Meta-methoxy Groups Research Articles

Bulk and In Situ Quantification of Coniferaldehyde Residues in Lignin.

Lignin is a group of cell wall localised heterophenolic polymers varying in the chemistry of the aromatic and aliphatic parts of its units. The lignin residues common to all vascular plants have an aromatic ring with one para hydroxy group and one meta methoxy group, also called guaiacyl (G). The terminal function of the aliphatic part of these G units, however, varies from alcohols, which are generally abundant, to aldehydes, which represent a smaller proportion of lignin monomers. The proportions of aldehyde to alcohol G units in lignin are, nevertheless, precisely controlled to respond to environmental and development cues. These G aldehyde to alcohol unit proportions differ between each cell wall layer of each cell type to fine-tune the cell wall biomechanical and physico-chemical properties. To precisely determine changes in lignin composition, we, herein, describe the various methods to detect and quantify the levels and positions of G aldehyde units, also called coniferaldehyde residues, of lignin polymers in ground plant samples as well as in situ in histological cross-sections.

Cyclization of methoxy groups on spiro-type hole transporting materials for efficient and stable perovskite solar cells

Hole transporting materials (HTMs) are vital in efficient and stable perovskite solar cells (PSCs). To improve the performance of PSCs, it is of great significance to design and optimize HTMs. Here, spiro-biOMe, an analogue of spiro-OMeTAD featuring one additional meta-methoxy group on each diarylamine moiety, is reported. The structure of this new HTM has been further elaborated to give another analogue, spiro-cyclOMe, where an alkyl chain links the two adjacent O atoms. The effect of chemical structure on molecular and photovoltaic properties has been studied. It was found that the hole mobility and thermal stability were noticeably increased in the case of spiro-cyclOMe. When used in the PSC device (used perovskite: Cs0.05FA0.95PbI3), spiro-cyclOMe delivers a power conversion efficiency (PCE) of over 23%, which is higher than spiro-biOMe (PCE = 20.19%) and spiro-OMeTAD (PCE = 22.61%). A device employing spiro-cyclOMe, with an active area of 0.56 cm2, exhibited a PCE of 21.64%. More importantly, PSCs employing spiro-cyclOMe as HTM also showed better stability than those employing spiro-OMeTAD.

Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents.

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50 =4.5-5.8 μM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50 =2.0-3.5 μM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T. b. brucei cells.

Demonstration of a Stereospecific Photochemical Meta Effect

A fundamental goal of photochemistry is to understand how structural features of a chromophore can make specific bonds within a molecule prone to cleavage by light, or photolabile. The meta effect is an example of a regiochemical explanation for photolability, in which electron donating groups on an aromatic ring cause photolability selectively at the meta position. Here, we show, using a chromophore containing one ring with a meta-methoxy group and one ring with a para-methoxy group, that two stereoisomers of the same compounds can react with light differently, based simply on the three-dimensional positioning of a meta anisyl ring. The result is that the stereoisomers of the compound with the same configuration at both stereogenic centers are photolabile while the stereoisomers with opposite configuration do not react with light. Furthermore, time-dependent density functional theory (TD-DFT) calculations show distinct excitation pathways for each stereoisomer.

Ethanol coordinated zinc trimethoxyphenylporphyrin: Structure, theoretical studies and formation of isoporphyrin

An axial ethanol bound zinc porphyrin, [Zn(TMPP)(C2H5OH)]·2CH2Cl21 (TMPP = 5,10, 15,20-tetrakis(3,4,5-trimethoxyphenyl)porphyrin) was synthesized and characterised using single crystal X-ray diffraction method. The complex 1 is a penta co-ordinated zinc porphyrin via the Zn–O(ethanol) bond and shows one - dimensional chain network through O-atom of axially bound ethanol to peripheral meta-methoxy group of a consecutive porphyrin unit. The hydroxy-isoporphyrin of complex 1 was synthesized on reaction with ceric ammonium nitrate (CAN) as oxidizing agent. The partial molecular energy diagram of selected frontier orbitals and the electronic transitions were determined for compound 1 using Gaussian 09 software. The Hirshfeld surface analysis and 2D fingerprint plots were also performed to understand the origin of H-bonding and other intermolecular short contacts present in the crystal lattice of compound 1. The electrochemical and luminescence properties of the complex 1 was studied and compared with its hydroxy isoporphyrin analogue.

Synthesis of meta-methoxyphenyl substituted tetraazaporphyrin and corrolazine phosphorus(V) complexes

Octa-(meta-methoxyphenyl) substituted tetraazaporphyrin (TAP, 1) and corrolazine (Cor, 4) phosphorus(V) complexes have been synthesized and characterized. 1 has a blue-shifted, small charge transfer (CT) band while para-methoxyphenyl substituted PTAP 2 has a red-shifted, intense CT band. The difference could be interpreted as an inductive effect of the meta-methoxy groups. The position and intensity of the absorption bands of 1 are well matched to the trend of para-substituted PTAPs. The synthesis of PCor from free-base TAP was also investigated. The PCor was not generated directly but from a PTAP intermediate

Expanding the Scope of Replicable Unnatural DNA: Stepwise Optimization of a Predominantly Hydrophobic Base Pair

As part of an ongoing effort to expand the genetic alphabet for in vitro and eventually in vivo applications, we have synthesized a wide variety of predominantly hydrophobic unnatural base pairs exemplified by d5SICS-dMMO2 and d5SICS-dNaM. When incorporated into DNA, the latter is replicated and transcribed with greater efficiency and fidelity than the former; however, previous optimization efforts identified the para and methoxy-distal meta positions of dMMO2 as particularly promising for further optimization. Here, we report the stepwise optimization of dMMO2 via the synthesis and evaluation of 18 novel para-derivatized analogs of dMMO2, followed by further derivatization and evaluation of the most promising analogs with meta substituents. Subject to size constraints, we find that para substituents can optimize replication via both steric and electronic effects and that meta methoxy groups are unfavorable, while fluoro substituents can be beneficial or deleterious depending on the para substituent. In addition, we find that improvements in the efficiency of unnatural triphosphate insertion translate most directly into higher fidelity replication. Importantly, we identify multiple, unique base pair derivatives that when incorporated into DNA are well replicated. The most promising, d5SICS-dFEMO, is replicated under some conditions with greater efficiency and fidelity than d5SICS-dNaM. These results clearly demonstrate the generality of hydrophobic forces for the control of base pairing within DNA, provide a wealth of new SAR data, and importantly identify multiple new candidates for eventual in vivo evaluation.

Abstract 2529: Structure-activity relationship studies of the type II topoisomerase poison amsacrine

Abstract Type II topoisomerases are essential, ubiquitously expressed enzymes that are required for the modulation of chromosomal topology. A critical intermediate in the catalytic cycle of topoisomerase II is the generation of the cleavage complex, a transient enzyme-linked DNA double-stranded break. Several classes of widely prescribed anticancer drugs kill cells specifically by stabilizing the topoisomerase II-DNA cleavage complex, resulting in an accumulation of genetic damage and eventually apoptosis. The anilinoacridine, amsacrine, is a topoisomerase II-targeted drug effective in the treatment of relapsed acute myeloid leukemia. The structure of the drug includes a DNA-intercalative acridine moiety and a substituent-bearing pendant ring. Amsacrine enhances in vitro topoisomerase II-mediated DNA cleavage ∼8-fold. It has long been known that movement of the methoxy group from the meta- to the ortho- position (relative to the methanesulfonamide group) abrogates drug action, but the basis for this effect is unknown. Therefore, the effects of eliminating the methoxy group on drug activity were determined. The resulting compound was intermediate to the meta- and ortho-methoxy compounds, suggesting that the meta-methoxy group favors drug-enzyme interaction while the ortho-methoxy group inhibits it. Substitution of the methanesulfonamide group with a hydroxy group or a proton attenuated enzyme-mediated DNA cleavage ∼5-fold or ∼2-fold, respectively. This implies that the methanesulfonamide promotes, but is not essential for, drug-enzyme interaction. To investigate the significance of DNA intercalation in the interaction between amsacrine and the topoisomerase II-DNA cleavage complex, the relative potencies of amsacrine and derivatives as DNA intercalators were determined. Correlations between structure and DNA intercalation were observed, but not between DNA intercalation and drug activity. This suggests that DNA intercalation alone is not sufficient for drug action; specific interaction with the enzyme through the pendant ring groups is required for effective drug activity. To further investigate the significance of DNA intercalation in amsacrine activity, the effects of the isolated pendant ring on enzyme-mediated DNA cleavage were determined. This compound enhanced DNA cleavage in the absence of DNA intercalation with efficacy and site-specificity similar to that of amsacrine, but with a 100-fold lower potency. Unlike amsacrine, the activity of the pendant ring was partially redox-dependent. We conclude from these results that the interaction between amsacrine and topoisomerase II is mediated through the pendant ring substituents, while the acridine moiety protects against redox activity and significantly increases the local concentration of amsacrine at the active site of the enzyme. This work was supported by NIH grants GM033944 and T32 GM065086. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2529. doi:10.1158/1538-7445.AM2011-2529

Antivascular and anticancer activity of dihalogenated A-ring analogues of combretastatin A-4

The generally accepted view is that the 3,4,5-trimethoxy-substituted aromatic A-ring of combretastatin A-4 (CA-4) and its analogues should be conserved in order to maintain biological activity through enforcing an active molecular conformation. Contrary to this, we have found that substituting the larger meta-methoxy groups of CA-4 with smaller halogen atoms results in compounds that are equipotent or more potent than CA-4 itself in vitro.

Structural Model for Phenylalkylamine Binding to L-type Calcium Channels

Phenylalkylamines (PAAs), a major class of L-type calcium channel (LTCC) blockers, have two aromatic rings connected by a flexible chain with a nitrile substituent. Structural aspects of ligand-channel interactions remain unclear. We have built a KvAP-based model of LTCC and used Monte Carlo energy minimizations to dock devapamil, verapamil, gallopamil, and other PAAs. The PAA-LTCC models have the following common features: (i) the meta-methoxy group in ring A, which is proximal to the nitrile group, accepts an H-bond from a PAA-sensing Tyr_IIIS6; (ii) the meta-methoxy group in ring B accepts an H-bond from a PAA-sensing Tyr_IVS6; (iii) the ammonium group is stabilized at the focus of P-helices; and (iv) the nitrile group binds to a Ca(2+) ion coordinated by the selectivity filter glutamates in repeats III and IV. The latter feature can explain Ca(2+) potentiation of PAA action and the presence of an electronegative atom at a similar position of potent PAA analogs. Tyr substitution of a Thr in IIIS5 is known to enhance action of devapamil and verapamil. Our models predict that the para-methoxy group in ring A of devapamil and verapamil accepts an H-bond from this engineered Tyr. The model explains structure-activity relationships of PAAs, effects of LTCC mutations on PAA potency, data on PAA access to LTCC, and Ca(2+) potentiation of PAA action. Common and class-specific aspects of action of PAAs, dihydropyridines, and benzothiazepines are discussed in view of the repeat interface concept.

Modeling L-type Calcium Channel with Phenylalkylamines

Phenylalkylamines (PAAs), a major class of L-type calcium channel (LCC) blockers, have aromatic rings A and B connected by a flexible chain with cyano and ammonium groups proximal to rings A and B, respectively. Structural aspects of ligand-channel interactions remain unclear. We have built LCC models as in (Tikhonov and Zhorov, 2008) with KvAP, MthK, Kv1.2 and KcsA as templates and used Monte Carlo energy-minimizations to dock devapamil, verapamil, and gallopamil, which have three, four, and five methoxy groups, respectively. The PAA-LCC models have the following common features: meta-methoxy group in ring A accepts an H-bond from Y1179(3i10) in domain 3 inner-helix position 10, the ammonium group is stabilized at the focus of P-helices, and the cyano group coordinates a Ca2+ ion bound to the selectivity-filter glutamates in domains 3 and 4. The latter feature can explain the well-known effect of Ca2+ potentiation of PAA action. Our models are also consistent with structure-activity and mutational studies. For instance, mutation of Y1490(4i11) affects action of devapamil, but not verapamil and gallopamil (Johnson et al., 1996). In our models, the single meta-methoxy group in ring B of devapamil accepts an H-bond from Y1490(4i11), while meta- and para-methoxy groups in ring B of verapamil and gallopamil chelate the Ca2+ ion. Mutation T1066(3o14)Y in domain 3 outer-helix position 14 enhances action of devapamil and verapamil, but not gallopamil (Huber et al., 2004). Our models predict that para-methoxy group in ring A of devapamil and verapamil accepts an H-bond from Y3o14, while tri-methoxylated ring A of gallopamil is too bulky to approach Y3o14. Docking of devapamil in different models shows that the Kv1.2 template is most consistent with the experimental data. The closed (KcsA-based) model has the same ligand-channel contacts, but with weaker interaction energy. Supported by CIHR.

Crystal Phases and Phase Transitions in a Highly Polymorphogenic Solid-State Molecular Gyroscope with meta-Methoxytrityl Frames

The energy landscape of molecular gyroscopes with meta-methoxy substituted trityl groups may include many stereoisomers due to the helicity of the two triarylmethyl propeller moieties and the stereochemical label provided by the meta-methoxy group. While low equilibration barriers and rapid equilibration in solution prevent isolation and observation by relatively slow techniques such as 1H and 13C NMR, their many structural options may offer opportunities to prepare several crystal forms, or conformational polymorphs. In this paper, we report the synthesis and characterization of 1,4-bis[tri-(meta-methoxyphenyl)propynyl]benzene (2), a crystalline molecular gyroscope with a phenylene rotator, a dialkyne axle, and two tri-meta-methoxy-substituted trityl frames. Using a combination of single-crystal X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), high resolution 13C cross-polarization magnetic-angle spinning (CPMAS) NMR, and polarized microscopy, we obtained experimental evidence for seven polymorphs labeled A−G and up to six phase transitions that relate them.

The design, synthesis and evaluation of novel HIV-1 protease inhibitors with high potency against PI-resistant viral strains.

Replacement of the pyridylmethyl moiety in indinavir with a pyridyl oxazole yielded HIV-1 protease inhibitors (PI) with greatly improved potency against PI-resistant HIV-1 strains. A meta-methoxy group on the pyridyl ring and a gem-dimethyl methyl linkage afforded compound 10 with notable in vitro antiviral activity against HIV-1 viral strains with reduced susceptibility to the clinically available PIs. Compound 10 also demonstrated favorable in vivo pharmacokinetics in animal models.

Meta−Ortho Effect in Organic Photochemistry: Mechanistic and Exploratory Organic Photochemistry

In early research, the meta effect was based on one-electron, Huckel computations and experimental observation, which revealed a selective transmission of electron density to the meta and ortho positions on an aromatic ring in the first excited singlet. However, attention was focused on the meta site. More recent results have confirmed electron density transmission to the ortho site as well. Typical examples involve benzylic cations. Not only are the S1 cations selectively stabilized by meta-methoxy groups compared with para-methoxy substituents but also the corresponding meta-substituted radicals prove of higher energy than the para-substituted counterparts. Additionally, the S0 − S1 energy gap is dramatically smaller for the meta-substituted cations and ion pairs compared with the gap for the para-substituted counterparts. Also, the radicals and radical pairs exhibit much larger ground-state − excited-state energy separations. With a closer approach of surfaces, the excited-state ion pairs have an avenu...

Substituent effects in aromatic substitution of aryltriethyltin compounds by mercuric halides

Second-order rate constants are reported for the reaction of some YC 6H 4SnEt 3 compounds with mercuric halides in tetrahydrofuran, and show that the reaction is one of low selectivity. The substituent effects can be correlated only in terms of Hammett σ-constants, and the data for the meta-methoxy group are anomalous. The results indicate that the rate determining step involves reaction of a π-complex. Activation parameters are reported, and are in accordance with the suggested mechanism.

Hydrogen rearrangement in molecular ions of alkyl benzenes: Appearance potentials and substituent effects on the formation of [C7H8]+ ions

AbstractThe mechanism of the formation of [C7H8]+ ions by hydrogen rearrangement in the molecular ions of 1‐phenylpropane and 1,3‐diphenylpropane has been investigated by looking at the effects of CH3O and CF3 substituents in the meta and para positions on the relative abundances of the corresponding ions and on the appearance energies. The formation of [C7H8]+ ions from 1,3‐diphenylpropane is much enhanced at the expense of the formation of [C7H7]+ ions by benzylic cleavage, due to the localized activation of the migrating hydrogen atom by the γ phenyl group. A methoxy substituent in the 1,3‐diphenylpropane, exerts a site‐specific influence on the hydrogen rearrangement, which is much more distinct than in 1‐phenylpropane and related 1‐phenylalkanes, the rearrangement reaction being favoured by a meta methoxy group. The mass spectrum of 1‐(3‐methoxyphenyl)‐3‐(4‐trideuteromethoxyphenyl)‐propane shows that this effect is even stronger than the effect of para methoxy groups on the benzylic cleavage. From measurements of appearance potentials it is concluded that the substituent effect is not due to a stabilization of the [C7H7X]+ product ions. Whereas the [C7H7]+ ions are formed directly from molecular ions of 1‐phenylpropane and 1,3‐diphenylpropane, the [C7H8]+ ions arise by a two‐step mechanism in which the s̀ complex type ion intermediate can either return to the molecular ion or fragment to [C7H8]+ by allylic bond cleavage. Obviously the formation of this s̀ complex type ion, is influenced by electron donating substituents in specific positions at the phenyl group. This is borne out by a calculation of the ΔHf values of the various species by thermochemical data. Thus, the relative abundances of the fragment ions are determined by an isomerization equilibrium of the molecular ions, preceding the fragmentation reaction.