Terminal Phenyl Group Research Articles

Understanding the Polymorphic Behavior of Sibenadet Hydrochloride through Detailed Studies Integrating Structural and Dynamical Assessment

Three polymorphs of sibenadet hydrochloride (AR-C68397AA, Viozan) have been shown to exist at ambient temperature and have been characterized. Each undergoes a solid-state transition to a common high temperature form, which melts at approximately 220 degrees C. X-ray powder diffraction (XRPD) indicates that Polymorphs I and II share a similar layered structure not exhibited by Polymorph III. All three ambient temperature polymorphs show evidence of varying degrees of dynamic disorder of the terminal phenyl group as shown by solid-state NMR spectroscopy. Furthermore, the carbons alpha to the ether link also undergo different rates of mobility in Polymorphs I and II. This variation in the extent of dynamic disorder results in an alteration in the short-range structure resulting in distinct polymorphs. Polymorph I is the thermodynamically stable form at room temperature as indicated by solution calorimetry and assessment by thermodynamically driven solution mediated phase transition studies. The present study aims to address the types of discriminatory data required to make a clear distinction between physical forms and define, unequivocally, the presence of polymorphism.

Potent Mechanism-based Inhibitors for Matrix Metalloproteinases

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play important roles in physiological and pathological conditions. Both gelatinases (MMP-2 and -9) and membrane-type 1 MMP (MMP-14) are important targets for inhibition, since their roles in various diseases, including cancer, have been well established. We describe herein a set of mechanism-based inhibitors that show high selectivity to gelatinases and MMP-14 (inhibitor 3) and to only MMP-2 (inhibitors 5 and 7). These molecules bind to the active sites of these enzymes, initiating a slow binding profile for the onset of inhibition, which leads to covalent enzyme modification. The full kinetic analysis for the inhibitors is reported. These are nanomolar inhibitors (Ki) for the formation of the noncovalent enzyme-inhibitor complexes. The onset of slow binding inhibition is rapid (k(on) of 10(2) to 10(4) M(-1) s(-1) and the reversal of the process is slow (k(off) of 10(-3) to 10(-4) s(-1)). However, with the onset of covalent chemistry with the best of these inhibitors (e.g. inhibitor 3), very little recovery of activity (<10%) was seen over 48 h of dialysis. We previously reported that broad spectrum MMP inhibitors like GM6001 enhance MT1-MMP-dependent activation of pro-MMP-2 in the presence of tissue inhibitor of metalloproteinases-2. Herein, we show that inhibitor 3, in contrast to GM6001, had no effect on pro-MMP-2 activation by MT1-MMP. Furthermore, inhibitor 3 reduced tumor cell migration and invasion in vitro. These results show that these new inhibitors are promising candidates for selective inhibition of MMPs in animal models of relevant human diseases.

Enantiomerically Pure Pentagonal-Bipyramidal Metal Complexes with Predetermined Helicity in the Solid and Solution States

New metal complexes with pentagonal-bipyramidal geometry have been synthesized with the chiral, pentadentate bis(oxazoline) ligand (R,R)-1, including the metal ions magnesium(II), iron(II), and cadmium(II). In the solid state, a complete transfer of chirality from the ligand is observed to exclusively yield enantiomerically pure P-helical, isostructural pentagonal bipyramidal complexes, as determined by X-ray analysis of four compounds. This uncommon coordination geometry is likely to be driven by pi-pi-stacking of the terminal phenyl groups of the linear ligands. The complex cations in [Fe((R,R)-1)(H2O)2](ClO4)2 (3), [Cd((R,R)-1)(H2O)2](ClO4)2 (4), and [Mg((R,R)-1)(H2O)2](ClO4)2 (5) are mononuclear with the two apical positions of the pentagonal bipyramide occupied by two water molecules. In contrast, the structure in dinuclear [Cd((R,R)-1)(MeOH)(mu-I)(CdI3)] (2c) can be described as pentagonal-bipyramidal around cadmium with MeOH and distorted-tetrahedral CdI4 (via one bridging iodo ligand) completing the coordination sphere in axial positions. The crystal packing of 3-5 shows a highly ordered orientation of the mononuclear helical cations into one-dimensional chains along the crystallographic axis a, stabilized by intermolecular pi-pi-stacking. In contrast, the dinuclear helices in 2c are tilted relative to one another, and consequently, directed, one-dimensional helicity in the solid state is not observed. Studies using a combination of mass spectrometry and NMR and CD spectroscopy indicate the presence of only one C2-symmetrical, mononuclear species in acetonitrile for each case, suggesting the formation of diastereo- and enantiomerically pure complexes also in the solution state. All compounds exhibit a very characteristic and almost identical CD pattern between 200 nm and 300 nm. This signal can be attributed to the P-helical, pentagonal arrangement of the ligand.

Phase Structures and Self-assembled Helical Suprastructures via Hydrogen Bonding in a Series of Achiral 4-Biphenyl Carboxylic Acid Compounds

A series of achiral 4-biphenyl carboxylic acid compounds (BPCA-Cn-PmOH) connected with alkoxyl chains having various carbon numbers (n = 6−10) and terminated by phenyl groups with meta-positioned hydroxyl groups was synthesized. Different phase structures including nematic, smectic A (SmA), smectic C (SmC), and highly ordered smectic liquid-crystalline phases along with crystalline phases were identified based on wide-angle X-ray diffraction and electron diffraction experiments. It was found via infrared spectroscopy that the hydrogen (H)-bonds were formed between the carboxylic acids to construct head-to-head dimers as the building blocks for these ordered structural formations. H-bonds formed via the meta-positioned hydroxyl groups also played an important role in forming ordered layers in these structures. The morphology of this series of BPCA-Cn-PmOH as observed under polarized light microscopy showed an oily streak (cylinder) texture with Myelin-figure in the SmA phase. When temperature cools to enter the SmC phase, these streaks (cylinders) started to twist into helical suprastructures, which were not only by the birefringence changes but also by the three-dimensional helical geometry observed in other microscopic techniques. The dynamic conformational changes of the aromatic and aliphatic parts in this series of BPCA-Cn-PmOH at different temperatures correspond well with the thermal transitions via solid-state carbon-13 nuclear magnetic resonance experiments. Computer simulation indicated that the head-to-head dimers possess a twisted rather than a bent conformation. It was deduced that the twisted conformation of the dimers and the terminal meta-substituted phenyl groups at both ends of the dimers are critically important in forming the helical suprastructures.

Antitumor agents 243. Syntheses and cytotoxicity of desmosdumotin C derivatives

New analogs of desmosdumotin C ( 1), in which other aromatic rings replaced the terminal phenyl group and the A-ring was modified, were synthesized. Compounds 2– 9, 13, and 16 were evaluated in vitro against human tumor cell replication. The 4-bromophenyl analog ( 2) showed potent cytotoxic activity in four different tumor cell lines.

Recognition Properties of Processing α‐Glucosidase I and α‐Glucosidase II

All four possible monodeoxy derivatives of p‐nitrophenyl α‐D‐glucopyranoside (PNP Glc) and 1‐amino‐2,6‐anhydro‐1‐deoxy‐D‐glycero‐D‐ido‐heptitol derivatives were prepared and used as substrates and inhibitors of rat liver processing α‐glucosidases. α‐Glucosidase II hydrolyzed the 2‐deoxy derivative of PNP Glc (1); the hydrolysis of 1 was more rapid than that of PNP Glc. These results indicate that the presence of a C‐2 hydroxyl group is not essential for the action of α‐glucosidase II. In contrast, PNP Glc and all of the deoxy derivatives of PNP Glc 1–4 inhibited α‐glucosidase I. These results indicate that α‐glucosidase I does not necessarily need all of the hydroxyl groups of the glycon moiety for binding to the enzyme. 2,6‐Anhydro‐1‐benzamide‐D‐glycero‐D‐ido‐heptitol (11), with a terminal phenyl group, inhibited α‐glucosidase I and α‐glucosidase II. Both α‐glucosidase I and II showed the same aglycon specificities. When probes 5–12 were assayed for their ability to inhibit processing by α‐glucosidases at the cellular level, no effects on glycoprotein processing were observed.

Ruthenium(II)‐Catalyzed Selective Intramolecular [2 + 2 + 2] Alkyne Cyclotrimerizations.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Photochromism of diarylethenes linked by hydrogen bonds in the single-crystalline phase.

Photochromic diarylethenes, which bear carboxyl groups at the ortho, meta, or para positions of both terminal phenyl groups, have been synthesized. The diarylethenes adopt linear chain structures as a result of hydrogen bonding in the crystalline phase, and the crystals exhibit photochromic properties. The absorption maximum of the photogenerated closed-ring isomer of the para-substituted derivative shows an 80 nm bathochromic shift in comparison with that of the ortho-substituted derivative. The maximum of the closed-ring isomer of the meta-substituted derivative is located in between those of the para- and ortho-substituted derivatives. The shifts can be attributed to the differences in conformation among the derivatives, arising from the restrictions imposed by the hydrogen-bonded chains.

Ruthenium(II)-catalyzed selective intramolecular [2 + 2 + 2] alkyne cyclotrimerizations.

In the presence of a catalytic amount of Cp*RuCl(cod), 1,6-diynes chemoselectively reacted with monoalkynes at ambient temperature to afford the desired bicyclic benzene derivatives in good yields. A wide variety of diynes and monoynes containing functional groups such as ester, ketone, nitrile, amine, alcohol, sulfide, etc. can be used for the present ruthenium catalysis. The most significant advantage of this protocol is that the cycloaddition of unsymmetrical 1,6-diynes with one internal alkyne moiety regioselectively gave rise to meta-substituted products with excellent regioselectivity. Completely intramolecular alkyne cyclotrimerization was also accomplished using triyne substrates to obtain tricyclic aromatic compounds fused with 5-7-membered rings. A ruthenabicycle complex relevant to these cyclotrimerizations was synthesized from Cp*RuCl(cod) and a 1,6-diyne possessing phenyl terminal groups, and its structure was unambiguously determined by X-ray analysis. The intermediary of such a ruthenacycle intermediate was further confirmed by its reaction with acetylene, giving rise to the expected cycloadduct. The density functional study on the cyclotrimerization mechanism elucidated that the cyclotrimerization proceeds via oxidative cyclization, producing a ruthenacycle intermediate and subsequent alkyne insertion initiated by the formal [2 + 2] cycloaddition of the resultant ruthenacycle with an alkyne.

Electronic structures of cumulene type carbyne model compounds: a typical example of one-dimensional quantum well

Ultraviolet photoelectron spectra of linear chain cumulene type carbyne model compounds with phenyl terminal groups to stabilize the chain have been measured and assigned with semi-empirical molecular orbital (MO) calculation. The spectra can be basically divided into two parts; contributions from phenyl groups and the chain part. The longer the chain length becomes, the lower the binding energy of the highest occupied molecular orbital (HOMO). The MO calculation reveals that the HOMO of these compounds derives from the carbon chain part and supports experimental results on chain length dependence of the HOMO. The HOMO and the lowest unoccupied molecular orbital (LUMO) of the model compounds are considered in terms of one-dimensional quantum well.

Rotational isomerism involving an acetylenic carbon IV: synthesis and structure of bis(1,1';3',1"-terphenyl-2'-yl)ethynes: molecular design of sterically congested alkynes toward restricted rotation about acetylenic axis.

The title diphenylethyne derivative with 4-methylphenyl (tolyl) groups at all the ortho positions was synthesized by the Stille or Sonogashira coupling from the corresponding iodide. The X-ray structure revealed that the two terminal phenyl groups at the sp carbons are twisted by 63 degrees out of the coplanar conformation to avoid steric interactions between the tolyl groups. The relative stabilities of possible conformers were analyzed by the PM3 calculations. The axially chiral derivative with two methoxymethyl groups showed no evidence of restricted rotation about the acetylenic axis by VT NMR measurements, its barrier being less than 35 kJ mol(-1). The spectroscopic features and reactivities of this sterically congested alkyne are also described.

Effect of analogs with modified prenyl side chains on growth of serum deficient HL60 cells.

This study was organized by Professor Karl Folkers with the objective of finding derivatives of coenzyme Q which could be more effectively absorbed and would give better biomedical effects. In this series all the compounds are 2,3 dimethoxy, 5 methyl p benzoquinone with modified side chains in the 6 position. The modifications are primarily changes in chain length, unsaturation, methyl groups and addition of terminal phenyl groups. The test system evaluates the growth of serum deficient HL60, 3T3 and HeLa cells in the presence of coenzyme Q10 or coenzyme Q analogs. Short chain coenzyme Q homologues such as coenzyme Q2 give poor growth but compounds with saturated short aliphatic side chains from C10 to C18 produce good growth. Introduction of a single double bond at the 2' or 8' position in the aliphatic chain retains growth stimulation at low concentration but introduces inhibition at higher concentration. Introduction of a 3' methyl group in addition to the 2' enyl site in the side chain decreases the growth response and maintains inhibition. Addition of a terminal phenyl group to the side chain from C5 to C10 can produce analogs which give strong stimulation or strong inhibition of growth. The action of the analogs is in addition to the natural coenzyme Q in the cell and is not based on restoration of activity after depletion of normal coenzyme Q. The effects may be based on any of the sites in the cell where coenzyme Q functions. For example, coenzyme Q2 is known to decrease mitochondrial membrane potential whereas the analog with a 10C aliphatic side chain increases potential. Both of these compounds stimulate plasma membrane electron transport. Inhibition of apoptosis by coenzyme Q may also increase net cell proliferation and the 10C analog inhibits the permeability transition pore.

Bicyclic nucleoside inhibitors of varicella-zoster virus: effect of terminal aryl substitution in the side-chain.

We have previously reported the discovery and preliminary structure-activity relationships of a new class of inhibitors of varicella-zoster virus (VZV). These novel furanopyrimidine nucleosides bear unusual bicyclic base moieties and exhibit complete specificity for VZV. Limited in vitro cytotoxicity has been detected and the bicyclic nucleosides are now well established as a new family of potent antivirals. Our initial studies revealed an absolute requirement of a long alkyl side-chain, with an optimal chain length of C8-C10, for antiviral activity. Following further studies, we recently reported a significant enhancement of both antiviral potency and selectivity by the inclusion of a phenyl group within the alkyl side-chain of these compounds. The new lead p-alkylphenyl analogues displayed EC50 values below 1 nM versus VZV and selectivity index values >1000000. We herein report the synthesis and characterization of a further series of alkylaryl analogues bearing terminal phenyl groups with varying n-alkyl side-chain lengths. Synthesis of the target bicyclic systems involved the Pd-catalysed coupling of terminal acetylenes with 5-iodo-2'-deoxyuridine to give intermediate 5-alkynyl nucleosides which were then cyclized in the presence of copper (I) iodide. The current compounds display excellent selectivity for VZV with no detectable in vitro cytotoxicity but despite being chemically isomeric with the previous lead p-alkylphenyl analogues, the compounds reported herein exhibit only moderate antiviral activities. A possible correlation between antiviral activity and conformational freedom of the side-chain is discussed.

Synthesis and mesomorphic properties of several series of fluorinated ester liquid crystals

Eight series of fluorosubstituted three-ring ester liquid crystals have been synthesized. Polarizing microscopic textural observations and DSC measurements of their phase transitions show that most are thermotropic liquid crystals with nematic and smectic A phases; furthermore, several show monotropic high order smectic phases. The results showed that the SmA phase is enhanced with the increasing number of fluoro-substituents at the para- and meta -positions of the terminal phenyl groups. The mesomorphic properties of these compounds are also affected by the direction of the ester bonds. The effect of the triple bond is also discussed.

Synthesis and Mesomorphic Properties of Some Fluorinated Benzoate Liquid Crystals

Three series of [4-(4′- n -alkyloxyphenyl)accetylenyl]-2,6-diffuorophenyl fluorinated benezoates and one series of fluorinated benzoates with 2,3,5,6-tetrafluorophenylene group and semi-perfluorocarbon chain have been synthesized. Their phase transition temperatures have been measured by texture observation in a polarizing microscope and confirmed by DSC. For the series without fluorocarbon chains, increasing the quantity of fluorosubstituents on the terminal phenyl groups decreased nematic stability ( T N-I ), but the breadth of the SmA phase range was increased. Lateral fluorosubstitution in the central group lowered the nematic stability ( T N-I ) and decreased the breadth of the SmA phase range. The series with semiperfluorocarbon chains were more likely to form SmA phases than the series with hydrogencarbon chains, and with the increasing of fluorosubstituents quantity on the terminal phenyl groups nematic and SmA stability ( T N-I and ( T SmA-N ) were both decreased.

Structure, Wettability, and Frictional Properties of Phenyl-Terminated Self-Assembled Monolayers on Gold

Alkanethiols possessing terminal phenyl groups (C6H5(CH2)nSH, n = 12−15) were adsorbed onto the surface of gold to afford phenyl-terminated self-assembled monolayers (SAMs). The SAMs were character...

Synthesis and mesomorphic properties of some fluorinated phenyl 4-[(4-n-alkoxyphenyl)ethynyl]benzoates

Eight homologous series of fluorinated phenyl 4-[(4-n-alkoxyphenyl)ethynyl]benzoates have been synthesized. Textural observations by polarizing microscopy and DSC measurements of the phase transitions show that most of these compounds are thermotropic liquid crystals with nematic and smectic A phases; furthermore, several show monotropic high order smectic phases. The results showed that the SmA phase is enhanced with increasing degree of fluorosubstitution on the para- and meta-positions of the terminal phenyl groups. The mesomorphic properties of these compounds are also affected by the direction of ester bonds. The effect of triple bonds is also discussed.

2,6-Bis[1-(phenylimino)ethyl]pyridine

The structure of the title compound, C21H19N3 (BIP1), has been determined. The mol­ecule lies on a crystallographic mirror plane. The terminal phenyl groups are rotated 60.2 (2)° from the plane of the ethyl­idene­pyridine system.

2,2′-{2-[(E)-3-Phenylprop-2-enyl]-2,3-dihydro-1H-isoindol-1,3-diylidene}dimalononitrile, a π-deficient system for π...π (1:1) stacking investigations

The title compound, C23H13N5, derived from cinnamyl alcohol and 2,2′-(isoindolin-1,3-diyl­idene)­bis­propane­di­nitrile, is a heterocyclic TCNQ analogue of interest as an electron-deficient component in charge-transfer complexes. A small perturbation of the four C—C≡N angles from linearity is observed, which are in the range 173.41 (18)–176.3 (2)°; the C≡N bond lengths are in the range 1.144 (2)–1.146 (2) Å. The terminal phenyl group is oriented at an angle of 77.17 (6)° to the C4N ring and the C=C bond is short, 1.319 (2) Å. There are no classical hydrogen bonds, although intramolecular C—H⋯N and intermolecular C—H⋯π(arene) interactions influence the crystal-structure packing.

Pyrrolo[2,3- d]pyrimidines Containing an Extended 5-Substituent as Potent and Selective Inhibitors of lck II

Pyrrolo[2,3- d]pyrimidines containing a 5-(4-phenoxyphenyl) substituent are novel, potent and selective inhibitors of lck in vitro. Exploration of C-6 position of the pyrrolo[2,3- d]pyrimidine and the terminal phenyl group structure–activity relationship (SAR) is detailed. Compound 1 is orally active in animal models.