Introduction Of Bulky Substituents Research Articles

Synthesis and receptor activity of 2-substituted 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles

A series of new 2-substituted 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles have been synthesized. Their activity profiles were studied on a broad panel of therapeutic targets including GPC-receptors, ion channels, and neurotransmitter transporters. One of the studied compounds, 2-methyl-3-{2-[8-methyl-5-(2-pyridin-2-ylethyl)-2,3,4,5-tetrahydropyridino[4,3-b]indol-2-yl]ethyl}-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, was found to be a highly active antagonist of adrenergic α1A, α1B, α1D, and α2A receptors and serotonin 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. The results were considered in terms of structure—activity relationships. It was established that introduction of bulky substituents into the 2-position of the other synthesized 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles led to an activity decrease of the corresponding derivatives as compared with that of the 2,8-dimethyl analogs.

Bottom-up synthesis and structures of π-lengthened tubular macrocycles

Belt-persistent tubular cycloarylenes possessing extended sp2-networks of finite single-wall carbon nanotubes (SWNT) have been synthesised from an abundantly available pigment possessing the dibenzo[def,mno]chrysene (anthanthrene) framework. The introduction of bulky substituents allowed for the diastereoselective production of a single helical isomer as a racemate, and the extension of the π-systems in the cycloarylene unexpectedly lowered the enthalpic barrier for the rotation of the arylene unit. Crystallographic analysis of the helical finite SWNT molecules revealed alternate layers of homohelical columns.

Sterically Crowding the Bridge of Dithienylcyclopentenes for Enhanced Photoswitching Performance

Better switching: The introduction of bulky substituents into the bridge moiety of dithienylethenes led to derivatives exhibiting high photocyclization quantum yields. This novel and versatile form of substitution facilitated tuning of the switching performance without compromising on the optical and redox properties of the ring-open and ring-closed forms (see scheme).

Synthesis and Electrochemical Properties of 2,6-Bis(quinoline-2-yl)pyridyl Ruthenium Complexes as Near-Infrared Sensitizers for Dye-Sensitized Solar Cells

New ruthenium(II)–polypyridyl complexes 1a–1d (1a: X= Y= H, 1b: X= H, Y= Cl, 1c: X= H, Y= Me, 1d: X= COOH, Y= H) having 2,6-bis(4-carboxyquinolin-2-yl)pyridine derivatives as ligands were synthesized as sensitizers for dye-sensitized solar cells (DSCs) and their photophysical and photochemical properties were characterized. The photovoltaic performance of DSCs sensitized with 1a–1d was found to be different. The DSC sensitized with 1a exhibits higher efficiency and IPCE value than those sensitized with 1b–1d. The APCE value of the DSC sensitized with 1a was almost 80% in the 500–800 nm range. Therefore, the performance of the DSC sensitized with 1a might improve if the adsorption of 1a on the TiO2 surface could be appropriately controlled by investigation of dye immersion condition or introduction of bulky substituents on the ligand in order to suppress dye aggregation.

Synthesis and Electrochemical Properties of 2,6-Bis(quinoline-2-yl)pyridyl Ruthenium Complexes as Near-Infrared Sensitizers for Dye-Sensitized Solar Cells

New ruthenium(II)–polypyridyl complexes 1a–1d (1a: X= Y= H, 1b: X= H, Y= Cl, 1c: X= H, Y= Me, 1d: X= COOH, Y= H) having 2,6-bis(4-carboxyquinolin-2-yl)pyridine derivatives as ligands were synthesized as sensitizers for dye-sensitized solar cells (DSCs) and their photophysical and photochemical properties were characterized. The photovoltaic performance of DSCs sensitized with 1a–1d was found to be different. The DSC sensitized with 1a exhibits higher efficiency and IPCE value than those sensitized with 1b–1d. The APCE value of the DSC sensitized with 1a was almost 80% in the 500–800 nm range. Therefore, the performance of the DSC sensitized with 1a might improve if the adsorption of 1a on the TiO2 surface could be appropriately controlled by investigation of dye immersion condition or introduction of bulky substituents on the ligand in order to suppress dye aggregation.

Isocyanurates with Planar Chirality: Design, Optical Resolution, and Isomerization

Designs and syntheses of isocyanurates (1-3) are described on the basis of a novel concept that two enantiotopic faces of C(s) -symmetric, prochiral planar molecules are differentiated with a location of groups at the top or bottom of the planar skeleton using a rigid linker. Such isocyanurates are atropisomeric. The planar-chiral structures of 1 and 2(anti) (anti-conformer of 2) were confirmed by single-crystal X-ray analyses, and the space groups were P1 (for 1) and P2(1)/c (for 2(anti)), resulting that the crystals were racemates. Optical resolutions of 1-3 were successfully accomplished by using chiral high-performance liquid chromatography technique in combination with circular dichroism, absorption, and nuclear magnetic resonance spectroscopies and mass spectrometry. Furthermore, the rotational barriers (ΔG(‡)s) related to isomerizations of 1-3 were estimated to be 27.2 (for 1 at 50 °C), 27.6 (for 2(anti) at 50 °C), and 40.6 (for 3(syn) at 150 °C) kcal/mol. The ΔG(‡)s of 2 and 3 were higher than that of 1 and, in particular, that of 3 was highest among them. This result indicates that an introduction of bulky substituents and an intramolecular bridging are effective for inhibitions of the isomerizations.

Ca2+ channel-blocking effect of the yohimbine derivatives, 14 beta-benzoyloxyyohimbine and 14 beta-pho-nitrobenzoyloxyyohimbine.

Yohimbine possesses a relatively selective alpha 2-adrenoceptor antagonistic effect and a weak Ca2+ channel blocking activity, so two derivatives, 14 beta-benzoyloxyyohimbine and 14 beta-rho-nitrobenzoyloxyyohimbine were compared with yohimbine using those parameters. The two derivatives blocked Ca2+-induced contraction of the rat perfused mesenteric vascular bed at 3 X 10(-6) M, and developed dose-dependent shifts of the dose-response curve to the right in concentrations from 3 X 10(-6) to 10(-5) M. Yohimbine showed a weak Ca2+ channel-blocking effect only at a concentration of 10(-5) M. On the other hand, both derivatives at 3 X 10(-6) M did not affect the dose-response curve to noradrenaline-induced vasoconstriction. Furthermore, at 10(-8) M they had no effect on the dose-response curve to clonidine-induced inhibition of the twitch response of the rat isolated vas deferens evoked by electric stimulation, whereas yohimbine significantly attenuated clonidine-induced inhibition. These results indicate that introduction of bulky substituents into the 14-position of yohimbine intensely potentiated the Ca2+ channel-blocking effects and reduced alpha-adrenoceptor antagonistic effects compared with those of yohimbine, and suggest that chemical modifications of yohimbine may lead to structurally new types of Ca2+ channel-blockers.

Carbonic Anhydrase Inhibitors: Binding of Indanesulfonamides to the Human Isoform II

Indanesulfonamides are interesting lead compounds for designing selective inhibitors of the different isoforms of the zinc enzyme Carbonic Anhydrase (CA). Herein, we report for the first time the X-ray crystal structure of two such derivatives, namely indane-5-sulfonamide and indane-2-valproylamido-5-sulfonamide, in complex with the physiologically dominant human isoform II. The structural analysis reveals that, although these two inhibitors have quite similar chemical structures, the arrangement of their indane ring within the enzyme active site is significantly diverse. Thus, our findings suggest that the introduction of bulky substituents on the indane-sulfonamide ring may alter the binding mode of this potent class of CA inhibitors, although retaining good inhibitory properties. Accordingly, the introduction of bulky tail moieties on the indane-sulfonamide scaffold may represent a powerful strategy to induce a desired physicochemical property to an aromatic sulfonamide or to obtain inhibitors with diverse inhibition profiles and selectivity for various mammalian CAs.

Effect of an alkyl substituted in salen ligands on 1,4‐Cis selectivity and molecular weight control in the polymerization of 1,3‐butadiene with (salen)Co(II) complexes in combination with methylaluminoxane

AbstractThe effect of an alkyl substituted in the aromatic ring of the salen ligand on the polymerization of butadiene (Bd) with (salen)Co(II) complexes in combination with methylaluminoxane (MAO) was investigated. The activity for the polymerization of Bd was influenced significantly by the introduction of alkyl groups at the 3,3′,5,5′‐positions in the aromatic ring of the salen ligand, and both the polymerization rate and 1,4‐cis contents increased in the following order with respect to the alkyl group: H < CH3 < t‐C4H9. This is in good agreement with the bulkiness of the alkyl groups. The activity for the polymerization of the (salen)Co(II) complex possessing t‐C4H9 at the 3,3′‐positions was higher than that of the (salen)Co(II) bearing t‐C4H9 at the 5,5′‐positions. Thus, the introduction of bulky substituents at the 3,3′‐positions of the salen ligand was an important factor in achieving both high activity and high 1,4‐cis selectivity in the polymerization of Bd with (salen)Co(II) complexes in combination with MAO. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4088–4094, 2006

Fine Tuning of the Rotary Motion by Structural Modification in Light-Driven Unidirectional Molecular Motors

The introduction of bulky substituents at the stereogenic center of light-driven second-generation molecular motors results in an acceleration of the speed of rotation. This is due to a more strained structure with elongated C=C bonds and a higher energy level of the ground state relative to the transition state for the rate-limiting thermal isomerization step. Understanding the profound influence that variation of the substituent at the stereogenic center holds over the rotational speed of the light-driven molecular motor has enabled the development of the fastest molecular motor reported thus far.

Carbaporphyrinoids Containing a Pyridine Moiety: 3‐Aza‐meta‐benziporphyrin and 24‐Thia‐3‐aza‐meta‐benziporphyrin

Abstract6,11,16,21‐Tetraaryl‐3‐aza‐m‐benziporphyrin, an analog of 5,10,15,20‐tetraarylporphyrin with one of the pyrrole units replaced by a pyridine ring pointing outwards, linked at β,β′ positions, was formed by condensation of 3,5‐bis[phenyl(2‐pyrrolyl)methyl]pyridine, pyrrole and p‐tolualdehyde catalyzed by TFA. The [3+1] approach, which involved a condensation of 3,5‐bis[phenyl(2‐pyrrolyl)methyl]pyridine with 2,5‐bis[hydroxy(p‐tolyl)methyl]thiophene was applied to afford 6,11,16,21‐tetraaryl‐24‐thia‐3‐aza‐m‐benziporphyrin. Introduction of bulky substituents at ortho positions of meso‐aryl compounds, adjacent to the pyridine ring, resulted in an increase in the yield of condensation. 3‐Aza‐m‐benziporphyrins and 24‐thia‐3‐aza‐m‐benziporphyrins have the 1H NMR spectroscopic features of non‐aromatic molecules. Crystal structures of 6,21‐diphenyl‐11,16‐di‐p‐tolyl‐3‐aza‐m‐benziporphyrin and 6,21‐diphenyl‐11,16‐di‐p‐tolyl‐24‐thia‐3‐aza‐m‐benziporphyrin were determined by X‐ray crystallography. Both molecules show a similar degree of nonplanarity with the pyridine ring sharply tipped out of the N(23)X(24)N(25) plane, making room for the 6,21‐phenyl groups which are almost coplanar with the macrocycle. The protonation of 6,21‐diphenyl‐11,16‐di‐p‐tolyl‐3‐aza‐m‐benziporphyrin with trifluoroacetic acid proceeds stepwise, subsequently yielding two dicationic and one tricationic species. Protonated 6,21‐diphenyl‐11,16‐di‐p‐tolyl‐24‐thia‐3‐aza‐m‐benziporphyrinreacts reversibly with water to give 6‐hydroxy‐6,21‐diphenyl‐11,16‐di‐p‐tolyl‐24‐thia‐3‐aza‐m‐benziphlorin. The protonation of 6,21‐dimesityl‐11,16‐di‐p‐tolyl‐24‐thia‐3‐aza‐m‐benziporphyrin initiates an unprecedented process, which converts the non‐aromatic carbaporphyrinoid reversibly into the aromatic 2‐hydroxy‐6,21‐dimesityl‐11,16‐di‐p‐tolyl‐24‐thia‐3‐aza‐m‐benzichlorin. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Design and Crystal Structures of Protein Kinase B-Selective Inhibitors in Complex with Protein Kinase A and Mutants

Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures and binding studies were performed to rationalize the selectivity and improve the design.

Divalent Silicon, Germanium, and Tin Compounds with Element—Heteroatom Bonds

AbstractFor Abstract see ChemInform Abstract in Full Text.

Divalent silicon, germanium, and tin compounds with element—heteroatom bonds

Principal results and trends in chemistry of organic derivatives of divalent silicon, germanium, and tin containing bonds between these elements and the halogen, nitrogen, oxygen, and sulfur atoms are briefly surveyed. Selected characteristics of compounds with the element--phosphorus and element--arsenic bonds are discussed for comparison. Data on the synthesis and structures of new types of these compounds, viz., germanium(ii) diacylates, the alkoxy derivatives E14(OR)2 and E14(OR)Y (E14 = Ge, Sn; R = Me2NCH2CH2; Y = Cl, AcO, (Me3Si)2N), and the ate-complexes Li(+)[E14(OCH2CH2NMe2)3](–) and [Li(thf)2](+)[TsiE14(SBu)2](–) (E14 = Ge, Sn; Tsi = (Me3Si)3C), are presented. It was established for the first time that germanium(ii) and tin(ii) derivatives can be stabilized in the monomeric form only through the intramolecular Nsp3→E14 coordination bonds and the σ-acceptor effect of the oxygen atoms without introduction of bulky substituents.

Novel Topological Polyphenylazomethines Having Controlled Metal‐Assembling Properties

AbstractFor Abstract see ChemInform Abstract in Full Text.

精密金属集積能を有するポリフェニルアゾメチン新ナノ構造体

Novel dendritic polyphenylazomethines (DPAs) were synthesized up to the fourth generation by the convergent method via dehydration of aromatic ketones with aromatic amines in the presence of titanium (IV) tetrachloride. DPAs show high thermal stability and high solubility unlike the con-ventional linear polyphenylazomethines. Novel cyclic phenylazomethine trimers (CPAs) were syn-thesized in a one-step dehydration of the 4-aminobenzophenone derivatives in the presence of TiCl4 or p-toluenesulfonic acid (PTS). When using TiCl4 as the dehydration agent, the introduction of bulky substituents as the α-position of the substrate enhanced the yields of the CPAs. On the other hand, PTS served as an effective catalyst for the synthesis of the phenyl-substituted CPA. Cyclization in hyperbranched polymer synthesis was first controlled on the basis of a steric effect using a Lewis acid with bulky ligands. A novel dendrimer with a cyclic structure was quantitatively obtained via controlled cyclization using a monomer with a bulky dendron.

Photochromic Reactions of Diarylethenes with Isopropyl Groups

Photochromic bisbenzothienylethene has two conformers, photo-reactive anti-parallel and inactive parallel ones. The cyclization quantum yield is dependent on the ratio of the two conformers. By the introduction of bulky substituents at 2-positions of the benzothiophene rings, the cyclization quantum yield increased along with the increase in the ratio of the anti-parallel conformer.

Introduction of Bulky Substituents at the Bridgehead Position of a 9-Silatriptycene: Pentacoordinate Hydridoorganylsilicates as Intermediates

The reaction of 10-phenyl-10-germa-9-silatriptycene (1b) with phenyllithium in THF/HMPA produced 9,10-diphenyl-10-germa-9-silatriptycene (1a), which had hitherto not been accessible. The reaction proceeds by attack of the phenyl anion on 1b via the intermediate silicate anion 7, which was identified by 29Si NMR spectroscopy. The structure of 1a was confirmed by X-ray crystallography. As a model reaction, the attack of phenyllithium on triphenylsilane (8) and diphenylsilane (14) was investigated by 29Si NMR spectroscopy, revealing the formation of a number of novel hydridosilicates analogous to 7.

Quantitative structure-activity studies of insect growth regulators: XVI. Substituent effects of dibenzoylhydrazines on the insecticidal activity to Colorado potato beetleLeptinotarsa decemlineata

Insecticidal activity against the Colorado potato beetle, Leptinotarsa decemlineata, was measured for a series of substituted N-tert-butyl-dibenzoylhydrazines, in which one of the benzoyl moieties closer to the tert-butyl group was fixed as being 2-chloro-substitued and the other variously substituted singly or doubly. The effects of substituents on the activity were quantitatively analysed using the classical quantitative structure–activity relationship (QSAR) procedure. The activity against the Colorado potato beetle increases with the molecular hydrophobicity. In addition, various types of steric effect are at work, depending upon the positions. Hydrogen-bonding acceptor substituents at the para position enhance the activity. There seem to be threshold (or optimum) values, albeit position-dependent, in the molecular hydrophobicity, above which the activity starts to decrease. This biphasic contribution of the molecular hydrophobicity to activity against coleopterous larvae is the most conspicuous difference in substituent effects from those found for similar compounds against lepidopterous pest insects, and may be the basis of the variations in the activity spectrum for certain compounds in this series. The introduction of bulkier substituents into the meta- and para-positions of the benzene ring, apart from the tert-butyl group, is unfavorable to activity. LD50 values against Colorado potato beetle larvae of methoxyfenozide (RH-2485) and tebufenozide (RH-5992) were in the order of 10−7 mol per insect, whereas those of RH-5849, and halofenozide (RH-0345) were very low, 10−9–10−10 mol per insect being selective to the coleopterous larvae. © 1999 Society of Chemical Industry

Quantitative structure-activity studies of insect growth regulators: XVI. Substituent effects of dibenzoylhydrazines on the insecticidal activity to Colorado potato beetleLeptinotarsa decemlineata

Insecticidal activity against the Colorado potato beetle, Leptinotarsa decemlineata, was measured for a series of substituted N-tert-butyl-dibenzoylhydrazines, in which one of the benzoyl moieties closer to the tert-butyl group was fixed as being 2-chloro-substitued and the other variously substituted singly or doubly. The effects of substituents on the activity were quantitatively analysed using the classical quantitative structure–activity relationship (QSAR) procedure. The activity against the Colorado potato beetle increases with the molecular hydrophobicity. In addition, various types of steric effect are at work, depending upon the positions. Hydrogen-bonding acceptor substituents at the para position enhance the activity. There seem to be threshold (or optimum) values, albeit position-dependent, in the molecular hydrophobicity, above which the activity starts to decrease. This biphasic contribution of the molecular hydrophobicity to activity against coleopterous larvae is the most conspicuous difference in substituent effects from those found for similar compounds against lepidopterous pest insects, and may be the basis of the variations in the activity spectrum for certain compounds in this series. The introduction of bulkier substituents into the meta- and para-positions of the benzene ring, apart from the tert-butyl group, is unfavorable to activity. LD50 values against Colorado potato beetle larvae of methoxyfenozide (RH-2485) and tebufenozide (RH-5992) were in the order of 10−7 mol per insect, whereas those of RH-5849, and halofenozide (RH-0345) were very low, 10−9–10−10 mol per insect being selective to the coleopterous larvae. © 1999 Society of Chemical Industry