Trimethoxyphenyl Rings Research Articles

Insight into the nucleoside transport and inhibition of human ENT1

The human equilibrative nucleoside transporter 1 (hENT1) is an effective controller of adenosine signaling by regulating its extracellular and intracellular concentration, and has become a solid drug target of clinical used adenosine reuptake inhibitors (AdoRIs). Currently, the mechanisms of adenosine transport and inhibition for hENT1 remain unclear, which greatly limits the in-depth understanding of its inner workings as well as the development of novel inhibitors. In this work, the dynamic details of hENT1 underlie adenosine transport and the inhibition mechanism of the non-nucleoside AdoRIs dilazep both were investigated by comparative long-time unbiased molecular dynamics simulations. The calculation results show that the conformational transitions of hENT1 from the outward open to metastable occluded state are mainly driven by TM1, TM2, TM7 and TM9. One of the trimethoxyphenyl rings in dilazep serves as the adenosyl moiety of the endogenous adenosine substrate to competitively occupy the orthosteric site of hENT1. Due to extensive and various VDW interactions with N30, M33, M84, P308 and F334, the other trimethoxyphenyl ring is stuck in the opportunistic site near the extracellular side preventing the complete occlusion of thin gate simultaneously. Obviously, dilazep shows significant inhibitory activity by disrupting the local induce-fit action in substrate binding cavity and blocking the transport cycle of whole protein. This study not only reveals the nucleoside transport mechanism by hENT1 at atomic level, but also provides structural guidance for the subsequent design of novel non-nucleoside AdoRIs with enhanced pharmacologic properties.

1-(Pyridin-2-yl)-2,4-bis[(pyridin-2-yl)carbonyl]-3,5-bis(3,4,5-trimethoxyphenyl)cyclohexanol 2.25-hydrate

In the title compound, C41H41N3O9·2.25H2O, the cyclohexanol ring adopts a chair conformation. The cyclohexanol ring makes dihedral angles of 87.89 (7) and 75.53 (8)° with the mean planes of the trimethoxyphenyl rings and dihedral angles of 84.18 (8), 85.07 (7) and 82.03 (8)° with the pyridine rings. In the crystal, the packing is stabilized by C—H...O, O—H...O and O—H...N hydrogen bonds involving water molecules and methoxy O atoms, resulting in a supramolecular network. One of the methoxy groups is disordered over two sets of sites with occupancy factors of 0.63 (3) and 0.37 (3).

Crystal structures of (Z)-5-[2-(benzo[b]thio-phen-2-yl)-1-(3,5-di-meth-oxy-phen-yl)ethen-yl]-1H-tetra-zole and (Z)-5-[2-(benzo[b]thio-phen-3-yl)-1-(3,4,5-tri-meth-oxy-phen-yl)ethen-yl]-1H-tetra-zole.

(Z)-5-[2-(Benzo[b]thio-phen-2-yl)-1-(3,5-di-meth-oxy-phen-yl)ethen-yl]-1H-tetrazole methanol monosolvate, C19H16N4O2S·CH3OH, (I), was prepared by the reaction of (Z)-3-(benzo[b]thio-phen-2-yl)-2-(3,5-di-meth-oxy-phen-yl)acrylo-nitrile with tri-butyl-tin azide via a [3+2]cyclo-addition azide condensation reaction. The structurally related compound (Z)-5-[2-(benzo[b]thio-phen-3-yl)-1-(3,4,5-tri-meth-oxy-phen-yl)ethen-yl]-1H-tetra-zole, C20H18N4O3S, (II), was prepared by the reaction of (Z)-3-(benzo[b]thio-phen-3-yl)-2-(3,4,5-tri-meth-oxy-phen-yl)acrylo-nitrile with tri-butyl-tin azide. Crystals of (I) have two mol-ecules in the asymmetric unit (Z' = 2), whereas crystals of (II) have Z' = 1. The benzo-thio-phene rings in (I) and (II) are almost planar, with r.m.s deviations from the mean plane of 0.0084 and 0.0037 Å in (I) and 0.0084 Å in (II). The tetra-zole rings of (I) and (II) make dihedral angles with the mean planes of the benzo-thio-phene rings of 88.81 (13) and 88.92 (13)° in (I), and 60.94 (6)° in (II). The di-meth-oxy-phenyl and tri-meth-oxy-phenyl rings make dihedral angles with the benzo-thio-phene rings of 23.91 (8) and 24.99 (8)° in (I) and 84.47 (3)° in (II). In both structures, mol-ecules are linked into hydrogen-bonded chains. In (I), these chains involve both tetra-zole and methanol, and are parallel to the b axis. In (II), mol-ecules are linked into chains parallel to the a axis by N-H⋯N hydrogen bonds between adjacent tetra-zole rings.

3,3′-Bis(3,4,5-trimethoxybenzoyl)-1,1′-(o-phenylene)dithiourea ethanol solvate

In the mol­ecule of the title compound, C28H30N4O8S2·C2H6O, the benzene ring is oriented at dihedral angles of 38.50 (6) and 5.68 (5)° with respect to the trimethoxy­phenyl rings, while the two trimethoxy­phenyl rings are oriented at a dihedral angle of 44.18 (5)°. Intra­molecular N—H⋯O and N—H⋯S hydrogen bonds result in the formation of non-planar six-, seven- and eight-membered rings. The twisting modes of the two side arms are different [C—N—C—O and C—N—C—N torsion angles = 0.1 (3) and 11.8 (3)°, respectively, in one arm, and 4.6 (3) and −11.5 (3)° in the other]. In the crystal structure, inter­molecular N—H⋯O and O—H⋯O hydrogen bonds link the mol­ecules.

3,6-Bis(3,4,5-trimethoxyphenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole

In the mol­ecule of the title compound, C21H22N4O6S, the planar central heterocyclic ring system is oriented with respect to the trimethoxy­phenyl rings at dihedral angles of 2.60 (5) and 3.60 (6)°. Intra­molecular C—H⋯N and C—H⋯S hydrogen bonds result in the formation of planar five- and six-membered rings. In the crystal structure, inter­molecular C—H⋯O hydrogen bonds link the mol­ecules. There is a C—H⋯π contact between a methyl group and a trimethoxy­phenyl ring, and a π–π contact between the central heterocyclic ring system and a trimethoxy­phenyl ring [centroid–centroid distance = 3.640 (1) Å].

6-(2-Methylphenyl)-3-(3,4,5-trimethoxyphenyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole

In the mol­ecule of the title compound, C19H18N4O3S, the planar central heterocylic ring system is oriented with respect to the trimethoxy­phenyl and 2-methyl­phenyl rings at dihedral angles of 4.43 (3) and 4.32 (3)°, respectively. The dihedral angle between the two benzene rings is 7.65 (4)°. In the crystal structure, inter­molecular C—H⋯N hydrogen bonds link the mol­ecules into centrosymmetric R 2 2(18) dimers. These dimers are connected via a C—H⋯π contact between the 2-methyl­phenyl and trimethoxy­phenyl rings, and a π–π contact between the thia­diazole and trimethoxy­phenyl rings [interplanar distance 3.51 Å, dihedral angles 4.17(4)°]. An intramolecular C—H⋯N hydrogen bond is also present.

Selective formation of heterodimeric resorcinarene capsules

C 2V -symmetrical resorcinarene tetraesters 1 form in CDCl 3 dimeric capsules encapsulating one Me 4N + cation. The homodimeric capsules of the tetra(3,4,5-trimethoxybenzoate) 1d and tetrabenzoate 1b or tetrafuroylate 1c disproportionate in solution to give quantitatively the heterodimers. The higher stability of the heterodimer is, most probably, caused by π–π attractions between the π-basic trimethoxyphenyl rings of 1d and relatively more π-accepting phenyl or furyl fragments of 1b or 1c .

Comparative molecular field analysis of colchicine inhibition and tubulin polymerization for combretastatins binding to the colchicine binding site on β-tubulin

A molecular modeling study using Comparative Molecular Field Analysis (CoMFA) was undertaken to develop a predictive model for combretastatin binding to the colchicine binding site of tubulin. Furthermore, we examined the potential contribution of lipophillicity (log P) and molecular dipole moment and were unable to correlate these properties to the observed biological data. In this study we first confirmed that tubulin polymerization inhibition (IC50) correlated (R2=0.92) with [3H]colchicine displacement. Although these data correlated quite well, we developed two independent models for each set of data to quantify structural features that may contribute to each biological property independently. To develop our predictive model we first examined a series of molecular alignments for the training set and ultimately found that overlaying the respective trimethoxyphenyl rings (A ring) of the analogues generated the best correlated model. The CoMFA yielded a cross-validated R2=0.41 (optimum number of components equal to 5) for the tubulin polymerization model and an R2=0.38 (optimum number of components equal to 5) for [3H]colchicine inhibition. Final non-cross-validation generated models for tubulin polymerization (R2 of 0.93) and colchicine inhibition (R2 of 0.91). These models were validated by predicting both biological properties for compounds not used in the training set. These models accurately predicted the IC50 for tubulin polymerization with an R2 of 0.88 (n=6) and those of [3H]colchicine displacement with an R2 of 0.80 (n=7). This study represents the first predictive model for the colchicine binding site over a wide range of combretastatin analogues.

Computational and molecular modeling evaluation of the structural basis for tubulin polymerization inhibition by colchicine site agents

The computer-automated structure evaluation programs MultiCASE and CASE were used to perform a quantitative structure-activity relationship study on tubulin polymerization inhibitors. A learning set of 536 chemicals (202 active, 27 marginal, and 307 inactive), built using IC 50 values for inhibition of tubulin polymerization or mitosis from this and previous studies, was used for artificial intelligence self-teaching. The algorithms successfully predicted the activity of agents in the learning set with > 90% accuracy. Seventeen MultiCASE and twelve CASE (mostly included in the MultiCASE set) biophores (substructures significantly correlated with activity) were identified with a probability > 0.95. Here we present the biophores of podophyllotoxins, colchicinoids, and certain combretastatins, each examined for structure-activity relationships. For the podophyllotoxins and colchicinoids in the learning set, the correlations between observed and predicted potencies were > 0.85. The algorithms recognized the importance of several known site, electronic, and steric effects in the two classes. A predictive QSAR ( R 2 = 0.98) was developed for combretastatin A-2 and dihydrocombretastatin analogues. The MultiCASE/CASE analyzes were used in combination with molecular models to study relative orientations of colchicine, podophyllotoxin, combretastatin A-4, and steganacin at the colchicine site. This resulted in a new hypothesis, consistent with extensive published experimental data, in which the C-ring and part of the B-ring of colchicine overlap with the A- and B-rings of podophyllotoxin. Consequently, the trimethoxyphenyl rings of colchicine and podophyllotoxin occupied different regions of space, each pointing out from a hydrophobic ‘core’ occupied by the overlapping biophores. The molecular model of the highly potent combretastatin A-4 could fit into the model binding site in at least three different ways. The developed QSARs were used to identify the potent microtubule stabilizer discodermolide. Its identification, in concert with recently reported findings, suggest potential overlap in the colchicine and paclitaxel binding sites on tubulin.

Platelet activating factor antagonists. Structure of N,N'-bis(3,4,5-trimethoxybenzoyl)-2-piperazinylmethyl 2,2-dimethylpropanoate

Racemic title compound, C30H40N2O10, Mr = 588.65, triclinic, P1-, a = 10.154 (7), b = 11.820 (9), c = 15.038 (8) A, alpha = 96.02 (5), beta = 1.07.54 (4), and gamma = 110.34 (5) degrees, V = 1569 (2) A3, Z = 2, Dx = 1.25 g cm-3, Cu K alpha, lambda = 1.5418 A, mu = 7.4 cm-1, F(000) = 628, T = 293 K, R = 0.0470, wR = 0.0481 for 1961 unique observed reflections. The piperazine ring adopts a chair conformation and the molecule shows limited flexibility of the pseudo-twofold-related trimethoxybenzoyl moieties. The planes through the piperazine and the two trimethoxyphenyl rings are oriented almost perpendicular to each other. Apart from a few possible weak hydrogen bonds, the molecules are held together by weak pi overlap and van der Waals forces.

Interaction of tubulin with bifunctional colchicine analogues: an equilibrium study.

The interaction of tubulin with simple analogues of colchicine that contain both its tropolone and trimethoxyphenyl rings has been characterized, and the results were analyzed in terms of the simple bifunctional ligand model developed for the binding of colchicine [ Andreu , J. M., & Timasheff , S. N. (1982) Biochemistry 21, 534-543] on the basis of interactions of tubulin with single-ring analogues. The compound 2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6- cycloheptatrien -1-one has been found to bind reversibly to 0.86 +/- 0.06 site of purified calf brain tubulin with an equilibrium constant of (4.9 +/- 0.3) X 10(5) M-1 (25 degrees C), delta H degrees app = -1.6 +/- 0.7 kcal mol-1, and delta S degrees app = 20.5 +/- 2.5 eu. The binding appears specific for the colchicine site. The closely related compound 2-methoxy-5-[[3-(3,4,5-trimethoxyphenyl)-propionyl]amino] -2,4,6- cycloheptatrien -1-one interacts weakly with tubulin. Binding of the first analogue is accompanied by ligand fluorescence appearance, quenching of protein fluorescence, perturbation of the far-ultraviolet circular dichroism of tubulin, and induction of the tubulin GTPase activity, similarly to colchicine binding. Substoichiometric concentrations of the analogue inhibit microtubule assembly in vitro. Excess analogue concentration under microtubule-promoting conditions induces an abnormal cooperative polymerization of tubulin, similar to that of the tubulin-colchicine complex.