Methoxyflavone Inhibitors of Cytochrome P450

Abstract  Cytochrome P450 enzymes are a superfamily of enzymes involved in the metabolism of endogenous compounds as well as xenobiotics. Due to the large number of reactions catalyzed by these enzymes and their importance in drug metabolism and carcinogenesis, they have been the focus of many studies over the years. Based on the knowledge that flavones are natural substrates of certain P450 enzymes (such as P450 1A2) involved in carcinogenesis, we have synthesized and studied a number of flavonoids as potential inhibitors of these enzymes. These compounds are structurally very similar to the natural flavone substrates of these enzymes but have methoxy substituents at various positions. Here we are reporting the synthesis, structural analysis, X-ray crystal structures, and preliminary inhibition studies of four methoxyflavones from this series. Crystallographic data: 2′-methoxyflavone, P-1, a = 7.2994(8) ?, b = 8.3322(7) ?, c = 10.8240(10) ?, α = 97.905(8)°, β = 92.779(10)°, γ = 111.105(8)°, V = 604.9(1) ?³; 3′-methoxyflavone, P2₁/n, a = 15.1313(16) ?, b = 3.9699(4) ?, c = 19.9454(16) ?, β = 91.673(8)°, V = 1197.6(2) ?³; 4′-methoxyflavone, P2₁/n, a = 16.451(12) ?, b = 3.881(1) ?, c = 19.529(16) ?, β = 106.65(1)°, V = 1195.1(4) ?³; 3′,4′-dimethoxyflavone, C2/c, a = 30.819(5) ?, b = 4.0857(7) ?, c = 26.100(3) ?, β = 124.21(1)°, V = 2717.6(7) ?³. Index Abstract  Methoxyflavone Inhibitors of Cytochrome P450 Michael McKendall, Tasha Smith, Kien Anh, Jamie Ellis, Terri McGee, Maryam Foroozesh, Naijue Zhu and Cheryl L. Klein Stevens* This paper is a report of the synthesis, structural analysis, X-ray crystal structures, and preliminary inhibition studies of 2′-methoxyflavone, 3′-methoxyflavone, 4′-methoxyflavone, and 3′,4′-dimethoxyflavone.

Aryl acetylene inhibitors for cytochrome P450-based monooxygenase isozymes

The structures of 1-propynylpyrene (1), 4-ethynylbiphenyl (2), 3-ethynylphenanthrene (3), 9-propynylphenanthrene (4) and 9-ethynylphenenthrene (5) have been determined using MoKα radiation.1 crystallizes in the monoclinic space groupP2₁/n witha=8.972(2)b=10.136(2),c=14.060(2)Å, β=99.77(1)°,V=1260.0(7) ų,Z=4. Refinement of 1261 reflections gaveR=0.042 andR _w =0.054.2 crystallizes in the orthorhombic space groupPbcn witha=17.7159(9),b=6.250(2),c=18.544(2) Å,V=2053(1) ų,Z=8. Refinement of 1710 observed reflections gaveR=0.046 andR _w =0.053.3 crystallizes in the orthorhombic space group Pbca witha=7.891(1),b=16.459(1),c=16.879(2) Å,V=2192.2(7) ų,Z=8. Refinement of 1520 observed reflections gaveR=0.032 andR _w =0.047.4 crystallizes in the orthorhombic space groupP2₁2₁2₁ witha=5.8867(6),b=13.476(1).c=14.838(2) Å,V=1177.1(4) ų,Z=4. Refinement of 1217 observed reflections gaveR=0.041 andR _w =0.055.5 crystallizes in the monoclinic space groupP2₁/c witha=27.755(7),b=5.1447(9),c=15.500(2) Å, β-105.53(2)°,Z=2133(2) ų,Z=8. There are two independent molecules in the unit cell. Refinement of 1276 observed reflections gaveR=0.061 andR _w =0.065. In2–5 there are no significant intermolecular interactions while in1 the molecules are associated in pairs via π-π stacking intarctions. Bond distances within the pyrene and phenanthrene portions of the molecules compare favorably with those found in other derivatives.     

Tyrphostin Tumor Growth Inhibitors of EGFR and ErbB2 Tyrosine Kinase

Tyrosine kinase inhibitors are small molecules that bind to the ATP binding site of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and disrupt the uncontrolled signaling reactions in cancer cells by inhibiting tyrosine phosphorylation. Tyrphostins (or malononitriles) are one class of compounds known to function as tyrosine kinase inhibitors. Our focus is to determine the structural features of these molecules that make them candidates for tyrosine kinase inhibitors. In this study, the X-ray crystal structures of four compounds shown to have EGFR tyrosine kinase inhibition have been determined. They are 4-methoxybenzylidenemalononitrile, (3,4,5-trihydroxybenzylidene) malononitrile, α-cyano-(3,5-di-t-butyl-4-hydroxy)thiocinnamide, and N-(3′,4′-dihydroxybenzylidenecyanoacetyl)indoline. Crystallographic data: 4-methoxybenzylidenemalononitrile, P2₁/c, a = 3.9173(6) Å, b = 24.909(3) Å, c = 9.6487(9) Å, β = 91.10(1)°, V = 941.3(2) ų; (3,4,5-trihydroxybenzylidene) malononitrile, P2₁/c, a = 7.0065(5) Å, b = 10.7158(9) Å, c = 13.4191(10) Å, β = 102.986(6)°, V = 981.7(1) ų; α-cyano-(3,5-di-t-butyl-4-hydroxy)thiocinnamide, P1bar, a = 9.6640(19) Å, b = 9.7204(13) Å, c = 10.3305(18) Å, α = 88.93(1)°, β = 83.88(2)°, γ = 66.12(1)°, V = 882.0(3) ų; N-(3′,4′-dihydroxybenzylidenecyanoacetyl)indoline, P1bar, a = 7.8887(7) Å, b = 8.220(1) Å, c = 12.967(2) Å, α = 94.42(1)°, β = 99.45(9)°, γ = 118.37(8)°, V = 718.0(2) Å³.     

Syntheses and X-ray structures of new phenoxy imino compounds

Four new phenoxy imino compounds were synthesized, and the solid-state structures of 1–3 were determined by single-crystal X-ray diffraction study, giving crystallographic data as follows. 2-Acetyl-6-[1-(2,6-diisopropylphenylimino)ethyl]-4-methylphenol (1): a = 13.5893(5) Å, b = 10.5781(4) Å, c = 15.6778(4) Å, = 113.1804(18), P2₁/c. 2,6-[1-(2,6-Diisopropylphenylimino)ethyl]-4-methylphenol (2): a = 12.1909(5) Å, b = 16.3324(6) Å, c = 15.9456(7) Å, = 96.990(2), P2₁/c. 2-Acetyl-6-[1-(4-bromine-2,6-dimethylphenylimino)ethyl]-4-methylphenol (3): a = 7.5337(4) Å, b = 10.0457(5) Å, c = 12.6163(4) Å, = 90.139(3), = 104.003(3), = 106.485(2), P–1. Their molecular structures show that the 2,6-substituted phenyl ring is located approximately orthogonal to the hydroxyphenyl ring with the dihedral angle varying from 85.2 to 101.4.for X-ray Diffraction     

Synthesis of a new dibenzo-14-crown-4 lariat ether and structure of its sodium perrhenate complex

A dibenzo-14-crown-4 ether with a novel monooxyacetone sidearm is prepared and its structure with sodium perrhenate is determined. The structure crystallizes in P2₁/c with cell dimensions: a = 8.107(2) Å, b = 28.138(3) Å, c = 10.293(2) Å, and = 104.173(9)°; giving a volume of 2276.6(7) ų. This structure is compared to other sodium complexes of dibenzo-14-crown-4 lariat ethers and is found to be the only one with intramolecular bonding between the sidearm and the cation. Possible reasons for this observation are discussed.     

Synthesis and Novel Crystal Structure Analysis of Anthracene-Based Chalcone Derivatives

Abstract

Four novel anthracene-based chalcone derivatives, (E)-1-(anthracen-9-yl)-3-(4-nitrophenyl)prop-2-en-1-one 1, (E)-1-(anthracen-9-yl)-3-(3-chlorophenyl)prop-2-en-1-one 2, (E)-1-(anthracen-9-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 3, and (E)-1-(anthracen-9-yl)-3-(pyridin-4-yl)prop-2-en-1-one four were synthesized and their structures were solved by single crystal X-ray diffraction methods. The anthracenyl chalcone 1 crystallizes in the centrosymmetric monoclinic P2₁/c space group. The crystal structure analysis shows that the molecules of one form two dimensional (2D) corrugated layer structure. The anthracenyl chalcone 2 crystallizes in the centrosymmetric triclinic P-1 space group and forms one dimensional (1D) tape like structure in the crystal. Compound 3 crystallizes in the centrosymmetric monoclinic P2₁/n space group. Anthracenyl chalcone 4 crystallizes in the centrosymmetric triclinic P-1 space group.     

锡溶液中半导体单晶CuSi2P3的生长与结构分析

Single crystals of CuSi2P3 as long as 1cm has been grown by using tin solution growth. X-ray powder photography technique showed that only CuSi2P3 can grow as a pure material without any exchanges of Si with Sn. The structure is in the form of Fcc with a lattice parameters of a=0.5248nm. Electron probemicro anaiysis (EPMA) has supported the X-ray data in regarding the single phase of this compound grown by solution growth.     

Synthesis and crystal structure of 2-anilino-6<Emphasis Type="Italic">H</Emphasis>-5-(1-phenyl-3-methyl-5-pyrazolone-4-ylene)-1,3,4-thiadiazine

A novel pyrazolone derivative 2-anilino-6H-5-(1-phenyl-3-methyl-5-pyrazolone-4-ylene)-1,3,4-thiadiazine (PMCP-PTSC) containing NNS hexa-atomic heterocycle has been obtained and characterized by means of single crystal X-ray diffraction, IR and ¹H NMR spectroscopies. It is interesting that when grown from two different solvents, two different crystalline structures are formed. The monoclinic crystal A belongs to a P2₁/c space group. The unit cell parameters are a = 16.414(4) Å, b = 12.530(3) Å, c = 8.432(1) Å, = 91.75(2) Å, and Z = 4. The triclinic crystal B belongs to a P space group. The unit cell parameters are a = 11.386(2) Å, b = 12.326(2) Å, c = 12.411(3) Å, = 83.07(1)°, = 87.76(2)°, = 86.52(2)°, and Z = 4. The structure analyses show the title compound is the keto-form. Dimers in crystal packing of A and supramolecular one-dimensional (B) concatenate structures were assembled by the intermolecular hydrogen bonds.     

The X-ray crystal structures of three bis(cyclopentadienyl)titanium(IV) derivatives

The X-ray crystal structures of (aqua)bis(cyclopentadienyl)chlorotitanium(IV) trifluoromethanesulfonate, bis(aqua)bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesul-fonate) and bis(cyclopentadienyl)bis(trifluoromethanesulfonato)titanium(IV) show a pseudo-tetrahedral array of Cp ring centroids and oxygen or oxygen and chloride donors around titanium, and varied long-range packing motifs dependent on the availability of hydrogen bond acceptors within the lattice.     

Na5[B2P3O13]晶体双晶结构的研究

采用泡生法和b向籽晶生长出尺寸为22mm×24mm×20mm的透明Na5[B2P3O13]晶体.晶体定向中发现(100)和(001)晶面的一级衍射出现双峰;正交偏光显微镜下观察晶体的(010)切片,看到清晰的明暗条纹;当一束激光正入射(010)切片时,产生衍射现象;用同步辐射白光X射线形貌术拍摄了(100)、(010)和(001)切片的Laue像,观察到了晶体的孪晶结构,再借助(010)切片的化学腐蚀研究,推出该晶体为规则的聚片双晶,其结合面为(001).     

The crystal structure of a heterobimetallic crown ether complex: [Na(dibenzo-18-crown-6)][FeCl4]

Slow evaporation of a solution of ferric chloride and dibenzo-18-crown-6 in 31 CH₃CNCH₃OH produced single crystals of the title complex. This heterobimetallic crown ether complex, [Na(dibenzo-18-crown-6)][FeCl₄], crystallizes in the monoclinic space group P2_t/n with cell parameters (at 22°C)a=14.608(6),b=10.466(9),c=17.276(9)Å, =91.47(6)°, andD _calc=1.46 g cm^–3 for Z=4. The structure consists of discrete ions with the shortest Na ... Cl distance a lengthy contact of 3.56(1)Å. The average Na...O separation is 2.69(3)Å. The [FeCl₄]^– anion exhibits a distorted tetrahedral geometry with an average Fe–Cl bond length of 2.16(2)Å.     

Synthesis and crystal structure of cyanohydrin trimethylsilyl ether of o-chlorobenzoylferrocene

The cyanohydrin trimethylsilyl ether of o-chlorobenzoylferrocene has been synthesized by the addition of trimethylsilyl cyanide (TMSCN) in methylene chloride in the presence of zinc iodide. Its structure was determined by X-ray single crystal diffraction. The crystal belongs to monoclinic, space group P2₁/n with the following crystallographic parameters: a = 9.480(3) ?, b = 22.319(6) ?, c = 9.783(3) ?, β = 101.197(4)°, μ = 0.943 mm^− 1, V=2030.5(10) ?³, Z=4, F(0 0 0) = 880, D _calc=1.386 mg/m³, T=293(2) K, 1.82° ≤ θ ≤ 26.40°, the final R factor: R ₁=0.0366, wR ₂=0.0802.     

以磷化铁为添加剂沿(111)面生长磷掺杂金刚石大单晶

掺杂是调控金刚石性能的一种重要手段。本文采用温度梯度法,在5.6 GPa、1 312 ℃的条件下,选用Fe₃P作为磷源进行磷掺杂金刚石大单晶的合成。金刚石样品的显微光学照片表明,随着Fe₃P添加比例的增加,金刚石晶体的颜色逐渐变深,包裹体数量逐渐增加,晶形由板状转变为塔状直至骸晶。金刚石晶形的变化表明Fe₃P的添加使生长金刚石的V形区向右偏移,这是Fe₃P改变触媒特性的缘故。红外光谱分析表明,Fe₃P的添加使金刚石晶体中氮含量上升,这说明磷的进入诱使氮原子更容易进入金刚石晶格中。激光拉曼光谱测试表明,随着Fe₃P添加比例的增加,所合成的掺磷金刚石的拉曼峰位变化不大,其半峰全宽(FWHM)值变大,这说明磷的进入使得金刚石晶格畸变增加。XPS测试结果显示,随着Fe₃P添加比例的增加,金刚石晶体中磷相对碳的原子百分含量也会增加,这意味着添加Fe₃P所合成的金刚石晶体中有磷存在。     

Crystal structure of [RuCl2[N-(2,4,6-trimethyl-benzyl)N-(n-butyl)]-imidazolidin-2-ylidene] and [RuCl2[N-(2,4,6-trimethyl-benzyl)-N-(2-methoxyethyl)]-imidazolidin-2-ylidene]

Two imidazolidin ruthenium complexes, [RuCl₂{[N-(2,4,6-trimethyl-benzyl)-N-(n-butyl)]-imidazolidin-2-ylidene}], 1, and [RuCl₂{[N-(2,4,6-trimethyl-benzyl)-N-(2-methoxyethyl)]-imidazolidin-2-ylidene}], 2, have been synthesised and their crystal structures have been determined from single crystal X-ray diffraction data. Compound 1 is monoclinic, of space group C2/c with a = 18.466(4) Å, b = 14.816(3) Å, c = 15.413(3) Å, β = 118.067(2)^∘, and V = 3720.9(12) ų with Z = 8 for d_calc = 1.536 g/cm³. Compound 2 is monoclinic, of space group P2₁/c with a = 8.1800(5) Å, b = 14.344(8) Å, c = 14.809(9), β = 91.604(10)^∘, and V = 1736.7(18) ų with Z = 4 for d_calc = 1.653 g/cm³. In each complex the ligand functions as an arene and carbene, occupying four coordination sites. The two chlorines in each compound complete a distorted octahedron.     

Formation and crystal structure of 1-methyl-2-phenylindolizine-3-acetonitrile

1-Methyl-2-phenylindolizine-3-acetonitrile was unexpectedly obtained in the reaction of 1-methyl-2-phenylindolizine-3-thioaldehyde with cyanide ions. Its structure was determined by IR, ¹H NMR, MS, elemental analyses, and X-ray crystallography. Colorless regular prism shaped crystals of C₁₇H₁₄N₂ crystallize in the space group C2/c with cell dimensions a = 12.956(3) Å, b =10.516(2) Å, c = 20.429(4) Å, and = 90°, = 104.98(3)°, = 90°, V =2688.7(9) ų, D _calc =1.217 Mg/m³, and Z = 8.     

Chiral bisphosphanes XII: Synthesis and molecular structure of cis-{rac,trans-1,2-bis[bis(morpholin-4-yl)-phosphino]cyclopentane}dimethylplatinum(II), cis-[C5H8{P[N(C2H4)2O-cyclo]2}2Pt(CH3)2]

Crystals of the title compound are monoclinic, space group P2₁/c, with a = 10.2621(8), b = 15.372(5), c = 17.612(2) Å, = 95.928(9)°, and Z = 4. Coordination about the central metal deviates slightly from ideal square-planar geometry. The five-membered chelate ring adopts an envelope conformation with one of the two P atoms (P1) deviating from the least-squares plane spanned by the central metal, the bridging CH carbons, and donor atom P2. While the morpholino substituents at the latter show little axial-equatorial discrimination for their orientation with respect to the coordination plane, the spatial alignments of the N(C₂H₄)₂O rings attached to P1 differ significantly between a more equatorial and a more axial disposition. The conformationally dissimilar arrangement of the two P donor groups within the envelope-like chelate ring manifests itself in unequal Pt–P bond lengths: d(Pt–P1) = 2.2677(16), d(Pt–P2) = 2.2825(16) Å. The Pt–CH₃ distances amount to 2.114(6) (trans to P2) and 2.141(6) Å (trans to P1), respectively.     

Crystal structure and vibrational spectra of two complexes of manganese(II) with glicyne

Two polymeric complexes of glicyne with manganese(II) have been prepared and characterized by means of spectroscopic and x-ray analyses. The first complex of the formula [Mn(Gly)Cl₂(H₂O)₂] crystallizes in the monoclinic space group P2₁/n with a = 6.519(2), b = 15.981(3), c = 7.893(2) Å, and = 97.18(3)°. The Mn atoms are in distorted octahedral environments with all ligands in cis positions. The adjacent manganese(II) ions are linked in polymeric chains via carboxylate groups. The second complex [Mn(Gly)₂Cl₂] crystallizes in the triclinic space group P with a = 4.968(2), b = 6.582(2), c = 7.925(3) Å, = 106.17(3), = 92.86(3), and = 107.21(3)°. The octahedral-coordinated manganese(II) ion is situated on a crystallographic center of symmetry and is bound to four carboxylate oxygen atoms from different glicyne molecules and two chloride ions.     

Crystal structures of [WI2(CO)3{Ph2P(CH2) n PPh2}] (n = 2 or 3)

[WI₂(CO)₃{Ph₂P(CH₂)₂PPh₂}] (1) crystallizes out in the monoclinic space group P2₁/n, with a = 13.852(7) Å, b = 14.789(19) Å, c = 14.915(19) Å, = 102.86(1)°, Z = 4. [WI₂(CO)₃{Ph₂P(CH₂)₃PPh₂}] (2) crystallizes out in the monoclinic space group P2₁/n, with a = 10.499(15) Å, b = 14.58(2) Å, c = 20.75(3) Å, = 103.59(1)°, Z = 4. Both structures show the metal in a seven-coordinate environment with a carbonyl in the unique capping position, two further carbonyls and a phosphorus in the capped face, and two iodides and the second phosphorus in the uncapped face.     

铁掺杂P型分子筛的合成及应用

采用水热合成法,按照摩尔比5Na_2O∶Al_2O_3∶8SiO_2∶xFe~(3+)∶(116～156)H_2O配料,草酸为铁离子的络合剂,经过室温搅拌成胶,100 ℃下于不锈钢反应釜中晶化20 h,合成了三种掺杂铁量不同的P型分子筛.利用XRD、FT-IR和SEM对产物进行了表征,分析结果表明铁掺杂P型分子筛与纯P型分子筛结构相同,其晶体粒度均匀且稍有增大;以合成的分子筛作为吸附剂考察了合成产物对水中氟离子、铅离子和钾离子的吸附性能,铁掺杂P型分子筛对氟离子的吸附性能明显增加,达到4.98 mg/g,而对铅离子和钾离子的吸附性能没有促进作用.     

Crystal structure and conformation of the antimalarial drug 5,7-methoxy-8-(3-methyl-1-buten-3-ol)-coumarin

The crystal and molecular structure of the antimalarial compound 5,7-methoxy-8-(3-methyl-1-buten-3-ol)-coumarin, C₁₆H₁₈O₅, M _r = 290.3 Da, has been determined from X-ray diffraction data. The material crystallizes in the monoclinic space group P2₁/c with 4 molecules per unit cell of dimensions a = 8.9044(9), b = 17.623(1), c = 10.175(1) Å, = 113.97(1)°, crystal density D _c = 1.322 g/cm³. The structure was determined using direct methods and refined by full-matrix least squares to a conventional R index of 0.066 for 2416 measured reflections and 206 parameters.The coumarin ring system is almost planar with the methoxy C atoms rotated slightly out of the coumarin mean plane. Apart from the terminal CH₃ groups C(12) and C(13), which are 1.184(3) Å above and –1.315(3) Å below the plane, the 3-methyl-1-buten-3-ol substituent is planar (rms deviation 0.009 Å) making an angle of 6.31(7)° with the phenyl ring. One intermolecular hydrogen bond is present in the crystal structure between O(5)–HO(5) and the symmetry related O(2) oxygen, generated by the symmetry operation (x, 1/2 – y, –1/2 + z).