Purine N-oxides: XXXVII. Derivatives from 6-chloropurine 3-oxide

Interaction of 6-chloropurine 3-oxide with several amines led to 6-substituted purine 3-oxides. 6-Chloropurine 3-oxide and selenourea gave 6-selenopurine 3-oxide. 6-Mereaptopurine 3-oxide, prepared from the 6-chloro derivative and ammonium dithioearbonate, was transformed with chlorine and hydrogen fluoride into 6-purinesulfonyl fluoride 3-oxide which upon ammonolysis afforded purine-6-sulfonamide 3-oxide. Methanelhiol and 6-ehloropurint: 3-oxide yielded the known 6-methylthiopurine 3-oxide, which by treatment with chlorine was oxidized to 6-methyl-sulfonylpurine 3-oxide. Reaction of the latter with hydroxylamine led to an improved synthesis of 6-hydroxylaminopurine 3-oxide, which by interaction with manganese dioxide was transformed into 6-nitrosopurine 3-oxide.     

Synthesis of novel 6-enaminopurines

Two different approaches have been used for the synthesis of 6-enaminopurines 6 from 5-amino-4-cyanoformimidoyl imidazoles. In the first approach imidazoles 1 were reacted with ethoxymethylenemalononitrile or ethoxymethylenecyanoacetate under mild experimental conditions and this led to 9-substituted-6-(1-amino-2,2-dicyanovinyl) purines 6a-f or 9-substituted-6-(1-amino-2-cyano-2-methoxycarbonylvinyl) purines 6g-k. These reactions are postulated to occur through an imidazo-pyrrolidine intermediate 7, which rapidly rearranges to the 6-enaminopurine 6. In the second approach 6-methoxyformimidoyl purines 3, prepared in two efficient steps from 5-amino-4-cyanoformimidoyl imidazoles 1, were reacted with malononitrile and methylcyanoacetate with a mild acid catalysis (ammonium acetate or piperidinium acetate) to give 6-enaminopurines 6a, 6d, 6f, 6g and 6k in very good yields. Only low yields were obtained for the 6-enaminopurine 6j, as competing nucleophilic attack on C-8 of either 3d or 6jcauses ring opening with formation of pyrimido-pyrimidines 11 and 10a respectively.     

催化裂化干气与苯烷基化催化蒸馏制乙苯反应网络热力学研究

 高温气相反应条件下的催化裂化干气制乙苯过程中，容易生成甲苯和二甲苯等副产物；在该过程中采用催化蒸馏技术，使苯与乙烯在低温条件下进行反应，可大幅度降低产品中二甲苯的含量．通过对催化裂化干气与苯烷基化催化精馏过程中的各反应步骤进行分析与热力学计算，结合反应的实际产物组成，提出了苯与乙烯烷基化的反应网络，探讨了苯与乙烯烷基化反应过程中甲苯和二甲苯的形成机理及影响因素．结果表明，增大苯／乙烯比对提高乙烯平衡转化率及乙苯收率有利；在较低温度下进行烷基化反应，可大大减缓C－C键裂解速度，抑制甲苯和二甲苯生成，提高乙苯产品质量．     

Isolation of 6-mercaptopurine in human plasma by aluminum ion complexation for high-performance liquid chromatographic analysis

A sample preparation technique and a high-performance liquid chromatographic method for 6-mercaptopurine (6-MP) that is simple, sensitive and without interference from its metabolites is described. 6-Thioguanine (6-TG) is added as an internal standard to the plasma sample, which is then treated with an aqueous solution of aluminum perchlorate to denature the plasma proteins and form complexes with 6-TG, 6-MP and its major metabolite, 6-thiouric acid (6-TUA). These complexes coprecipitate with proteins on centrifugation. 6-MP and its analogues are then extracted from the precipitate with perchloric acid containing sodium hydrosulfite and the extract is chromatographed on an Ultrasphere ODS column eluted with 0.1 M phosphoric acid and 0.001 M dithiothreitol in deionized water. The eluate is monitored at 340 nm. No interfering peak was encountered in over 300 clinical plasma samples. 6-TUA was separated from 6-MP and was found to be present in much higher concentration than 6-MP itself throughout the sampling time (6 h) following oral administration of the drug.     

Arachno, nido, and closo aromatic isomers of the Li6B6H6 molecule

We analyzed chemical bonding in low-lying isomers of the recently computationally predicted B(6)H(6)Li(6) molecule. According to our calculations the benzene-like B(6)H(6)Li(6) (D(2h), (1)A(1g)) arachno structure with the planar aromatic B(6)H(6)(6-) anion is the most stable one. A nido isomer with two aromatic B(6)H(6)(4-) (pentagonal pyramid) and Li(3)(+) (triangular) moieties, which can be considered as derived from the global minimum structure through a two-electron intramolecular transfer from B(6)H(6)(6-) to three Li(+) cations, was found to be 10.7 kcal/mol higher in energy. A closo isomer with three aromatic moieties (octahedral B(6)H(6)(2-) and two Li(3)(+)) was found to be 31.3 kcal/mol higher in energy than the global minimum. Another isomer with three aromatic moieties (two B(3)H(3)(2-) and Li(3)(+)) was found to be substantially higher in energy (74.4 kcal/mol). Thus, the intramolecular electron transfers from the highly charged B(6)H(6)(6-) anion to cations are not favorable for the B(6)H(6)Li(6) molecule, even when a formation of three-dimensional aromatic B(6)H(6)(2-) anion and two sigma-aromatic Li(3)(+) cations occurs in the closo isomer.     

Structures and Chemistry of Methanofullerenes: A Versatile Route into N-[(Methanofullerene)carbonyl]-Substituted Amino Acids

The reaction of C₆₀ with oxadiazole 13 afforded the dimethoxymethanofullerene 7 in 32% yield as a 6-6-ring-bridged isomer with a closed transannular bond. A literature survey showed that all 6-6-ring-bridged methanofullerenes are σ-homoaromatic with a closed transannular bond (6-6-closed) and all 6-5-ring-bridged are π-homoaromatic with an open transannular bond (6-5-open). The preference for 6-6-closed and 6-5-open structures is not due to substituent effects but is best explained with the conservation in these isomers of the favorable bonding seen in C₆₀ with higher double-bond character at 6-6 bonds and higher single-bond character at 6-5 bonds. Reaction of C₆₀ with diazo diester 15 gave the fullerene diester 14 which was hydrolyzed with BBr₃ in benzene to the methanofullerenecarboxylic acid 10 , a versatile synthon for the preparation of amphiphilic fullerene derivatives. Treatment of 10 with alcohols and amino acid esters under DCC coupling conditions afforded the esters 5 and 17 and the amino-acid derivatives 11 and 12 , respectively.     

Isolation of 6-mercaptopurine in human plasma by aluminum ion complexation for high-performance liquid chromatographic analysis

A sample preparation technique and a high-performance liquid chromatographic method for 6-mercaptopurine (6-MP) that is simple, sensitive and without interference from its metabolites is described. 6-Thioguanine (6-TG) is added as an internal standard to the plasma sample, which is then treated with an aqueous solution of aluminum perchlorate to denature the plasma proteins and form complexes with 6-TG, 6-MP and its major metabolite, 6-thiouric acid (6-TUA). These complexes coprecipitate with proteins on centrifugation. 6-MP and its analogues are then extracted from the precipitate with perchloric acid containing sodium hydrosulfite and the extract is chromatographed on an Ultrasphere ODS column eluted with 0.1 M phosphoric acid and 0.001 M dithiothreitol in deionized water. The eluate is monitored at 340 nm. No interfering peak was encountered in over 300 clinical plasma samples. 6-TUA was separated from 6-MP and was found to be present in much higher concentration than 6-MP itself throughout the sampling time (6 h) following oral administration of the drug.     

Remarkable supramolecular catalysis of glycoside hydrolysis by a cyclodextrin cyanohydrin

(6AR,6DR)-6A,6D-di-C-cyano-beta-cyclodextrin (3) was synthesized and shown to catalyze hydrolysis of nitrophenyl glycosides with the reaction following Michaelis-Menten kinetics. At pH 7.4 and 25 degrees C, hydrolysis of 4-nitrophenyl-beta-glucopyranoside (2) was catalyzed with KM = 15 mM, kcat = 8.2 x 10-6 s-1, and kcat/kuncat = 1217. Catalysis was observed with concentration of 3 as low as 10 muM. Hydrolysis of the corresponding alpha-glucoside, alpha-galactoside, alpha-mannoside, and 2-nitrophenyl-beta-galactoside was also catalyzed by 3, with kcat/kuncat ranging from 283 to 2147. A series of analogues of 3 was prepared and investigated for catalysis of the hydrolysis of 2: (6AR,6DR)-6A,6D-di-C-propyl-beta-cyclodextrin (9) was not catalytic, while 6A,6D-di-C-cyano-6A,6D-dideoxy-beta-cyclodextrin (12) had a low catalytic activity (kcat/kuncat = 4). A kcat/kuncat = 48 was found for 6A,6D-dialdehydo-beta-cyclodextrin dihydrate (11). It was proposed that 3 acts by general acid catalysis on the bound substrate.     

Mechanisms of cytotoxicity in human ovarian carcinoma cells exposed to free Mce6 or HPMA copolymer-Mce6 conjugates

It is essential to understand cellular responses on photodynamic therapy (PDT) to design delivery systems that maximize cytotoxic effects coupled with minimal induction of side effects or protective mechanisms (or both). Here, we investigated mechanisms of toxicity in human ovarian carcinoma A2780 cells treated with structurally diverse N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer (P)-mesochlorin e6 monoethylenediamine (Mce6) conjugates that possessed differential subcellular accumulation or covalent attachments of photosensitizers (or both). Apoptosis and necrosis were observed after photoactivation, with increased apoptotic responses observed in cells exposed to conjugates possessing Mce6 linkage via a lysosomally degradable tetrapeptide spacer (HPMA copolymer-Mce6 conjugates containing Mce6 bound via glycylphenylalanylleucylglycine [GFLG] linker [P-GFLG-Mce6], HPMA copolymer-Mce6 conjugates containing Mce6 bound via a GFLG spacer and containing nuclear localization sequence, PKKKRKV132K(FITC)C [NLS(fluorescein-5-isothiocyanate [FITC])] bound via a thioether linkage [P-NLS(FITC)-GFLG-Mce6]). Furthermore, the induction of necrosis was more pronounced in cells exposed to conjugates containing both a nuclear localization sequence (NLS) and Mce6 bound by a degradable linker (P-NLS(FITC)-GFLG-Mce6). Caspase-independent mechanisms of cell death were identified in cells treated with nuclear-targeted conjugates possessing Mce6 attached using a nondegradable tether (HPMA copolymer-Mce6 conjugates containing Mce6 bound via a GG spacer and containing NLS(FITC) bound via a thioether linkage [P-NLS(FITC)-GG-Mce6]), whereas low levels of apoptosis and necrosis were detected in cells exposed to photoactivated nontargeted HPMA copolymer-Mce6 conjugates containing Mce6 coupled through a nondegradable spacer (HPMA copolymer-Mce6 conjugates containing Mce6 bound via GG linker [P-GG-Mce6]). Variations in gene expression were observed in cells on PDT. Specifically, HSP70 expression was solely detected in cells treated with P-GFLG-Mce6, whereas the loss of detection of several genes were observed in cells treated with P-NLS(FITC)-GFLG-Mce6. Variations in cellular responses on PDT using different HPMA copolymer-Mce6 conjugates will prove useful in the design of optimal HPMA copolymer PDT delivery systems.     

Ligand substitution reactions of W6S8L6 with tricyclohexylphosphine (L = 4-tert-butylpyridine or n-butylamine): 31P NMR and structural studies of W6S8(PCy3)n(4-tert-butylpyridine)6-n (0 < n < or = 6) complexes

The substitution reactions by bulky tricyclohexylphosphine (PCy3) ligands on W6S8L6 (L = 4-tert-butylpyridine or n-butylamine) clusters were investigated to prepare clusters with mixed axial ligands for low-dimensional cluster linking. When 4-6 equiv of PCy3 are used to react with W6S8(4-tert-butylpyridine)6 (4) in THF, cis-W6S8(PCy3)4(4-tert-butylpyridine)2 (1) is preferentially formed. But when starting with W6S8(n-butylamine)6 (2), only W6S8(PCy3)6 (3) is produced with 6 equiv of PCy3. Other conditions with fewer equivalents of PCy3 led to mixtures of partially substituted complexes in the W6S8L6-n(PCy3)n (0 < or = n < or = 6, L = 4-tert-butylpyridine or n-butylamine) series. A significantly distorted structure for 1 helps to explain its preferential formation. 1H NMR spectra were collected for clusters 1 and 2 and 31P NMR spectra for 1 and W6S8(4-tert-butylpyridine)6-n(PCy3)n complexes. P-P coupling through P-W-W-P is reported for the first time in octahedral metal clusters and shown to be very useful in identifying nearly all the W6S8L6-n(PR3)n complexes and their stereoisomers in the mixtures even before individual species are isolated.     

Hexanuclear cobalt carbonyl carbide clusters: the interplay between octahedral and trigonal prismatic structures

The six-vertex cobalt carbonyl clusters [Co6C(CO)n](2-) (n = 12, 13, 14, 15, 16) with an interstitial carbon atom have been studied by density functional theory (DFT). These DFT studies indicate that the experimentally known structure of [Co6C(CO)15](2-) consisting of a Co6 trigonal prism with each of its edges bridged by carbonyl groups is a particularly stable structure lying more than 20 kcal/mol below any other [Co6C(CO)15](2-) structure. Addition of a CO group to this [Co6C(CO)15](2-) structure gives the lowest energy [Co6C(CO)16](2-) structure, also a Co6 trigonal prism with one of the vertical edges bridged by two CO groups and the remaining eight edges each bridged by a single CO group. However, this [Co6C(CO)16](2-) structure is thermodynamically unstable with respect to CO loss reverting to the stable trigonal prismatic [Co6C(CO)15](2-). This suggests that 15 carbonyl groups is the maximum that can be attached to a Co6C skeleton in a stable compound. The lowest energy structure of [Co6C(CO)14](2-) has a highly distorted octahedral Co6 skeleton and is thermodynamically unstable with respect to disproportionation to [Co6C(CO)15](2-) and [Co6C(CO)13](2-). The lowest energy [Co6C(CO)13](2-) structure is very similar to a known stable structure with an octahedral Co6 skeleton. The lowest energy [Co6C(CO)12](2-) structure is a relatively symmetrical D3d structure containing a carbon-centered Co6 puckered hexagon in the chair form.     

Reactivity of 4-hydroxy-2-methyl-7,8,9,10-tetrahydrobenzo[h] quinoline towards base-catalyzed cyclization,mannich and turpin reactions

Mannich reaction upon 4-hydroxy-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinoline ( 1 ) as well as its nitration were studied. Condensation of the chloroquinoline 6b with sodium azide, benzylamine and ethanolamine gave the quinoline derivatives 6c, 6f and 6g , respectively. Phenylhydrazine and sodium borohydride effected reduction of the azidoquinoline 6c to the corresponding amino- and hydroxyamino derivatives 6d and 6e , respectively. Also, Turpin's reaction gave the benzoquinobenzoxazines 7a-d when applied to 6b . Treatment of 6f, 6g with alkali and the condensation of 6b with glycine in alcoholic sodium carbonate solution afforded the imidazo[4,5-c]quinoline derivatives 9a-c , respectively.     

355 nm光作用下C6F6-HNO2水溶液的反应机理

利用激光闪光光解-瞬态吸收光谱技术研究了355 nm 光作用下六氟苯(C6F6)-HNO2水溶液的反应机理, 探讨了中间产物及其动力学行为, 并对终产物进行了分析. 实验表明, C6F6可与HNO2光解产生的OH自由基反应生成加合物C6F6…OH, 二级反应速率常数为1.8×109 L·mol -1·s-1, 加合物吸收峰位置在250、270和400 nm处; C6F6…OH 加合物通过消除反应生成C6F5O·, 其表观生成常数为6.1×105 s-1. C6F6…OH与O2复合转化为C6F6OHO2, 二级反应速率常数为2.8×106 L·mol-1·s-1, C6F6OHO2峰位置与C6F6…OH 加合物相似. 终产物分析表明, OH自由基与六氟苯发生消除HF的反应而生成C6F5OH, 有O2时, 还产生四氟醌C6F4O2, 但无论有氧还是无氧体系, 均不发生硝基化反应.     

Reactions of 6-hydrazino-, 6-hydroxylaminopurines and related derivatives

7H-Tetrazolo[5,1-i]purine was prepared by nitrosation of 6-hydrazinopurine and by reaction of 6-chloropurine with sodium azide; it was converted to adenine upon catalytic hydrogenation. 6-Hydroxylaminopurine was oxidized to 6-nitrosopurine with manganese dioxide, while alkaline treatment of the former gave 6,6′-azoxypurine. Nitrosation of 6-hydroxylaminopurine afforded 6-(N-nitroso)hydroxylaminopurine. Reaction of 6-chloropurine with 6-hydrazinopurine led to 6,6′-bisadenine; the corresponding ribosyl derivatives gave 6,6′-bisadenosine. Upon air oxidation, 6,6′-bisadenine was converted into 6,6′-azopurine. The related 6-thiosemicarbazino- and 6-(N-methyl)ureidopurine derivatives are also described. 6-N-(Nitroso)hydroxylaminopurine showed an inhibitory activity against several mouse tumors and leukemias.     

Preparation of 6-styrylphenanthridines

(6-Phenanthridinylmethyl)magnesium halides do not react with aromatic and aliphatic aromatic ketones but do react with aromatic aldehydes to give the corresponding carbinols. The latter are readily dehydrated to the corresponding 6-styrylphenanthridines. 6-Cyanomethylphenanthridine reacts with aromatic aldehydes in the presence of sodium ethoxide to give 6-(α-cyanostyryl)phenanthridines and is converted to 5-acyl-6-cyanomethylene-5,6-dihydrophenanthridine on heating with acetic anhydride or benzoyl chloride.     

Syntheses, structures and properties of 1-ethyl-3-methylimidazolium salts of fluorocomplex anions

Fluoroacid-base reactions of a room-temperature ionic liquid, 1-ethyl-3-methylimidazolium fluorohydrogenate (EMIm(HF)2.3F, EMIm = 1-ethyl-3-methylimidazolium cation), and Lewis fluoroacids (BF3, PF5, AsF5, NbF5, TaF5 and WF6) give EMIm salts of the corresponding fluorocomplex anions, EMImBF4, EMImPF6, EMImAsF6, EMImNbF6, EMImTaF6 and EMImWF7, respectively. Attempts to prepare EMImVF6 by both the acid-base reaction of EMIm(HF)2.3F with VF5 and the metathesis of EMImCl with KVF6 failed due to the strong oxidizing power of the pentavalent vanadium, whereas EMImSbF6 was successfully prepared only by the metathesis of EMImCl and KSbF6. EMImBF4, EMImSbF6, EMImNbF6, EMImTaF6 and EMImWF7 are liquids at room temperature whereas EMImPF6 and EMImAsF6 melts at around 330 K. Raman spectra of the obtained salts showed the existence of the EMIm cation and corresponding fluorocomplex anions. IR spectroscopy revealed that strong hydrogen bonds are not observed in these salts. EMImAsF6(mp 326 K) and EMImSbF6(mp 283 K) are isostructural with the previously reported EMImPF6. The melting point of the hexafluorocomplex EMIm salt decreases with the increase of the size of the anion (PF6- < AsF6- < SbF6- 相似文献   

富烯与2-吡啶甲基锂及2-喹啉甲基锂的反应: 含氮杂环取代二茂 铁的合成

在四氢呋喃-乙醚溶剂中,6-甲基-2-吡啶甲基锂与6,6-二烷基富烯或6,6-n亚甲基富烯(n=4,5,6)均发生环外双键加成反应。在类似反应条件下,2-喹啉甲基锂与6-甲基-6-乙基富烯或6,6-五亚甲基富烯皆发生加成反应和α-攫氢的竞争反应。用上述反应产生的取代环戊二烯基锂与二氯化铁配位,合成了一系列含氮杂环取代二茂铁衍生物。其结构经^1HNMR,元素分析和MS确证。在该类化合物的质谱裂解中,发现吡啶环对铁原子存在配位作用。     

Aminoacid and protein conjugates with biologically active purines

Condensation products of amino acids and proteins with biologically active purines have been obtained to study their potential tumor inhibitory activity and as models for the preparation of conjugates with tumor specific antibodies. Among the new compounds are 2-glycinyl-6-methylmercaptopurine ( 5 ), 2-glycinyl-6-mercaptopurine ( 6 ), 2-glycinyl-6-chloropurine ( 16 ), 2-glycinyl-6-hydroxylaminopurine ( 18 ), 2-glycinylpurine ( 8 ) and 2-glycinyl-6-methylpurine ( 7 ). 9-Alkylpurines led to new purine derivatives, such as 6-chloro-9H-purine-9-acetic acid (22) and 6-hydroxylamino-9H-purine-9-acetylhydroxamic acid ( 23 ). These derivatives were coupled to bovine serum albumin (BSA) to yield conjugates. The amino acid-purines 6-cysteinyl ( 27 ) and 6-glutathionyl-S-purine 3-oxide ( 28 ) were obtained from 6-chloropurine 3-oxide ( 26 ). Other protein-purine 3-oxide conjugates were obtained with 6-mercaptopurine 3-oxide ( 29 ) and 6-bromomethylpurine 3-oxide ( 33 ).     

Penning ionization electron spectroscopy of C6H6 by collision with He*(2 3 S) metastable atoms and classical trajectory calculations: optimization of ab initio model potentials

The potential energy surface of benzene (C(6)H(6)) with a He*(2(3)S) atom was obtained by comparison of experimental data in collision-energy-resolved two-dimensional Penning ionization electron spectroscopy with classical trajectory calculations. The ab initio model interaction potentials for C(6)H(6)+He*(2(3)S) were successfully optimized by the overlap expansion method; the model potentials were effectively modified by correction terms proportional to the overlap integrals between orbitals of the interacting system, C(6)H(6) and He*(2(3)S). Classical trajectory calculations with optimized potentials gave excellent agreement with the observed collision-energy dependence of partial ionization cross sections. Important contributions to corrections were found to be due to interactions between unoccupied molecular orbitals and the He*2s orbital. A C(6)H(6) molecule attracts a He*(2(3)S) atom widely at the region where pi electrons distribute, and the interaction of -80 meV (ca. -1.8 kcal/mol) just cover the carbon hexagon. The binding energy of a C(6)H(6) molecule and a He* atom was 107 meV at a distance of 2.40 A on the sixfold axis from the center of a C(6)H(6) molecule, which is similar to that of C(6)H(6)+Li and is much larger than those of the C(6)H(6)+[He,Ne,Ar] systems.     

Octacyclic and decacyclic ent‑abietane dimers with cytotoxic activity from Euphorbia fischeriana steud.

A novel Diels-Alder adduct possesses a 6/6/6/5/6/6/6/6 octacyclic skeleton featured with bicyclo[2.2.2]octane moiety, biseupyiheoid A (1), along with another decacyclic 6/6/6/3/5/6/5/6/6/6 fused diterpenoid dimer, bisfischoid C (2), were isolated from Euphorbia fischeriana. Their structures were determined by spectroscopic, X-ray crystallographic approaches, and quantum mechanical calculations. The structural features of 1 and 2 were hypothesized to involve intramolecular Diels-Alder reactions with different coupling patterns. Dimer 1 showed antiproliferative activity through apoptosis activation in LoVo cells.