Diastereoselective formal total synthesis of the DNA polymerase alpha inhibitor,aphidicolin, using palladium-catalyzed cycloalkenylation and intramolecular Diels-Alder reactions

[structure: see text] A novel diastereoselective formal synthesis of aphidicolin has been achieved by exploiting a unique characteristic of a bicyclo[3.2.1]octane prepared by employing a palladium-catalyzed cycloalkenylation process.     

Chemical modification of dispersed silica by pyrimidine derivatives

Results are given of the chemical modification of silicas containing and groups on their surface by pyridimidines in the gaseous phase. IR spectroscopy and field desorption mass spectrometric methods were used to obtain information on the structure of the surface compounds prepared. Possible reaction schemes are suggested. The high hydrolytic stability of some of the immobilized hydroxypyrimidines has been established.Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 22, No. 4, pp. 495–499, July–August, 1986.     

Chemical modification of fumagillin. II. 6-Amino-6-deoxyfumagillol and its derivatives.

6-Amino-6-deoxyfumagillol (5) was synthesized by reductive amination of 6-oxo-6-deoxyfumagillol (4), which was obtained by oxidation of fumagillol (2). The reduction proceeded stereoselectively by the equatorial attack of hydride and 5 was found to have the same stereochemistry as that of 2. Several derivatives of 5 were prepared and most of them showed anti-angiogenic activity comparable to that of fumagillol derivatives.     

Chemical modification of coumarin dimer and HIV-1 integrase inhibitory activity

A systematic series of chemically modified coumarin dimmers has been synthesized and tested for their inhibitory activity against HIV-1 integrase. We observed that modified coumarin dimmers containing hydrophobic moiety on the linker display potent inhibitory activities.     

Evaluation of inhibitory effects of benzothiazole and 3-amino-benzothiazolium derivatives on DNA topoisomerase II by molecular modeling studies

There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies.     

Chemical analysis of the semipurified extract of Paullinia cupana and evaluation of in vitro inhibitory effects against Helicobacter pylori

Abstract

Paullinia cupana Kunth, commonly known as guarana, is a native Brazilian plant species from the Amazon area that presents various biological effects, including antimicrobial action. The aim of this study was to chemically analyse the semipurified aqueous extract (AqF) of the plant and to evaluate the activity of crude (CE), ethyl-acetate (EAF), and AqF extracts against Helicobacter pylori. The chemical profile of AqF was determined based on solid analysis ¹³C-NMR, direct infusion mass spectrometry (ESI-MS), and MALDI-TOF. The ¹³C-NMR spectrum showed characteristics of flavan-3-ol and oligomeric proanthocyanidins. ESI-MS revealed the presence of procyanidin, caffeic acid and its derivatives. MALDI-TOF analysis detected procyanidins of up to 6 units and profisetinidins of up to 5 units. Whereas CE and EAF showed inhibitory activity against H. pylori, CE, EAF, and AqF presented not high inhibitory activity against urease. The results demonstrate the potential of P. cupana to control and prevent H. pylori infection.     

Chemical modification based on diterpene alkaloids — New derivatives of karakoline and talatisidine

The preparation and spectral characteristics of five new derivatives of karakoline (1) and talatisidine (2) are described; 14-benzoylanhydrooxykarakoline (4),8,14-dibenzoylanhydrooxykarakoline(5), 14-benzoylkarakoline (6), 14-O-methyltalatisidine (7), and 1-benzoyl-14-O-methyltalatisidine (8).     

Chemical transformations of mackinazolinone and its derivatives

The thioanalog of mackinazolinone (2,3,4,10-tetrahydro-1 H-pyrido[2,1-b]quinazolin-10-one) was synthesized for the first time by reacting it with P₂S₅. The thioanalog was reacted with aromatic aldehydes and Vilsmeier- Haack reagent (DMF + POCl₃) to produce 4-arylidene- and -hydroxymethylidenemackinazolinthiones, respectively. The reactions of 4-hydroxymethylidenemackinazolinone with isomeric aminophenols and aminobenzoic acids and of hydroxymethylidenemackinazolinthione with thionylchloride were studied. Subsequent reaction of the obtained 4-chloromethylidene derivative with sodium hydroselenide was synthesized a new Se-containing derivative of mackinazolinone. It was shown that 4-formylmackinazolinthione existed in the enol form whereas 4-formylmackinazolinone existed as the enaminoaldehyde tautomer.     

Chemical modification of L-asparaginase with N, O-carboxymethyl chitosan and its effects on plasma half-life and other properties

E.coli L-asparaginase,an antitumor enzyme,was chemically modified with N,O-carboxymethyl chitosan to lower its artigenicity and increase its plasma half-life.The results showed that the modified L-asparaginase has almost the same apparent Km value as that of native enzyme.The modified L-asparaginase also showed a higher protease stability against trypsin and a-chymotrypsin.After being modified,the enzyme exhibited the complete loss of antigenicity towards antiasparaginase serum.In addition,the higher the molecular weight of modifying reagents,the better the effects on reduction of antigenicity.When tested in vivo,the plasma half-life of the modified enzyme (t1/2=40 h) was over 33 times longer than that of the native enzyme (t1/2=1.2 h).     

Inhibitory effects of curcumin derivatives on nonenzymatic glucosylation in vitro

In this paper, curcumin, demethoxycurcumin, bisdemethoxycurcumin and another curcum in derivative are investigated for their inhibitory effects on nonenzymatic glucosylation in vitro, their binding reaction with bovine serum albumin (BSA) and their influence on the conformational changes of BSA. It demonstrated that all of these curcumin derivatives inhibited the formation of advanced glycation end products (AGE). Curcumin showed the most potent inhibitory activity, followed by demethoxycurcumin and bisdemethoxycurcumin. Moreover, it indicated that they extensively binded to the protein and induced the conformational changes of BSA. __________ Translated from Zhong shan Daxue Xue bao/Acta Scientiarum Natralium University Sunyatseni, 2005, 44(3)(in Chinese)     

Micellar effects on the alkaline hydrolysis of isatin and its derivatives

Herein we have investigated the hydrolysis of 1H-indol-2,3-dione (isatin, I) and its derivatives of different hydrophobicities, viz. N-dimethylaminomethyl indol-2,3-dione (II), N-morpholinomethyl indol-2,3-dione (III), N-pipridinomethyl indol-2,3-dione (IV), N-heptylaminomethyl indol-2,3-dione (V), N-dodecylaminomethyl indol-2,3-dione (VI), N-hexylanilinomethyl indol-2,3-dione (VII), N-decylanilinomethyl indol-2,3-dione (VIII), and N-hexadecylanilinomethyl indol-2,3-dione (IX), in the presence of an excess amount of sodium hydroxide. All the isatin derivatives were synthesized in the laboratory. The progress of the reactions was studied by exploiting UV-visible spectrophotometry. The observed rate constant, k(w), increases linearly on increasing the hydroxide ion concentration, indicating first-order dependence on [OH(-)]. The effects of surfactants, cationic (cetyltrimethylammonium chloride, CTACl), and anionic (sodium dodecyl sulfate, SDS) were also investigated. The rate of reaction increased on increasing the concentration of CTACl and, after reaching a maximum, it started decreasing. Conversely, anionic micelles of SDS inhibited the rate of hydrolysis of isatin and its derivatives. The results of the effect of CTACl were analyzed using a pseudophase ion-exchange model while the inhibition by SDS was analyzed using a simple Menger-Portnoy model. The effects of added salts, such as NaBr, NaCl, and (CH(3))(4)NBr, were also seen on the isatin hydrolysis. It was found that the addition of salts decreased the rate enhancement efficiency of the CTACl.     

Fluorous base-pairing effects in a DNA polymerase active site

We describe selective "fluorous" effects in the active site of a DNA polymerase, by using nucleotide analogues whose pairing edges are perfluorinated. The 5'-triphosphate deoxynucleotide derivatives of DNA base analogues 2,3,4,5-tetrafluorobenzene ((F)B) and 4,5,6,7-tetrafluoroindole ((F)I), as well as hydrocarbon controls benzene (B) and indole (I), were synthesized and studied as substrates for the DNA Polymerase I Klenow fragment (KF exo-). Modified nucleotides were present in the DNA template or were supplied as nucleoside triphosphates in studies of the steady-state kinetics of single nucleotide insertion. When supplied opposite the non-natural bases in the template strand, the hydrophobic nucleoside triphosphates were incorporated by up to two orders of magnitude more efficiently than the natural deoxynucleoside triphosphates. The purine-like fluorinated indole nucleotide ((F)I) was the most efficiently inserted of the four hydrophobic analogues, with the most effective incorporation occurring opposite the pyrimidine-like tetrafluorobenzene ((F)B). In all cases, the polyfluorinated base pairs were more efficiently processed than the analogous hydrocarbon pairs. A preliminary test of polymerase extension beyond these pairs showed that only the (F)B base is appreciably extended; the inefficient extension is consistent with recently published data regarding other nonpolar base pairs. These results suggest the importance of hydrophobicity, stacking, and steric interactions in the polymerase-mediated replication of DNA base pairs that lack hydrogen bonds. These findings further suggest that the enhanced hydrophobicity of polyfluoroaromatic bases could be employed in the design of new, selective base pairs that are orthogonal to the natural Watson-Crick pairs used in replication.     

喜树碱及其衍生物的聚乙二醇化学修饰药物研究进展

目的：喜树碱及其衍生物药物是一类重要的抗肿瘤药物,但其存在水溶性差、生物利用度低、毒副作用大等问题,喜树碱及其衍生物的聚乙二醇化学修饰具有十分诱人的前景,但目前国内研究较少,本文综述近年来喜树碱及其衍生物药物的聚乙二醇化学修饰研究进展。方法：以喜树碱（Camptothecin, CPT）、伊立替康（Irinotecan, CPT-11）、7-乙基-10-羟基喜树碱（7-ethyl-10-hydroxycamptothecin, SN38）、聚乙二醇（Polyethylene glycol, PEG）、聚乙二醇化喜树碱（PEG-CPT）等为关键词,查阅近几年国内外相关研究文献。结果与结论：综述了喜树碱及其衍生物的聚乙二醇化学修饰药物的研究进展与临床研究报道,为发掘结构明确、组成稳定的新型化学修饰药物提供理论基础和技术支撑。     

Chemical modification of plant alkaloids. 6. T-reactions of anabasine derivatives

T-reactions of anabasine derivatives were performed for the first time. Condensation of 5-nitro-2-[2-(3pyridyl)piperidino]benzaldehyde with 1,3-dimethylbarbituric acid formed an annelated tetrahydroquinoline system containing a spiropyrimidine moiety as the T-reaction product. Condensation of this same aldehyde with Meldrum’s acid was accompanied by recyclization that led to opening of the piperidine ring and closing of the tetrahydroquinolone system. A third version of the T-reaction that also led to opening of the piperidine ring but without recyclization was the condensation with dimedone.     

Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization

Oleanolic acid derivatives with different lengths of 3-O-acidic acyl chains were synthesized and evaluated for their inhibitory activity against HIV-1 protease. The lengths of the acidic chains were optimized to 6 and 8 carbons. Changing a 3-ester bond to an amide bond or dimerization of the triterpenes retained their inhibitory activity against HIV-1 protease. Introduction of an additional acidic chain to C-28 of oleanolic acid increased the inhibitory activity appreciably, though a derivative with only one acidic chain linked at C-28 also showed potent activity against HIV-1 protease. The inhibitory mechanism was proved directly by size exclusion chromatography to be inhibition of dimerization of the enzyme polypeptides. The ester bonds of the triterpene derivatives were found to be stable to lipase under mild alkaline conditions.     

Potent inhibitory effects of N-aryl S-alkylthiocarbamate derivatives on the dopa oxidase activity of mushroom tyrosinase

This study reports the potent inhibitory effect of N-aryl S-alkylthiocarbamate derivatives on mushroom tyrosinase (MT) activity. N-Aryl S-alkylthiocarbamate derivatives were found to exhibit a potent inhibitory effect on the dopa (3,4-dihydroxyphenylalanine) oxidase activity of mushroom tyrosinase. Most of the N-aryl S-alkylthiocarbamate derivatives (compounds from A to J) exhibited higher inhibitory effects than kojic acid (IC50=318 microM), a well known tyrosinase inhibitor. Tyrosinase was the most inhibited by S-phenetyl N-phenylthiocarbamate (compound E, IC50=7.25 microM), and this inhibition was 44 times stronger than that of kojic acid. Compound E exhibited 95.0% of inhibition at 100 microM. A kinetic study of MT inhibition by compound E using the Lineweaver-Burk plots analysis was performed. And the kinetics profiles observed suggest that compound E competitively inhibits MT.     

Humulene derivatives from Zingiber zerumbet with the inhibitory effects on lipopolysaccharide-induced nitric oxide production

A new humulene sesquiterpene, 5-hydroxyzerumbone (5-hydroxy-2E,6E,9E-humulatrien-8-one) (1) and a known compound, zerumboneoxide (2) were isolated from the rhizomes of Zingiber zerumbet (Zingiberaceae), and found to inhibit lipopolysaccharide-induced nitric oxide production in murine macrophage RAW 264.7 cells with IC50 values of 14.1 and 23.5 microM, respectively, by bioassay-guided fractionation (positive control: N(omega)-monomethyl-L-arginine, IC50=21.3 microM). The structure of 1 was determined by spectroscopic methods including 1D and 2D-NMR.     

Chemical modification of pectin to improve its sorption properties

The sorption properties of natural polysaccharide (apple pectin) with respect to heavy metals in a Ringer salt solution were studied as influenced by the procedures and process parameters of its chemical modification.     

Surface modification of MCM-41 and its application in DNA adsorption

Three types of MCM-41 absorbents, namely, Al~(3+)–MCM-41, La~(3+)–MCM-41, and Zn~(2+)–MCM-41, were prepared through amine grafting, phosphonate modification, and metal ion chelation and characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, and N2adsorption–desorption analysis. Results revealed that functionalized MCM-41 maintains the original structure of the molecular sieve and that the pore diameter and surface area are reduced compared with those of pure MCM-41. The adsorption behavior of DNA molecules on the surface of the modified molecular sieves was discussed according to the hard-soft acid–base(HSAB) principle. Experimental results showed that DNA purification could be effectively carried out on functionalized MCM-41 and that DNA is easily released by3–4 molL~(-1)NaCl solution. This study could be used as a general platform for future work on DNA adsorption and enrichment.     

Electronic effects of substituents in ferrocene and its derivatives

Conclusions The nature of the interring electronic effect in the ferrocene molecule was studied in detail. The transmission of the influence of substituents along the ring-metal bond is primarily inductive in character.Report at the General Meeting of the Department of General and Technical Chemistry, Academy of Sciences of the USSR, December 16, 1965.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 1551–1558, September, 1966.