alcohol into the primary acetate or eventually to primary alcohol (Scheme 1 and Table 1). The reaction of Baylis-Hillman adducts with acetic anhydride (1.5 equiv.) in the presence of sulfuric acid (10 mol%) gave the corresponding rearranged cinnamyl acetates quantitatively in dichloromethane at room temperature within 30 min (Actually, the cinnamyl acetate derivatives could be isolated in 92-95% yields.). In order to obtain the corresponding cinnamyl alcohols in a one-pot we tried some reaction conditions for the next partial hydrolysis. Addition of water to the reaction mixture (two-phase system) afforded the hydrolyzed cinnamyl alcohols in trace amounts. The use of THF instead of CH2Cl2 showed better results in the hydrolysis step. However, neither the acetylation in THF nor the subsequent acidic hydrolysis in aq. THF was efficient. As a next choice, we used methanol as solvent after the formation of rearranged acetate in CH2Cl2 and added K2CO3. However, this process showed incomplete reaction and produced some side products. Thus, we finally adapted the two-step procedure involving the well-known hydrolysis protocol, K2CO3 in methanol, after simple workup process of the primary acetates (vide infra). The representative examples are shown in Table 1. As shown in Table 1, the method can be applicable to both of the Baylis-Hillman adducts derived from acrylates or acrylonitrile. The yields are higher than the reported in all cases. The formation of the cinnamyl alcohols is highly stereoselective (E for the ester and acetyl derivatives and Z for the nitrile analogs) as reported. The method has some advantages over the previous methods: (1) higher yields in

A Practical and Stereoselective Synthesis of Cinnamyl Alcohols Bearing α-Cyano or α-Ester Functional Group from Baylis-Hillman Adducts

Cinnamyl alcohols bearing ester, acid, or nitrile functional group at the 2-position are very useful synthons for the synthesis of various biologically important compounds. Synthesis of cinnamyl alcohol derivatives from the BaylisHillman adducts has been reported by us and other groups. The conversion can be carried out directly by using 20% aqueous sulfuric acid (for the Baylis-Hillman adducts derived from acrylonitrile) or trifluoroacetic acid (for the Baylis-Hillman adducts derived from acrylates). Recently, Basavaiah and coworkers have reported the two-step, onepot conversion method: TMSOTf-assisted conversion of Baylis-Hillman alcohol into the corresponding primary acetate with acetic anhydride and the following partial hydrolysis with K2CO3 in methanol. In the above chemical transformation, the conversion of secondary acetate into the primary one is the key step. Rearrangement of secondary acetate into the primary one was conducted by following reaction conditions such as DABCO/THF/reflux, montmorillonite K10 clay/microwave, and TMSOTf (cat.)/CH2Cl2. Direct conversion of BaylisHillman alcohol into the corresponding primary acetate can be carried out by the Basavaiahs method: acetic anhydride in the presence of TMSOTf. However, TMSOTf is a moisturesensitive and somewhat expensive reagent. During the preparation of Baylis-Hillman acetate, we found that the use of acetic anhydride in the presence of a catalytic amount of sulfuric acid in CH2Cl2 afforded directly the corresponding primary acetate in excellent yield. In these regards we envisioned that we could develop the more convenient and practical method to convert the BaylisHillman alcohol into the primary acetate or eventually to primary alcohol (Scheme 1 and Table 1). The reaction of Baylis-Hillman adducts with acetic anhydride (1.5 equiv.) in the presence of sulfuric acid (10 mol%) gave the corresponding rearranged cinnamyl acetates quantitatively in dichloromethane at room temperature within 30 min (Actually, the cinnamyl acetate derivatives could be isolated in 92-95% yields.). In order to obtain the corresponding cinnamyl alcohols in a one-pot we tried some reaction conditions for the next partial hydrolysis. Addition of water to the reaction mixture (two-phase system) afforded the hydrolyzed cinnamyl alcohols in trace amounts. The use of THF instead of CH2Cl2 showed better results in the hydrolysis step. However, neither the acetylation in THF nor the subsequent acidic hydrolysis in aq. THF was efficient. As a next choice, we used methanol as solvent after the formation of rearranged acetate in CH2Cl2 and added K2CO3. However, this process showed incomplete reaction and produced some side products. Thus, we finally adapted the two-step procedure involving the well-known hydrolysis protocol, K2CO3 in methanol, after simple workup process of the primary acetates (vide infra). The representative examples are shown in Table 1. As shown in Table 1, the method can be applicable to both of the Baylis-Hillman adducts derived from acrylates or acrylonitrile. The yields are higher than the reported in all cases. The formation of the cinnamyl alcohols is highly stereoselective (E for the ester and acetyl derivatives and Z for the nitrile analogs) as reported. The method has some advantages over the previous methods: (1) higher yields in

Synthesis and structure-activity relationships of carboxylated chalcones: a novel series of CysLT1 (LTD4) receptor antagonists.

The synthesis and CysLT1 antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1 microM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.

Natural product analogs: Stable mimics of aldehyde pheromones

AbstractUnder field conditions, the aldehyde components of the pheromones of important lepidopteran and coleopteran pests undergo chemical transformations (oxidation, polymerization, etc.) resulting in behaviorally inactive compounds. In our search for pheromone analogs with favorable chemical and biological properties, a series of nitriles, oximes and isothiocyanates, as novel functional group mimics of some cyclic and long chain pheromones, were prepared and tested. The biological activities of these nitrogen‐containing analogs were studied by electrophysiological and field experiments with three different insect species showing the nitrile analogs to be the most potent mimics, but their activities were lower than those of the natural pheromones. Thus, a 1:1 mixture of pheromone analogs in place of the corresponding natural aldehyde components III and IV elicited dose‐dependent electroantennogram (EAG) responses of antennal preparations of the female boll weevil, Anthonomus grandis. In field trials, the nitrile analogs were poor substituents for the corresponding aldehydes. In EAG experiments with antennal preparations of males of the southwestern corn borer, Diatraea grandiosella, Z11‐16:Nitrile ((Z)‐11‐hexadecenonirile) elicited dose‐dependent responses while single neuron recording from antennal preparations of this species revealed that a neuron responsive to the pheromone component was also stimulated by the mimic Z11‐16:Nitrile. In field experiments, a 97:3 mixture of nitriles Z11‐16:Nitrile and Z9‐16:Nitrile ((Z)‐9‐hexadecenonitrile) effectively attracted males of the cranberry girdler moth, Chrysoteuchia topiaria. © 1993 Wiley‐Liss, Inc.

Papain in organic solvents: Determination of conditions suitable for biocatalysis and the effect on substrate specificity and inhibition

Synthesis of N-CBZ-(N-Carbobenzoxy)-1-amino-acid methyl esters from N-CBZ-amino acids and methanol has been used as an assay to examine the properties of papain in organic solvents containing small amounts of water. Papain is active in solvents ranging in polarity from acetonitrile to tetrachloromethane. The optimal activity in each solvent varied only about three to four fold, but the amount of added water required to achieve it varied from 4% (v/v) in acetonitrile to 0.05% (v/v) in tetrachloromethane. The enzyme was generally more stable in hydrophobic solvents and at lower water contents. The apparent K(m) value of CBZ-glycine was 26 times higher in acetonitrile than in toluene due to differential partitioning of the substrate between aqueous and organic phases. The substrate specificity of the enzyme was qualitatively little different from that in aqueous solution, with amino acid derivatives still the best substrates. Nitrile analogs of substrates inhibited the enzyme, as they do in aqueous solution, and inhibition by a variety of substituted aromatic hydrocarbons showed that the main specificity of papain for hydrophobic side chains at its S(2) subsite, was little affected. The results show that papain can catalyze reactions under a variety of conditions in organic solvents but its substrate specificity is little changed from that in aqueous media.

First Evidence for an Intermediate Nitrilo‐λ5‐phosphane

(iPr2N)2PN—a nitrene or a nitrile analogue? As suggested by ab initio calculations on H2PN, the intermediate compound 2, obtained from azide 1, proves to be a “nitrile” in trapping reactions.