Nitrostyrene Derivatives Research Articles

ChemInform Abstract: One‐Pot Synthesis of Pyrrolo[1,2‐a]pyrazines via Three Component Reaction of Ethylenediamine, Acetylenic Esters and Nitrostyrene Derivatives.

Abstract An effective route to pyrrolo[1,2- a ]pyrazines is described via reaction of ethylenediamine, acetylenic esters and nitrostyrene derivatives in the presence of 20 mol% of sulfamic acid.

One-pot synthesis of pyrrolo[1,2-a]pyrazines via three component reaction of ethylenediamine, acetylenic esters and nitrostyrene derivatives

Abstract An effective route to pyrrolo[1,2- a ]pyrazines is described via reaction of ethylenediamine, acetylenic esters and nitrostyrene derivatives in the presence of 20 mol% of sulfamic acid.

A Facile Regioselective Synthesis of Novel Spiroacenaphthene Pyrroloisoquinolines Through 1,3-Dipolar Cycloaddition Reactions

An efficient one-pot three-component procedure for the synthesis of novel spiroacenaphthene pyrroloisoquinolines with high regioselectivity is described. These compounds were prepared from 1,3-dipolar cycloaddition of an azomethine ylide generated from acenaphthenequinone and 1,2,3,4-tetrahydroisoquinoline via [1,5]-H shift, with chalcone and nitrostyrene derivatives as dipolarophiles. The structure and stereochemistry of the cycloadducts have been established by single crystal X-ray structure and spectroscopic techniques.

ChemInform Abstract: A New Kind of Organophosphorus Compounds as an Efficient Catalyst for Asymmetric C—C Bond Formation Reactions.

AbstractA chiral pyrrolidine‐phosphite organocatalyst is successfully applied in the asymmetric Michael reaction of nitrostyrene derivatives with cyclic ketones.

ChemInform Abstract: Nitrostyrene Derivatives of Adenosine 5′-Glutarates as Selective Inhibitors of the Epidermal Growth Factor Receptor Protein Tyrosine Kinase.

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Synthesis and evaluation of nitrostyrene derivative compounds, new snake venom phospholipase A 2 inhibitors

Several nitrostyrene derivatives were synthesized and their inhibitive activities on phospholipase A 2 (PLA 2) from Bothrops jararacussu venom were evaluated. Some compounds were very efficient as inhibition agents against edema-inducing, enzymatic and myotoxic activities. Data revealed that the size of the substitute and substitution position in the nitrostyrene moiety had important influence on the inhibition capacities. The enzymatic kinetic studies show that the nitrostyrene derivatives compounds inhibit PLA 2 in a non-competitive manner. The electronic, molecular and topologic parameters were calculated using ab initio quantum calculations (density functional theory—DFT) and analyzed by chemometric methods (principal component analysis (PCA) and hierarchical cluster analysis (HCA)) in order to build models able to establish relationships between the electronic features and the structure–activity presented by the target compound. Compounds with the nitro group in the ortho, meta and para position (compounds 2–4) on the aromatic ring were more efficient in the inhibition of PLA 2 activity in all tests. These results indicate that the influence of the nitro group in the aromatic ring is, in fact, important. In addition, quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA 2 present lower values of highest occupied molecular orbital (HOMO) energy and polarizability, suggesting the formation of a charge-transferring complex between the nitrostyrene compounds and PLA 2.

Trans-β-Nitrostyrene Derivatives as Slow-Binding Inhibitors of Protein Tyrosine Phosphatases

Protein tyrosine phosphatases (PTPs) catalyze the hydrolysis of phosphotyrosyl (pY) proteins to produce tyrosyl proteins and inorganic phosphate. Specific PTPs inhibitors provide useful tools for studying PTP function in signal transduction processes and potential treatment for human diseases such as diabetes, inflammation, and cancer. In this work, trans-beta-nitrostyrene (TBNS) and its derivatives are found to be slow-binding inhibitors against protein tyrosine phosphatases PTP1B, SHP-1, and Yop with moderate potencies (K(I*) = 1-10 microM). Competition experiments with a substrate (pNPP) and iodoacetate indicate that TBNS is active site-directed. The mechanism of inhibition was investigated by UV-vis absorption spectroscopy, (1)H-(13)C heteronuclear single-quantum correlation NMR spectroscopy, and site-directed mutagenesis. These studies suggested a mechanism in which TBNS acts a pY mimetic and binds to the PTP active site to form an initial noncovalent E.I complex, followed by nucleophilic attack on the TBNS nitro group by Cys-215 of PTP1B to form a reversible, covalent adduct as the tighter E.I* complex. TBNS derivatives represent a new class of neutral pY mimetic inhibitors of PTPs.

Potent inhibition of human telomerase by nitrostyrene derivatives.

Telomerase activity is expressed in most types of cancer cells but not in normal somatic cells, suggesting that telomerase may be an important target for cancer chemotherapy. Inhibition of telomerase results in telomere erosion, leading to the subsequent growth arrest of cancer cells followed by senescence or cell death. In this study, we screened a chemical library for the inhibition of human telomerase, identifying three inhibitors. All compounds contained a common nitrostyrene moiety conjugated to different side chains. One of these compounds, 3-(3,5-dichlorophenoxy)-nitrostyrene (DPNS), showed the most potent inhibitory effect, with 50% inhibition at approximately 0.4 microM and did not inhibit DNA and RNA polymerases, including retroviral reverse transcriptase. A series of enzyme kinetic experiments suggests that DPNS is a mixed-type noncompetitive inhibitor, with an inhibitor-binding site distinct from the binding sites for the telomeric substrate primer and the deoxynucleoside-5'-triphosphates. Extensive propagation of cancer cell line in the presence of DPNS resulted in progressive telomere erosion followed by the induction of senescence phenotype. The results presented here demonstrate that DPNS is a highly selective, small-molecule telomerase inhibitor in vitro and could be useful as a lead molecule for the further development of inhibitors with an improved potential for efficacy in vivo.

Structure activity analysis of the pro-apoptotic, antitumor effect of nitrostyrene adducts and related compounds

In the present study, we outlined the part of the molecule mediating the prominent pro-apoptotic effect of the Michael adduct of ascorbic acid with p-chloro-nitrostyrene, a new synthetic phosphatase inhibitor. The nitrostyrene (NS) moiety was identified as the structure essential for apoptosis induction. NS and its ascorbic acid adducts displayed lc 50 values of 10–25 μM with no significant reduction of potency in okadaic acid resistant cells overexpressing the MDR1 P-glycoprotein. Induction of apoptosis by NS derivatives and the protein phosphatase 2A inhibitor cantharidic acid was proven by the analysis of caspase-3 activation and subsequent fragmentation of DNA. Further structure activity analysis revealed the necessity of the nitro group at the β-position of the side chain. The pro-apoptotic potential of adducts of NS with pyrimidine- or pyridine-derivatives varied between NS and a progressive reduction in potency up to a nearly complete loss of cytotoxicity. Substitutions at the benzene core of NS suggested a prominent enhancement of toxicity only by substitutions at the 2- or 3-position. Heterocyclic aromatics can substitute for the benzene ring of NS albeit with a 2–3-fold reduced potency. In conclusion, nitrostyrene was identified as the core structure mediating the pro-apoptotic effect of a new synthetic phosphatase inhibitor. Further studies defined a nitrovinyl side chain attached to an aromatic ring as the pharmacophore structure of a new group of pro-apoptotic agents. These observations present the basis for the development of a new group of anticancer drugs.

Infrared spectra of nitrostyrene derivatives

The IR spectra of a series of 6 phenylnitroethenes (PNE) and 6 phenylnitropropenes (PNP) were assigned, based on a normal coordinates calculation performed on styrene and styrene-d 8. Some frequencies were sensitive to the electronic properties of the substituents, and others to the substitution on Cβ. AM1 minimum energy conformations and rotational barriers around the ClCα bond were calculated. According to these calculations, PNE are planar and PNP display an angle of 45° between the ethylenic and aromatic planes. AM1 underestimates the height of the electronic barriers, which is however modulated by the electron donor properties of the substituent on the ring. A correlation between the calculated electronic barrier and the CC ethylenic stretching frequency was observed.

Nitrostyrene Derivatives of Adenosine 5′‐Glutarates Modified with an Alkyl Spacer and their inhibitory activity on epidermal growth factor receptor protein tyrosine kinase

Abstractβ‐Nitrostyrene derivatives of adenosine 5′‐glutarates are potent and selective bisubstrate‐type inhibitors of the epidermal growth factor receptor protein tyrosine kinase (EGF‐R PTK). In an attempt to improve the inhibitory activity, this type of compounds was modified with alkyl spacers of varying length between the nitrostyrene and the glutaryl units. The spacers consisted of 1, 3, 4, and 5 atoms to give compounds of the benzyl, oxyethyl, oxypropyl, and oxybutyl series, respectively (Schemes 1 and 2). Adenosine 5′‐esters were prepared in the benzyl and oxypropyl series only. Compared to the compounds in the parent series without spacer (IC50 = 0.7–12 μM), most of the modified compounds inhibited the EGF‐R PTK only marginally or were inactive (IC50 ≥ 100 μM). The only exceptions were the free acids 19 and 20 with IC50 values of ca. 5 μM. It is noteworthy that esterification of these two hydrogen glutarates with either MeOH or adenosine yielded inactive compounds, which is in contrast to the corresponding substances without spacers.

Nitrostyrene Derivatives of Adenosine 5′‐Glutarates as Selective Inhibitors of the Epidermal Growth Factor Receptor Protein Tyrosine Kinase

AbstractThe syntheses and biological activities of some nitrostyrene derivatives of adenosine 5′‐glutarates, a novel class of selective, bi‐substrate‐type inhibitors of the EGF receptor protein tyrosine kinase with IC50 values around 1 μM. Only marginal inhibition of the tyrosine kinases v‐able and c‐src and of the serine/threonine kinase PKC was observed. Compounds 8, 9, 11, and 12 – lacking the adenosine moiety – were ten times less active than the most potent derivatives, whereas 17 – lacking the nitrostyryl part – showed no inhibitory activity at all. Most of the compounds showed potent antiproliferative activity against an EGF‐dependent mouse keratinocyte cell line.

Novel Synthesis of Indoles via Palladium-Catalyzed Reductive N-Heterocyclization of o-Nitrostyrene Derivatives

Abstract Indole derivatives were readily prepared from the reductive N-heterocyclization of o-nitrostyrene derivatives in the presence of a catalytic amount of PdCl2(PPh3)2–SnCl2 under carbon monoxide pressure (20 kg/cm2) at 100 °C for 16 h. With o-nitrostilbene, 2-phenylindole was obtained in 75% yield.

Correlations between structure of nitrostyrene derivative fungicides and their reactivity toward low molecular weight thiols

Reactivity of 27 fungitoxic β-nitrostyrene derivatives against l-cysteine, glutathione, and 2-mercaptoacetic acid was studied for modeling their reactions with essential sulfhydryl groups in fungi. A significant linear correlation was found between the reactivity of ring-substituted derivatives and the Hammett σ constant of the substituents in the case of each thiol. Principal component analysis and stepwise regression analysis were used to reveal other possible correlations. The reactivity order of nitrostyrene derivatives against the three thiols was very similar. The reactivity was increased the most by nitro and cyano substitutions (except substitutions in the ortho position), the presence of halogen atoms influenced to a lesser extent the reactivity of each parent compound. Ortho substitutions generally lessened the reaction rate. Methyl substitution on the α carbon atom of the styryl double bond strongly decreased the reaction rate. The molecular lipophilicity of these nitrostyrene derivatives did not significantly influence the reaction rates.

ChemInform Abstract: Stereospecific Synthesis of the Cyclopenta(e)phenanthridine Ring System: Tetracyclic and Pentacyclic Analogues of Cephalotaxus Alkaloids.

Abstract Methylenedioxy- and dimethoxy-derivatives of the hexahydrocyclopenta[e]phenanthridine ring system. (21a) and (21b), have been synthesised stereospecifically in six steps starting from piperonal (50% overall yield) and dimethoxybenzaldehyde (27% overall yield), respectively. Piperonal was converted into nitrostyrene derivative (13a) by the known procedure; compound (13a) on reaction with butadiene sulphone afforded the butadiene cycloaddition product (14a) which reacted with methyl acrylate in base to yield nitro-ester (15a) in a stereospecific Michael addition. Reductive cyclisation of compound (15a) using zinc and hydrochloric acid gave spirolactam (16a) which was reduced with lithium aluminium hydride to yield spiropyrrolidine (18a); this compound was converted into the pentacyclic system (21a) by reaction with formaldehyde under Pictet-Spengler conditions. Thiolactam (17a), was obtained from reaction of lactam (16a) and phosphorus pentasulphide, and was methylated with methyl iodide to give lactlminium salt (19a) which reacted with sodium borohydride to yield thiolactim derivative (20a). The route to tetracyclic compound (21b) directly paralleled this sequence.

Lipophilicity determination of some nitrostyrene derivatives on RP-2, PR-8 and RP-18 layers

The lipophilicity of 33 nitrostyrene derivatives was determined by reversed-phase thin-layer chromatography on RP-2, RP-8 and RP-18 layers using methanol as the organic phase. The RM value of each compound linearly decreased with increasing concentration of the organic solvent. The retention strength of RP-2 layer was lower than that of RP-8 and RP-18 layers. Between the retention strength of RP-8 and RP-18 layers no significant difference was detected. Minor differences among the selectivities of the layers were also observed. The impact of the change of methanol concentration on the retention was higher on RP-2 than on RP-18 layers probably due to the sterically favourable interaction of methanol with the shorter alkyl groups on the silica surface.

Stereospecific synthesis of the cyclopenta [e] phenanthridine ring system: tetracyclic and pentacyclic analogues of [formula omitted] alkaloids

Methylenedioxy- and dimethoxy-derivatives of the hexahydrocyclopenta[e]phenanthridine ring system. (21a) and (21b), have been synthesised stereospecifically in six steps starting from piperonal (50% overall yield) and dimethoxybenzaldehyde (27% overall yield), respectively. Piperonal was converted into nitrostyrene derivative (13a) by the known procedure; compound (13a) on reaction with butadiene sulphone afforded the butadiene cycloaddition product (14a) which reacted with methyl acrylate in base to yield nitro-ester (15a) in a stereospecific Michael addition. Reductive cyclisation of compound (15a) using zinc and hydrochloric acid gave spirolactam (16a) which was reduced with lithium aluminium hydride to yield spiropyrrolidine (18a); this compound was converted into the pentacyclic system (21a) by reaction with formaldehyde under Pictet-Spengler conditions. Thiolactam (17a), was obtained from reaction of lactam (16a) and phosphorus pentasulphide, and was methylated with methyl iodide to give lactlminium salt (19a) which reacted with sodium borohydride to yield thiolactim derivative (20a). The route to tetracyclic compound (21b) directly paralleled this sequence.

A highly stereoselective synthesis of an azaspirolactam related to cephalotaxus alkaloids

Azaspirolactam (5) has been stereoselectively synthesised from nitrostyrene derivative (2) in high yield by sequential cycloaddition, Michael addition and reductive cyclisation reactions; the stereochemistry of compound (5) is confirmed by X-ray analysis of azaspirothiolactam (6).

Complexation of nitrostyrenes with soluble ?-cyclodextrin polymer studied by reversed-phase thin-layer chromatography

Cyclodextrin complexation decreases the apparent lipophilicity of hydrophobic guest molecules. A higher complex stability results in a larger decrease of lipophilicity as determined by reversed-phase thin-layer chromatography. The method was applied to study the complex formation of 33 nitrostyrene derivatives with a water soluble cross linked β-cyclodextrin polymer (weight average molecular weight: 4300). The substituents in thepara position of the benzene ring had a higher impact on the complex stability than those in themeta andortho positions. The substituents on the alkyl side chain influenced the complex stability to the same extent as those on the benzen ring.