N-decyl Chain Research Articles

Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK.

Glioblastoma is a refractory malignant tumor that requires novel therapeutic strategies for effective treatment. We have previously reported that JCI-20679 (1), an analog of annonaceous acetogenins, shows potent antitumor activity against glioblastomas. However, the synthesis of 1 requires 23 steps, including 16 steps for the preparation of a tetrahydrofuran (THF) moiety. This study reports the design and synthesis of 11 analogs with a triethylene glycol moiety in place of the THF moiety in 1. Among these, the analog 2k with an n-decyl chain exhibited potent inhibitory activity against the growth of glioblastoma stem cells by inhibiting mitochondrial function and synergistically enhancing the effect of temozolomide (TMZ). Furthermore, 2k significantly suppressed tumor growth without critical toxicity in vivo. Hence, this study presents novel potential anticancer agents and a strategy for the development of these agents that can be produced easily.

Crystal structure, Hirshfeld surface analysis and inter-action energy calculation of 1-decyl-2,3-di-hydro-1H-benzimidazol-2-one.

The title mol-ecule, C17H26N2O, adopts an L-shaped conformation, with the straight n-decyl chain positioned nearly perpendicular to the di-hydro-benzimidazole moiety. The di-hydro-benzimidazole portion is not quite planar as there is a dihedral angle of 1.20 (6)° between the constituent planes. In the crystal, N-H⋯O hydrogen bonds form inversion dimers, which are connected into the three-dimensional structure by C-H⋯O hydrogen bonds and C-H⋯π(ring) inter-actions. Hirshfeld surface analysis indicates that the most important contributions for the crystal packing are from H⋯H (75.9%), H⋯C/C⋯H (12.5%) and H⋯O/O⋯H (7.0%) inter-actions. Based on computational chemistry using the CE-B3LYP/6-31 G(d,p) energy model, C-H⋯O hydrogen bond energies are -74.9 (for N-H⋯O) and -42.7 (for C-H⋯O) kJ mol-1.

N-Decyltrimethylammonium bromide

The title compound, C13H30N+·Br− (systematic name: N,N,N-trimethyl-1-decanaminium bromide), forms crystals having a bilayer structure, comprised of layers of trimethylammonium cations and bromide anions separated by the inter-digitated n-decyl groups of the cation; close ammonium-methyl-C—H...Br contacts connect the ions. The n-decyl chain adopts a slightly distorted all-trans conformation. The n-decyl chain exhibits positional disorder with all atoms at half occupancy. The sample was a racemic twin.

Nonresonant and Local Field Effects in Peptidic Nanostructures Bearing Oligo(p-phenylenevinylene) Units

Peptide nanostructures with built-in electronic functions offer a new platform for biomaterial science. In this report, we interrogate the influences of the immediate peptide environment around oligo(p-phenylenevinylene) (OPV3) electronic units embedded within one-dimensional peptide nanostructures on the resulting photophysics as assessed by UV-vis, photoluminescence (PL), and circular dichroism spectroscopies. To do so, we studied peptide-core-peptide molecules where the core was either OPV3 or an aliphatic n-decyl chain. Coassemblies of these molecules wherein the π-core was diluted as a minority component within a majority aliphatic matrix allowed for the variation of interchromophore exciton coupling commonly found in homoassemblies of peptide-OPV3-peptide monomers. Upon coassembly of the peptides, a hydrophilic tripeptide sequence (Asp-Asp-Asp-, DDD-) promoted the dilution/isolation of the peptide-π-peptide molecules in the majority peptide-decyl-peptide matrix whereas a hydrophobic tripeptide sequence (Asp-Val-Val-, DVV-) promoted the formation of self-associated stacks within the nanostructures. We also performed temperature variation studies to induce the reorganization of π-electron units in the spatially constrained n-decyl environment. This study elucidates the nonresonant (e.g., conformational) and local peptide field effects enforced within the internal environment of peptide nanomaterials and how they lead to varied photophysical properties of the embedded π-electron cores. It offers new insights on tuning the optoelectronic properties of these types of materials on the basis of the local electronic and steric environment available within the nanostructures.

Helix-Sense-Selective and Enantiomer-Selective Living Polymerization of Phenyl Isocyanide Induced by Reusable Chiral Lactide Using Achiral Palladium Initiator

Polymerization of phenyl isocyanide using achiral Pd(II) initiator with the presence of chiral l- or d-lactide (l-LA or d-LA) as additive was found to proceed in helix-sense-selective manner. The polymerization of achiral phenyl isocyanide, 4-isocyanobenzoyl-2-aminoisobutyric acid decyl ester (1) by this method produced optically active helical poly-1m(L), whose chirality was solely come from the helical conformation without containing of any other chiral atoms. The added chiral LA can be facilely recovered and reused in the helix-sense-selective polymerizations without significantly loss of its chiral induction, and the chiral economy of the polymerization is high. When enantiomerically pure phenyl isocyanide bearing an R- or S-alanine pendent with a long n-decyl chain (1r or 1s) were polymerized by this method, the polymerization was found to proceed in a highly enantiomer-selective manner with one of the enantiomers preferentially polymerized over the antipode by a factor of 3.6. Single-handed helical ...

Structure–activity relationship studies of 4-methylcoumarin derivatives as anticancer agents

Context: Cancer is a leading cause of death worldwide and novel chemotherapeutic agents with better efficacy and safety profiles are much needed. Coumarins are natural polyphenolic compounds with important pharmacological activities, which are present in many dietary plants and herbal remedies.Objectives: The objective of this study is to investigate natural and synthetic coumarin derivatives with considerable anticancer capacity against three human cancer cell lines.Materials and methods: We synthesized 27 coumarin derivatives (mostly having 4-methyl moiety) and examined their cytotoxic effect on three human cancer cell lines, K562 (chronic myelogenous leukemia), LS180 (colon adenocarcinoma), and MCF-7 (breast adenocarcinoma) by MTT reduction assay. Screened compounds included 7-hydroxy-4-methylcoumarins (7-HMCs), 7-acetoxy-4-methylcoumarins (7-AMCs), and different dihydroxy-4-methylcoumarin (DHMC) and diacetoxy-4-methylcoumarin (DAMC) derivatives. Some compounds with methoxy, amine, and bromine substitutions were also examined.Results: 7,8-DHMCs bearing alkyl groups at C3 position were the most effective subgroup, and of which, the most potent is compound 11, with an n-decyl chain at C3, which had IC50 values of 42.4, 25.2, and 25.1 µM against K562, LS180, and MCF-7 cells, respectively. The second most active subgroup was 7,8-DAMCs containing ethoxycarbonylmethyl and ethoxycarbonylethyl moieties at C3 position. Compound 27 (6-bromo-4-bromomethyl-7-hydroxycoumarin), the only derivative containing bromine also showed reasonable cytotoxic activities (IC50 range: 32.7–45.8 µM).Discussion and conclusion: This structure–activity relationship (SAR) study of 4-methylcoumarins shows that further investigation of these derivatives may lead to the discovery of novel anticancer agents.

Well-Defined Alternating Copolymers of Oligo(phenylenevinylene)s and Flexible Chains

A series of alternating copolymers containing oligomeric bis(2-ethylhexyl)-p-phenylenevinylene (BEH-PPV) chromophores and conformational-flexible n-decyl or tetraethylene glycol chains were prepared. The polymerization was carried out using Sonogashira coupling conditions between monomers composed of an iodo-terminated PPV oligomer (trimer, pentamer, or septamer) and a bis(phenylacetylene)-containing flexible chain. Polymers containing the n-decyl chain attained higher molecular weights compared to the tetraethylene glycol-containing polymers. 4-Ethynylanisole-capped oligomers (trimer, pentamer, or septamer) were prepared, and their solution photophysical properties were compared to the analogous polymeric materials. The solution optical properties of the polymers were primarily determined by chromophore length of the constituent oligomers. In contrast, the thin film fluorescence spectra of the polymers showed substantial differences between n-decyl and tetraethylene glycol containing materials, suggestin...

Enantiomer-Selective and Helix-Sense-Selective Living Block Copolymerization of Isocyanide Enantiomers Initiated by Single-Handed Helical Poly(phenyl isocyanide)s

Rigid-rodlike right (P)- and left (M)-handed helical polyisocyanides (P-poly-L-1 and M-poly-L-1) prepared by the living polymerization of an enantiomerically pure phenyl isocyanide bearing an L-alanine pendant with a long n-decyl chain (L-1) with the mu-ethynediyl Pt-Pd catalyst were found to block copolymerize L-1 and D-1 in a highly enantiomer-selective manner while maintaining narrow molecular weight distributions. The M-poly-L-1 preferentially copolymerized L-1 over the antipode D-1 by a factor of 6.4-7.7, whereas the D-1 was preferentially copolymerized with P-poly-L-1 composed of the same L-1 units, but possessing the opposite helicity by a factor of 4.0. Circular dichroism and high-resolution atomic force microscopy revealed that the enantiomer-selective block copolymerizations proceed in an extremely high helix-sense-selective fashion, and the preformed helical handedness determines the overall helical sense of the polyisocyanides irrespective of the configuration of the monomer units of the initiators during the block copolymerizations. The block copolymers are rigid-rod helical polymers with a narrow molecular weight distribution and exhibit a lyotropic smectic liquid crystalline phase.

Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

Typical CYP2D6 substrates generally contain a basic nitrogen atom that interacts with Asp(301) and/or Glu(216) and an aromatic moiety adjacent to the site of metabolism. Recently, we found novel acidic substrates for CYP2D6, pactimibe, and its indole metabolite, R-125528, that are not protonated but are negatively charged at physiological pH. The K(m) value of R-125528 in CYP2D6-expressing microsomes was determined to be 1.74 microM, which was comparable with those of typical basic CYP2D6 substrates (1-10 microM). Pactimibe has lower affinity than R-125528; however, the K(m) value was comparable with that of metoprolol. Interestingly, their sites of metabolism, the omega-1 position of the N-octyl indoline/indole group, were relatively distant from the aromatic moiety. A pactimibe analog with an N-decyl chain was similarly labile against CYP2D6; however, analogs with N-hexyl or N-dodecyl chains were stable to CYP2D6. An induced fit docking of the ligands with an X-ray crystal structure of substrate-free CYP2D6 (Protein Data Bank code 2F9Q) indicated the involvement of an electrostatic interaction between the carboxyl group and Arg(221) and hydrophobic interaction between the aromatic moiety and Phe(483). The docking model correctly positioned the site of metabolism above the heme. The effect of the N-alkyl chain length of pactimibe analogs on their CYP2D6 metabolic stability was plausibly explained by the docking model. In conclusion, we report herein a novel CYP2D6 binding mode for the acidic substrates pactimibe and R-125528. Further investigation, such as a site-directed mutation, will be necessary to directly demonstrate the involvement of Arg(221) in CYP2D6 binding.

Helix-Sense-Controlled Polymerization of Optically Active Phenyl Isocyanides

A series of optically active phenyl isocyanides bearing various chiral functional groups, such as l-alanine, l-alaninol, l-phenylalanine, and l-lactic acid residues, with a long n-decyl chain as the pendants were prepared, and these were polymerized with an achiral nickel catalyst (NiCl2) in various organic solvents at different temperatures. The chiroptical properties and structures of the resulting helical polyisocyanides investigated by circular dichroism (CD) and IR spectroscopy revealed that the Cotton effect signs and intensities of the polyisocyanides, which correspond to their helical senses (right- or left-handed helix) and the excess of one helical sense, respectively, were significantly dependent on the pendant structures of the polymers and the polymerization conditions, such as the solvent polarity and temperature. The effect of the alkyl chain length of l-alanine-bound phenyl isocyanides on the helix-sense-controlled polymerization was also investigated.

Two- and Three-Dimensional Smectic Ordering of Single-Handed Helical Polymers

Rodlike polymers with precisely defined architectures are ideal building blocks for self-assembled structures leading to novel nanometer-scale devices. We found that the living polymerization of a single isocyanide enantiomer bearing an l-alanine pendant with a long n-decyl chain simultaneously produced diastereomeric right- and left-handed helices with different molecular weights and narrow molecular weight distributions. Each single-handed, rodlike helical polymer with a controlled length and handedness isolated by a facile solvent fractionation method with acetone self-assembled to form well-defined two- and three-dimensional smectic ordering on the nanometer scale on a substrate and in a liquid crystalline state as evidenced by direct atomic force microscopic observations and X-ray diffraction measurements, respectively.

Novel, Highly Potent Adenosine Deaminase Inhibitors Containing the Pyrazolo[3,4-d]pyrimidine Ring System. Synthesis, Structure−Activity Relationships, and Molecular Modeling Studies

This study reports the synthesis of a number of 1- and 2-alkyl derivatives of the 4-aminopyrazolo[3,4-d]pyrimidine (APP) nucleus and their evaluation as inhibitors of ADA from bovine spleen. The 2-substituted aminopyrazolopyrimidines proved to be potent inhibitors, most of them exhibiting K(i) values in the nanomolar/subnanomolar range. In this series the inhibitory activity is enhanced with the increase in length of the alkyl chain, reaching a maximum with the n-decyl substituent. Insertion of a 2'-hydroxy group in the n-decyl chain gave 3k, whose (R)-isomer displayed the highest inhibitory potency of the series (K(i) 0.053 nM), showing an activity 2 orders of magnitude higher than that of (+)-EHNA (K(i) 1.14 nM), which was taken as the reference standard. Docking simulations of aminopyrazolopyrimidines into the ADA binding site were also performed, to rationalize the structure-activity relationships of this class of inhibitors.

Evaluating the cytotoxicity of ionic liquids using human cell line HeLa

This paper presents cytotoxicity data of selected imidazolium ionic liquids evaluated in vitro on the human tumor cell line HeLa. It was found that for 1-n-butyl-3-methylimidazolium entities the toxicity depends strongly on the associated anion; EC50 values are lowest for tetrafluoroborate. No direct dependence of the reduced effect concentration was found on elongating the short, methyl chain to ethyl or n-hexyl. Only for the ionic liquid with an n-decyl chain, the longest one studied, did higher hydrophobicity result in a EC50 one order of magnitude lower than that obtained with the n-butyl entity. The effect concentrations of imidazolium ionic liquids in the HeLa system used are lower than the values obtained for conventional organic solvents such as dichloromethane, toluene or xylene.

Crystal and molecular structure of bis(N-n-decyl-o-hydroxyacetophen-oniminato) copper(II)

Thetitlecompound crystallizes in the triclinic space groupP, with a= 7.990(8),b= 17.963(10),c= 6.689(10)A. α=80.1(6), β=110.9(4),γ=100.0(6)°,Z= 1. The structure was solved by the heavy-atom method and refined to R 0.083 for 1 753 observed visually estimated data. Copper is four-co-ordinate planar with Cu–0 1.975 and Cu–N 2.047 A. In the co-ordination polyhedron copper is displaced from the o-hydroxyacetophenone plane by 1 .1 7 A giving rise to a ‘step’ between the two halves of the molecule. The plane of the n-decyl chain makes a dihedral angle of 106° with the co-ordination plane. The carbon atoms of this chain have no contacts sufficiently close to the copper atom to affect its electronic configuration, but the presence of methyl and methylenc groups causes distortion in the chelate ring.