Pyridine Analogues Research Articles

Solid phase synthesis of 2,4-disubstituted pyridine and tetrahydropyridine derivatives: Resin activation/capture approach/REACAP technology

The resin-bound dihydropyridone scaffold generated using the Resin Activation/Capture Approach (REACAP) Technology was further elaborated to afford 2,4-disubstituted pyridine and tetrahydropyridine derivatives. This process car be envisaged as the functionalization of pyridine analogues on solid support by a traceless linker approach.

Photocatalytic decomposition of triclopyr over aqueous semiconductor suspensions

The photocatalytic degradation of 3,5,6-trichloro-2-pyridinyloxyacetic acid (Triclopyr), a pyridine analogue of the phenoxy herbicides, has been investigated in aqueous heterogeneous solutions containing TiO 2 or ZnO as photocatalyst. The disappearance of the organic molecule follows approximately a pseudo-first kinetic order according to the Langmuir-Hinselwood model. As mineralization products, CO 2 and Cl − ions have been identified, whereas the nitrogen atom forms only NH 4 + ions. Various commercial photocatalysts were compared with respect to their overall efficiency, as well as the production of CO 2. The effect of pH and H 2O 2 on the reaction rate was ascertained. The photooxidation of Triclopyr has also been monitored with FTIR spectroscopy.

Synthetic analogues of netropsin and distamycin--synthesis of a new pyridine and carbocyclic analogues of the pyrrolecarboxamide antitumour antibiotics.

A new series of pyridine-containing analogues III-XXII of distamycin A and netrop sin was investigated by the molecular mechanics technique and molecular modelling. A pyridine analogue of netropsin (VII) is described, the first compound based on molecular studies, and two carbocyclic analogues of distamycin A with an N-terminal chloro- or bromoacetyl group (VIa, VIIa) were synthesized, as well as carbocyclic analogues of netropsin (VIIIb, Xb), potential carriers of alkylating elements. The potential use of VIa, VII, VIIa, VIIIb and Xb as carriers to place into the minor groove of DNA chemical groups capable of modifying DNA, is discussed.

Use of lanthanide shift reagents for studying pyridine analogs of isoflavones

The interaction of lanthanide shift reagents (LSR) with pyridine analogs of isoflavone and their derivatives has been studied. It was found that the pyridine nitrogen atom can increase the coordinating ability of electron donor groups in the molecule, in particular the sulfur atom in chromone thiones. It has been shown that LSR interact actively with pyridinium methylsulfate salts containing the 3-chromone substituent. The efficiency of the coordination is influenced by the occurrence of steric hindrance around the chromone carbonyl. The structure of the adducts of these salts with LSR is discussed.

Comparative antitumor efficacy of docetaxel and paclitaxel in nude mice bearing human tumor xenografts that overexpress the multidrug resistance protein (MRP)

Multidrug resistance has been associated with expression of the multidrug resistance protein (MRP). Recently, MRP-expression has been detected in human tumor samples of patients with breast cancer and non-small-cell lung cancer. Since taxoids are the most active drugs in the treatment of both tumor entities, the antitumor efficacies of paclitaxel and docetaxel were compared in nude mice bearing human tumor xenografts that express MRP. Athymic nude mice (nu/nu) bearing tumor xenografts of parental human sarcoma HT1080 or MRP-expressing HT1080/DR4 cells (as confirmed by Northern blot analysis) were treated with the maximum tolerated doses (MTD) of doxorubicin ([Dx] 10 mg/kg i.v. push), paclitaxel ([PC] 50 mg/kg three-hour i.v. infusion), or docetaxel ([DC] 40 mg/kg three-hour i.v. infusion). In vitro, the activity of doxorubicin, paclitaxel and docetaxel was evaluated by the sulphorhodamine B (SRB) assay using the pyridine analogue PAK-104P (5 microM), a potent inhibitor of MRP-function. At their MTDs both taxoids showed significant activity against MRP-negative HT1080 xenografts with response rates of 80% (40% CR) for PC and 100% (60% CR) for DC. In contrast, DC was significantly more active than PC in nude mice bearing doxorubicin resistant MRP-expressing HT1080/DR4 tumor xenografts (overall response rates: 100% (60% CR) for DC; 10% (0% CR) for PC; 0% for Dx). Since treatment of mice with the MTD of PC or DC yielded similar overall toxicity (maximum weight loss for HT1080: PC 8.6 +/- 2.2%; DC 7.5 +/- 2.2% and for HT1080/DR4: PC 11.6 +/- 3.0%; DC 7.6 +/- 1.8%, respectively), these results demonstrate the increase in the therapeutic index for docetaxel against MRP-expressing tumors. In vitro, HT1080/DR4 cells were 270-fold, 6.4-fold and 2.8-fold more resistant than parental cells to doxorubicin, PC and DC, respectively. Pyridine analogue PAK-104P completely restored drug sensitivity to PC and DC, while no effect of PAK-104P on parental HT1080 cells was observed. Both taxoids, when given at their MTDs, showed significant efficacy against parental HT1080 tumor xenografts. However, docetaxel at its MTD was significantly more active against MRP-expressing tumor xenografts than paclitaxel. Furthermore, in vitro resistance of HT1080/DR4 cells was higher for PC (6.4-fold) than for DC (2.8-fold). Since PAK-104P completely restored sensitivity to both taxoids, the observed resistance appears to be related to MRP. These data suggest, that docetaxel is not as readily transported by MRP as paclitaxel leading to an increased therapeutic ratio in MRP-expressing tumors in vivo. Therefore, docetaxel may have therapeutic advantages in the clinical treatment of MRP-expressing tumors.

Oxo Ligand Reactivity in the [ReO(2)L(4)](+) Complex of 1-Methylimidazole. Preparation and Crystal Structures of Salts Containing the ReOL(4)(3+) Core and Apical CH(3)O(-), BF(3)O(2)(-), and (CH(3)O)(2)PO(2)(-) Groups.

The oxo group of [ReO(2)(1-MeIm)(4)](+) can be methylated with excess methyl trifluoromethanesulfonate in CH(2)Cl(2) under mild conditions, leading to [ReO(OCH(3))(1-MeIm)(4)](CF(3)SO(3))(2), which is converted to the B(C(6)H(5))(4)(-) and PF(6)(-) salts. When the reaction is carried out in methanol in the presence of excess PF(6)(-), the phosphate ester complex [ReO{OP(O)(OCH(3))(2)}(1-MeIm)(4)](PF(6))(2) is isolated. [ReO(2)(1-MeIm)(4)](+) in the presence of acid, 2,2-dimethoxypropane, and excess BF(4)(-) transforms to the oxo-boron adduct [ReO(OBF(3))(1-MeIm)(4)](+). The presence of the trans-O=Re-OR core was demonstrated by crystallographic studies on one compound of each type: [ReO(OCH(3))(1-MeIm)(4)](PF(6))(2), tetragonal, P4/ncc, Z = 4, a = 13.022(3) Å, c = 17.218(5) Å, R = 0.0271; [ReO{OP(O)(OCH(3))(2)}(1-MeIm)(4)](PF(6))(2).toluene, monoclinic, P2(1)/c, Z = 4, a = 14.165(4) Å, b = 13.052(6) Å, c = 20.931(6) Å, beta = 95.83(2) degrees, R = 0.0373; [ReO(OBF(3))(1-MeIm)(4)](I(3)), monoclinic, P2(1)/c, Z = 4, a = 13.373(4) Å, b = 13.237(3) Å, c = 16.689(6) Å, beta = 103.67(3) degrees, R = 0.0445. The IR spectra show nu(Re=O) vibrations near 960 cm(-)(1) in all cases. The solution UV-vis spectra of the CH(3)O(-) and BF(3)O(2)(-) compounds are similar to that of the parent oxo-hydroxo [ReO(OH)(1-MeIm)(4)](2+) species, whereas the visible spectrum of the blue phosphate ester compound resembles that of the oxo-aquo [ReO(OH(2))(1-MeIm)(4)](3+) ion. The compounds were also characterized by solution (1)H, (13)C, and (31)P NMR spectroscopy. This work confirms earlier conclusions that ReO(2)L(4)(+) units with good sigma-donor imidazole ligands are more resistant to ligand loss than the pyridine analogues.

Reversal of Heavy Metal Resistance in Multidrug-Resistant Human KB Carcinoma Cells

Human KB carcinoma C-A120 cells that express multidrug resistance-associated protein (MRP) were cross-resistant to trivalent and pentavalent antimonials and arsenicals. Intracellular glutathione (GSH) content was higher in C-A120 than its parental KB-3-1 cell line. Glutathione-S-transferase (GST) was similar in both cell lines. Depletion of cellular GSH by treatment of the cells with the inhibitor of γ-glutamylcysteine synthetase(γ-GCS), buthione sulfoximine (BSO), significantly increased the sensitivity of both KB-3-1 and C-A120 cells to heavy metals. A pyridine analog, PAK-104P, almost completely reversed the resistance to antimonials and arsenicals in C-A120 cells. BSO at 100 μM or PAK-104P at 10 μM enhanced the accumulation of antimony potassium tartrate in C-A120 cells to the level of that in KB-3-1 cells without the agents. PAK-104P inhibited the ATP-dependent efflux of antimony potassium tartrate. These findings suggest that MRP transports antimony conjugated with GSH ATP-dependently outside the cells and PAK-104P inhibits the transporting activity of MRP.

ChemInform Abstract: Synthesis and Bioactivity of Novel Bis(heteroaryl)piperazine (BHAP) Reverse Transcriptase Inhibitors: Structure‐Activity Relationships and Increased Metabolic Stability of Novel Substituted Pyridine Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

1-Aryl-2-pyridyl-3,4-dihydronaphthalenes: Photofluorogenic Ligands for the Estrogen Receptor

Three 1,2-substituted-3,4-dihydronaphthalenes that are pyridine analogs of the antiestrogen desmethylnafoxidine were prepared and evaluated as fluorescent ligands for the estrogen receptor. These compounds represent a class of fluorescent probes that we term “photofluorogenic”, denoting their ability to exist initially as a high affinity though weakly fluorescent stilbazole form which can be photocyclized−oxidized to a highly fluorescent though low affinity azaphenanthrenoid form. These probes also contain an aziridine function that provides a means for their permanent, covalent attachment to the receptor. The three dihydronaphthalene systems were prepared by efficient routes from α-(2-, 3-, and 4-pyridyl)acetophenone precursors. They demonstrate high apparent affinity for the estrogen receptor and show time-dependent irreversible inactivation, consistent with their covalent attachment to the receptor via the aziridine function. Each system is converted into an azaphenanthrene by photocyclization−oxidation of the cis-stilbazole unit. The absorbance and fluorescence emission spectra of the dihydronaphthalene precursors and azaphenanthrene products have been characterized, and they display marked sensitivity to both solvent polarity and pH. The azaphenanthrenoids derived from the 2- and 4-pyridyl isomers exhibit intense emission at wavelengths that exceed 500 nm under certain conditions and appear to be well suited as fluorescent probes for the estrogen receptor.

Conversion of OsH 2(CO)(PPh 3) 3 to [OsH(CO)(PPh 3) 2L 2] +(L = pyridine, 4-tert-butylpyridine) by oxidation, hydride abstraction and protonation

Two bis(pyridine) analogues of the 2,2′-bipyridine complex [OsH(CO)(PPh 3) 2(bpy)] − have been synthesized from the dihydride OsH 2(CO)(PPh 3) 3 ( 1). Chemical or electrochemical oxidation of 1, even in the presence of excess pyridine, is an overall oneelectron process. The oxidation is proposed to involve the reaction of radical cations with the starting dihydride to form a 1:1 mixture of the 17-electron complex OsH(CO)(PPh 3) 3 and the trihydride [OsH 3(CO)(PPh 3) 3] +. Both oxidation of the 17-electron complex and reductive elimination of H 2 from the trihydride cation, both accompanied by pyridine coordination, would give [OsH(CO)(PPh 3) 3(Py)] +. Reaction of this proposed intermediate with excess pyridine yields [OsH(CO)(PPh 3) 3(Py) 2] + as the observed final product. This bis(pyridine) complex is also produced by hydride abstraction from 1 in the presence of pyridine and by protonation of 1 with HBF 4 followed by reaction with pyridine. 4-Tertbutylpyridine participates in the same reactions. The pyridine complexes are very similar to the previously reported 2,2′-bipyridine complex except that they do not display the bipyridine-localized reduction or metal—ligand charge transfer band. Their geometry is the same, with trans-oriented phosphines and cis-pyridines.

Polyamine analogue regulation of NMDA MK-801 binding: a structure-activity study.

A series of analogues and homologues of spermine were synthesized, and their impact on MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor was evaluated. These tetraamines encompass both linear and cyclic compounds. The linear molecules include norspermine, N1, N11-diethylnorspermine, N1,N12-bis(2,2,2-trifluoroethyl)spermine, homospermine, and N1,N14-diethylhomospermine. The cyclic tetraamines consist of the piperidine analogues N1,N3-bis(4-piperidinyl)-1,3-diaminopropane, N1,N4-bis(4-piperidinyl)-1,4-diaminobutane, N1,N4-bis(4-piperidinylmethyl)-1,4-diaminobutane, and N1,N4-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane and the pyridine analogues N1,N3-bis(4-pyridyl)-1,3-diaminopropane, N1,N4-bis(4-pyridyl)-1,4-diaminobutane, N1,N4-bis(4-pyridylmethyl)-1,4-diaminobutane, and N1,N4-bis[2-(4-pyridyl)-ethyl]-1,4-diaminobutane. This structure-activity set makes it possible to establish the importance of charge, intercharge distance, and terminal nitrogen substitution on polyamine-regulated MK-801 binding in the NMDA channel. Four families of tetraamines are included in this set: norspermines, spermines, homospermines, and tetraazaoctadecanes. Calculations employing a SYBYL modeling program revealed that the distance between terminal nitrogens ranges between 12.62 and 19.61 A. The tetraamines are constructed such that within families cyclics and acyclics have similar lengths but different nitrogen pKa's and thus different protonation, or charge, states at physiological pH. The pKa values for all nitrogens of each molecule and its protonation state at physiological pH are described. The modifications at the terminal nitrogens include introduction of ethyl and beta,beta,beta-trifluoroethyl groups and incorporation into piperidinyl or pyridyl systems. The studies clearly indicate that polyamine length, charge, and terminal nitrogen substitution have a significant effect on how the tetraamine regulates MK-801 binding to the NMDA receptor. Thus a structure-activity basis set on which future design of MK-801 agonists and antagonists can be based is now available.

Do High-Spin Topology Rules Apply to Charged Polyradicals? Theoretical and Experimental Evaluation of Pyridiniums as Magnetic Coupling Units

Ab initio calculations on pyridine and pyridinium analogues of m-xylylene indicate that the neutral heterocycle is essentially equivalent to benzene as a ferromagnetic coupling unit, while the cationic pyridiniums behave much differently. Depending on the substitution pattern, a protonated pyridine can serve as a ferromagnetic coupling unit or an antiferromagnetic coupling unit. Both valence bond and molecular orbital arguments provide qualitative rationalizations of these results. In an effort to test the theoretical predictions, bis(trimethylenemethane) analogues of the pyridine and pyridinium biradicals were synthesized and analyzed by electron paramagnetic resonance spectroscopy. General support for the theoretical predictions is obtained.

Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs.

The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delavirdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropylamino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP analogs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replaces the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ability to inhibit non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant recombinant HIV-1 RT and NNRTI resistant variants of HIV-1. This report describes an approach to preventing this degradation which involves the replacement of the 3-ethyl- or 3-isopropylamino substituent with either a 3-tert-butylamino substituent or a 3-alkoxy substituent. The synthesis, bioactivity and metabolic stability of these analogs is described. The majority of analogs retain inhibitory activities in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopropoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent was somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of the indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.

Synthesis, Optical Absorption, Fluorescence, Quantum Efficiency, and Electrical Conductivity Studies of Pyridine/Pyridinium Dialkynyl Organic and Pt(II)-σ-Acetylide Monomers and Polymers

Synthesis of a variety of 2,5- and 2,6-diethynylpyridine based organic and PtII-σ-acetylide monomers and polymers is reported. Quaternization of pyridine nitrogen via solution nucleophilic substitution reactions with methyl iodide and methyl triflate yields stable pyridinium analogs and is accompanied by strong red shifts in the UV−vis absorption spectra. The latter is indicative of enhanced π-electron delocalization along the backbone upon quaternization. These compounds exhibit strong fluorescence with quantum yields of 0.015−0.058 for the monomers and 0.060−0.223 for the polymers. Quaternization leads to enhanced fluorescence intensities and quantum efficiencies. These polymers are insulators in the ground state, however, and, upon doping with iodine, they exhibit semiconducting behavior.

Important Role of Tetrahydrofuran Ring in Activation of Hydrogen Peroxide in the Presence of Binuclear Iron(III) Complexes with Linear μ-Oxo Bridge

Abstract Binuclear μ-monooxo bridged iron(III) complex with tripodal-like ligand containing tetrahydrofuran ring exhibits much higher activity for alkane hydroxylation reaction in the presence of hydrogen peroxide than that of pyridine analogue; origin for high activity of the former complex was developed.

Synthesis and dopaminergic activity of pyridine analogs of 5-hydroxy-2-(di-n-propylamino)tetralin.

The pyridine analogs of 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT), 4-6, were synthesized, and their biological activity was compared to that of 5-OH-DPAT. Compounds 4 and 6 exhibited activity similar to 5-OH-DPAT in dopamine (DA) D2 and D3 receptor binding and in autoreceptor activation as measured by their ability to reverse the gamma-butyrolactone-induced increase in rat DA synthesis. Behaviorally, 4 and 6 decreased locomotor activity (LMA) in rats (sc) at low doses but did not increase LMA to the same extent as 5-OH-DPAT at higher doses, indicating that 4 and 6 may be more selective for the DA autoreceptor. While 4 was less active orally in rats, 6 appeared to retain most of its behavioral potency. Analog 5 showed little activity in vivo or in vitro.

Electronic structure of donor-spacer-acceptor molecules of potential interest for molecular electronics. IV. Geometry and device properties of P3CNQ and Q3CNQ

Z-β-(1-hexadecyl-4-quinolinium)-α-cyano-4-styryldicyanomethanide (C16H33-Q3CNQ) and the pyridinium analogue Z-β-(1-hexadecyl-4-pyridinium)-α-cyano-4-styryldicyanomethanide (C16H33-P3NCQ) are two very promising candidates for molecular device design. We obtain the geometry of the ground and excited state of these systems using the PM3 quantum mechanical model. The absorption spectra in vacuum and in solution are calculated using the INDO/Cl model, and compared to experimental spectra. The solvatochromic shift of the absorption spectra was calculated using a self-consistent reaction field approach. The observed bleaching of Langmuir-Blodgett films and solutions of C16H33-Q3CNQ and C16H33-P3CNQ is explained as resulting from a twisted configuration formed without barrier upon absorption into a twisted intramolecular charge transfer state. The observed rectification is explained from a ground state potential energy surface with two minima, one of which is characterized by a very large dipole moment. The relative energy of these minima is easily shifted by an electric field. The overall electron transport rate is found to be very small due to the small electronic coupling between the mono-layers of the L-B film. Thus, the electron transport through the sample is likely through defects of the L-B film. A way to increase the electronic coupling between the mono-layers is also discussed.

3-Pyridines as replacements for an isoxazole ring: The antirhinoviral activity of pyridine analogues related to disoxaril

In a series of rhinovirus inhibitors related to Disoxaril, replacement of 3-methylisoxazole with all 3 isomers of pyridine showed the 3-pyridyl isomer most similar to 3-methylisoxazole in spectrum of activity over 15 human rhinovirus serotypes.

Synthesis and antiinflammatory activity of certain 5,6,7,8-tetrahydroquinolines and related compounds.

Modification of some 8-benzylidene-5,6,7,8-tetrahydroquinolines, which have good antiulcer activity, led to three distinct classes of compounds with good in vivo antiinflammatory activity. Initial efforts led to a series of alkenes derived from 5,6,7,8-tetrahydroquinolines substituted at the 8-position. A second approach concentrated on replacing the CH linkage of these 8-benzylidene-substituted compounds with other spacer groups and increasing the size of the cycloalkyl ring from a six- to seven-membered ring, which provided 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine analogues. Finally, the substituent was switched from the cycloalkyl ring to the 2-position of the pyridine ring. Variation of the 2-substituent was also examined. Optimal antiinflammatory activity after oral administration was found in both the rat carrageenan paw edema and rat developing adjuvant arthritis models with 2-substituted 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridines, and of particular interest was 27 (WY-28342).

Metabolism of a nitrate ester, dihydropyridine derivative in rabbit hepatic microsomes and cytosol.

1. The metabolism of a nitrate ester-substituted dihydropyridine derivative (NND) in vitro was characterized with rabbit hepatic microsomes and cytosol. 2. Denitration activity was located in both the microsomal and cytosolic fractions, whereas oxidation to the pyridine analogue was solely located in the microsomal fraction. 3. Oxidation to the pyridine analogue required NADPH and was inhibited by carbon monoxide, miconazole and SKF-525A, suggesting that oxidation was catalysed by P450. 4. Denitration activity in the microsomes required either NADPH or GSH. Together with these results, responses to various inhibitors indicate participation of both P450 and glutathione S-transferase (GST). 5. Denitration activity in cytosol was activated by glutathione (GSH), and by dithiothreitol (DTT) to a greater extent. GSH-dependent denitration was inhibited by S-hexyl GSH, an inhibitor of GST, but DTT-dependent denitration was not. Moreover, the formation patterns of the mono-denitrated metabolites, M1 and M2, were shown to be different in each incubation condition. 6. These results suggest that the denitration of NND in cytosol could be catalysed by a GSH-independent enzyme as well as the GSH-dependent enzyme, GST.