Syntheses and biological activity of amamistatin B and analogs

Amamistatins A and B, natural products isolated from a strain of Nocardia, showed growth inhibition against three human tumor cell lines (IC(50) 0.24-0.56 microM). Structurally related mycobactins affect the growth of both mycobacterial and human cells through interference with iron chelation. To further probe the biological activity of this class of compounds, the total syntheses of amamistatin B and two analogs were completed, and the synthetic samples were screened for tumor cell growth inhibition, HDAC inhibition, and Mycobacterium tuberculosis growth inhibition. Amamistatin B (15) and diastereomer 18 were both active against MCF-7 cells (IC(50) 0.12-0.20 microM), and less so against PC-3 cells (IC(50) 8-13 microM). Amamistatin B only moderately inhibited the growth of M. tuberculosis (MIC 47 microM) but showed growth promotion of Mycobacterium smegmatis and other bacteria.     

Synthesis of peptidoglycan fragments and evaluation of their biological activity

The peptidoglycan (PG) bacterial cell wall glycoconjugate has been well known as a strong immunopotentiator. Partial structures of PG were chemically synthesized for elucidation of precise biological activities. Effective construction of distinct repeating glycans of PG was accomplished by the coupling of a key disaccharide glucosaminyl-beta(1-4)-muramic acid unit. Stereoselective glycosylation of disaccharide units was achieved by neighboring group participation of the N-Troc (Troc = 2,2,2-trichloroethoxycarbonyl) group and appropriate reactivity of N-Troc-glucosaminyl trichloroacetimidate. By using an efficient synthetic strategy, mono-, di-, tetra- and octasaccharide fragments of PG were synthesized in high yields. The biological activity of synthetic fragments of PG was evaluated by induction of tumor necrosis factor-alpha (TNF-alpha) from human monocytes, and toll-like receptor 2 (TLR2) and Nod2 dependencies by using transfected HEK293 cells, respectively. Here we reveal that TLR2 was not stimulated by the series of synthetic PG partial structures, whereas Nod2 recognizes the partial structures containing the MDP moiety.     

Synthesis of sulfonamides and evaluation of their histone deacetylase (HDAC) activity

A simple synthesis of sulfonamides 4-22 as novel histone deacetylase (HDAC) inhibitors is described. The key synthetic strategies involve N-sulfonylation of L-proline benzyl ester hydrochloride (2) and coupling reaction of N-sulfonyl chloride 3 with amines in high yields. It was found that several compounds showed good cellular potency with the most potent compound 20 exhibiting an IC50 = 2.8 microM in vitro.     

Syntheses of 4-methoxymethylbenzyl permethrinates containing fluorine and their insecticidal activity

In order to investigate the relationship between the position of fluorine atom and insecticidal activity about 4-methoxymethylbenzyl permethrinates containing fluorine, 2 and 3-fluoro-4-methoxymethylbenzyl (±)-cis-permethrinate were synthesized. Their insecticidal activities were tested and the fluorine effect of title compounds was discussed.     

Assays for determination of matrix metalloproteinases and their activity

Matrix metalloproteinases (MMPs) are involved in many physiological and pathological processes. Due to their ability to cleave and to remodel components of surrounding tissues, MMPs may affect cell migration, differentiation, growth, inflammatory processes, neovascularization, wound healing, apoptosis, the uterine cycle and many other actions within the body, including those needed for tumorigenesis and other diseases.MMPs can therefore be used as potential markers for detecting various cancers, neurodegenerative, and immune and cardiovascular diseases. Numerous MMP assays were developed for clinical and research purposes, but far more attention has been devoted to understanding their biological functions.Due to differences in methodology, results obtained in various laboratory settings are difficult to compare because of the lack of standards and analytical methods of validation. Limits of detection of particular methods used for identifying MMPs are also disputable.Enzymatic, immunochemical and fluorimetric methods are particularly suitable for clinical use. In-vivo imaging methods offer many potential advantages in cancer research and diagnostics. Other methods are subject to investigation [e.g., phage display, multiple-enzyme/multiple-reagent assay system (MEMRAS) and activity-based profiling].     

Synthesis of lupane triterpenoids with triphenylphosphonium substituents and studies of their antitumor activity

New derivatives of lupane triterpenoids, viz., 20,29-dihydrobetulinic and 3-epi-20,29-dihydrobetulinic acid derivatives containing triphenylphosphonium fragments as substituents were synthesized. These compound considerably exceed betulinic acid in antitumor activity.     

Syntheses and antitumor and anti-aids activities of polymers containing pyrimidine derivative

The new monomer, 5'-O-methacryloyl-3'-azido-3'-deoxy-thymidine (MAZT), was synthesized from methacryloyl chloride (MAC) and 3'-azido-3'-deoxythymidine (AZT). Poly(MAZT), poly(MAZT-co-AA) and terpoly(MAZT-FUR-MAH) were synthesized by radical polymerizations. The average molecular weights of synthesized polymers were in the range of 8,800 ∼23,000 depending on polymers. The in vivo antitumor activities of polymers at 800mg/kg were increased in the following order: terpoly(MAZT-FUR-MAH) >x poly(MAZT-co-AA) > poly(MAZT) > AZT > 5-FU. The in vitro anti-HIV activities of synthesized polymers were less effective than those of AZT and D4T. But the cytotoxicities of the polymers on the MT-4 cell line were found to be much less toxic than AZT.     

The introduction of antibacterial drug pipemidic acid into the POM field: Syntheses, characterization and antitumor activity

Two new compounds based on polyoxometalates (POMs) and the quinolone antibacterial drug pipemidic acid (HPPA), {[Ni(PPA)₂]H₄[SiW₁₂O₄₀]}·HPPA·3H₂O (1), and {[Zn(PPA)₂]₂H₄[SiW₁₂O₄₀]}·3H₂O (2), have been synthesized under hydrothermal conditions and structurally characterized by routine technique. Single-crystal X-Ray diffraction analysis shows that compound 1 is constructed by Keggin clusters grafted by binuclear nickel clusters, isolated HPPA and water molecules, while compound 2 consists of Keggin clusters grafted by binuclear zinc clusters and water molecules. Due to the selection of different transition metal (TM) ions, compounds 1 and 2 exhibit different structures and antitumor activities. Compound 1 possesses 0D structure and shows no antitumor activities. However, compound 2 possesses 1D structure and exhibits higher antitumor activities than its parent compound. The results show that introduction of different TM-PPA moieties onto the polyoxoanion surface can affect not only the final structures but also their antitumor activities.     

Electrochemical modeling of antioxidants action and determination of their activity

The method of pulse voltammetry was applied to the investigation of the antioxidant activity of sulfur-containing biologically active substances. Three models were considered to characterize the substances in aqueous medium: First, the interaction of antioxidants with a ferrous ion to characterize the preventive activity on the initiation stage of free radical oxidation, second and third describing the interaction of an antioxidant with electrochemically generated hydroxy radicals and hydrogen peroxide, to characterize the inhibitory activity in the initial stages of propagation and branching of the chain of free radical oxidation. A synergistic effect of ascorbic acid and other studied compounds at their combined action on hydroxy radicals and hydrogen peroxide was revealed.     

Factors affecting the specific activity of immobilized antibodies and their biologically active fragments.

Factors affecting the specific activity of immobilized antibodies and their biologically active fragments were studied with goat anti-mouse and goat anti-human immunoglobulin G. Antibodies were immobilized on HW 65 polymeric support matrix activated with carbonyldiimidazole, hydrazide and iodoacetic acid. The most significant factors influencing the specific activity of stochastic coupling of antibodies are multi-site attachment, multiple orientations and steric hindrance imposed by crowding of antibody and the size of the antigen. In oriented immobilization the specific activity is affected only by steric hindrance. The specific activity of immunosorbents prepared by immobilization of F(ab') fragments can be improved to almost 100% by limiting the amount of protein immobilization and the size of the antigen. The present study shows the protocols for optimizing immobilized antibody performance.     

熊果酸C-3,C-28位衍生物的合成及其抗肿瘤活性研究

以天然产物熊果酸为原料,经过氧化、酰化、酯化等反应合成了11个未见报道的熊果酸衍生物,其结构经过MS、1H NMR及元素分析确定。以氟尿嘧啶和吉非替尼为阳性对照药,经MTT法对A549和SGC-7901细胞进行初步体外抗肿瘤活性研究。结果表明,目标化合物对两种细胞株的抑制率均明显高于母体化合物,且化合物4b和5a的抑制效果高于阳性对照药,值得进一步研究。     

Synthesis of some nitrogen heterocycles and in vitro evaluation of their antimicrobial and antitumor activity

Treatment of ethyl β-aryl-α-cyanoacrylate (2a, b) with thiourea, guanidine hydrochloride, and thiosemicarbazide in presence of anhydrous potassium carbonate in methanol led to formation of pyrimidine derivatives 3 and 5 and thiosemicarbazone derivative 9. Thiazole derivative 10 was prepared via cyclization of thiosemicarbazone derivative 9 with 4-methoxy phenacyl bromide. Acetylation of 3a, 5, and 10 with acetic anhydride yielded the acetoxy and N-acetyl derivatives 4, 6, and 11. The mass-spectral fragmentation patterns of nitrogen heterocycles were investigated to elucidate the structure of the prepared compounds. Biological studies of nitrogen heterocycles were carried out to investigate their antimicrobial and anticancer activities; it was found that compounds 5, 10, and 11 were highly active against bacteria and fungi, and compounds 3a and 3b were also active against bacteria and fungi.     

Synthesis of some novel imidazolidine derivatives and their metal complexes with biological and antitumor activity

Halogenated imidazo(pyrazine,[1,4]diazocine and quinoxaline), 9,10‐anthraquinone‐ [6,7‐e], phenanthroline[5,6‐e] {imidazo[4,5‐b]pyrazine}, and naphtho[1,8‐ef]imidazo[4,5‐b][1,4] diazipen were obtained through interaction of imidazolidineiminothiones with the corresponding diamino compounds. Imidazo[4,5‐e] triazine and pyrrolo[2,3‐d]imidazole were prepared when the iminothiones were reacted with thiocarbohydrazide and with ethylphenyl acetate, separately. Some of the synthesized compounds exhibited better biological and antitumor activities. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:634–647, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20244     

Synthesis of some oxazolo and oxazinopyrano[3,2-c]quinolines and their antitumor activity

3-Amino-4-hydroxy-6-phenylpyrano[3,2-c]quinoline-2,5(6H)-dione was produced by a smooth reduction of its nitro precursor. Reaction of this 3-amino-4-hydroxypyranoquinoline derivative with different electrophiles, leading to a variety of oxazolo and oxazinopyrano[3,2-c]quinoline derivatives, was described. The structure of the new products was elucidated via elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectra. Also, screening the antitumor activity of new compounds against two human cell lines (HepG-2 and HCT-116) was carried out. Some new products showed significant antitumor activities.     

Spectrophotofluorimetric determination of 3-carbon fragments and their precursors with anthrone. Application to air pollution

Summary Two modifications of an anthrone procedure for the characterization and determination of compounds and their precursors are described. Two main types of fluorescence spectra are obtained. The procedure for analysis of precursors works well for the aldopentoses; by comparison, aldo-and ketohexoses react poorly.Water-soluble fractions of airborne particulates were analyzed by the anthrone procedure. At least three families of compounds were found: two give fluorogens, of which one is a precursor, and a third gives a chromogen(s) absorbing at 423 and 540 nm.

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Zusammenfassung Zwei Modifikationen eines Verfahrens zum Nachweis und zur Bestimmung von Verbindungen mit den Gruppen und deren Ausgangsstoffen mit Hilfe von Anthron wurden beschrieben.Zwei Haupttypen von Fluoreszenzspektren wurden festgestellt. Das Verfahren zur Analyse von Stoffen, die Brenztraubenaldehyd-Derivate bilden, eignet sich gut für Aldopentosen, Aldo- und Ketohexosen reagieren vergleichsweise nur schwach.Wasserlösliche Fraktionen atmosphärischer Verunreinigungen wurden nach dem Anthronverfahren analysiert. Dabei wurden drei Arten von Verbindungen gefunden: zwei davon geben Fluorogene, darunter eines, das die Gruppe > CH · CO · CHO zu bilden vermag, die dritte gibt Chromogene, die bei 423 bzw. 540 nm absorbieren.

     

Synthesis of novel fluorophenylpyrazole-picolinamide derivatives and determination of their anticancer activity

Abstract

A series of fluorophenylpyrazole-picolinamide derivatives were synthesized in high yields using a cross-coupling reaction catalyzed by in situ formed palladium-N-heterocyclic carbenes (Pd-NHCs). The synthesized novel derivatives were evaluated for in vitro anticancer activity against a panel of four human tumor cell lines, HeLa (cervical), A-549 (lung), MCF-7 (breast), and IMR-32 (neuroblastoma). Four compounds, 11c, 11e, 11j, and 11k, showed growth inhibition (low µM) comparable with the standard drug cisplatin, providing a preliminary structure–activity relationship for the series. The present procedure is operationally simple and works with a wide range of substrates and may thus be useful in further compound optimization.     

四苯骈卟啉及其金属配合物的合成

卟啉类化合物作为电子给体在光合作用模拟研究中占据着重要位置 ,在卟啉环上引入供电子基团以增大共轭体系 ,常有利于卟啉环的给电子作用 ,过去常用的卟啉化合物为四苯基卟啉及其衍生物 ,但由于空阻作用 ,四个亚甲基上的苯基不能很好与卟啉环共平面而降低了共轭效应 ,为了寻求一种更有利于卟啉环共轭大Π键形成的结构 ,我们合成了比四苯基卟啉共平面效果更好的卟啉化合物———四苯骈卟啉 (Ｈ2 ＴＢＰ)及其与Ｎｉ2 + 、Ｃｏ2 + 、Ｚｎ2 + 的金属配合物以及研究它的给电子作用效果。四苯骈卟啉配合物早在 1 92 8年就为人们所认识[1] ,但其研…