Synthesis and biological evaluation of nonylprodigiosin and macrocyclic prodigiosin analogues

Nonylprodigiosin (4) and various of its analogues have been prepared by Suzuki cross-coupling reactions of a well accessible pyrrolyl triflate with (hetero)aryl boronic acid derivatives bearing alkenyl side chains. The resulting alkenes or dienes were subjected to metathesis dimerization or ring-closing metathesis (RCM) reactions, respectively, by using a ruthenium indenylidene complex as the catalyst. The biological activity of the products thus obtained was tested in two different assays monitoring i) the proliferation of murine spleen cells induced by lipopolysaccharides (LPS) and concanavalin A (Con A), and ii) the vacuolar acidification of baby hamster kidney (BHK) cells. Compounds 4 and 21 suppressed Con A-induced T-cell proliferation much more potently than LPS-induced B-cell proliferation. Furthermore, compounds 4 and 26 markedly inhibited vacuolar acidification, although other compounds exhibited no or only marginal effects. Thus, the immunosuppressive activity of prodigiosins toward T-cell proliferation seems to be mediated through cellular targets distinct from vacuolar acidification, and the prodigiosin analogues might be powerful tools to dissect these biological responses. The X-ray crystal structure of the macrocyclic product 25 has been determined, showing that the replacement of one pyrrole ring of the parent compound 4 by a phenyl group does not alter the overall electronic features of the remaining heterocyclic ring system of these alkaloids.     

新型芳腙基噻唑衍生物的合成及抗菌活性研究

以取代苯甲醛与氨基硫脲为原料合成了11种芳基噻唑衍生物,经IR、1HNMR、MS及元素分析确定了化合物的结构,并分别测试了这些化合物对8种革兰氏阳性、阴性菌和3种真菌的抑菌活性。     

新型二氯乙酰胺类化合物的制备及生物活性研究

以1,4-丙二胺与乙酰丙酸为原料反应得二氮杂二环,然后加入缚酸剂三乙胺与二氯乙酰氯一锅法反应制备了二氯乙酰胺类化合物6-二氯乙酰基-7-甲基-10-氧杂-1,6-二氮杂二环[5.3.0]癸烷,采用红外光谱、氢核磁、碳核磁进行了表征,并利用室内生物测定法研究其在土壤中豆磺隆残留时对玉米的保护效果。     

新型含吡啶环双酰胺衍生物的合成及生物活性

以吡啶羧酸和取代邻氨基苯甲酸为起始原料,设计并合成12个双杂环双酰胺类化合物,其结构经1HNMR、13CNMR、IR及元素分析确证。初步生物活性测试结果表明,在200、500μg/mL浓度下部分化合物对青枯病病原菌(Pseudomonas solanacearum)进行活性测试,结果表明所合成的化合物对青枯病病原菌有一定抑菌活性,其中N-(2-(6-乙氧基苯并噻唑-2-氨基甲酰基)-4-甲基苯基)-3-吡啶甲酰胺在500μg/mL浓度下对青枯病病原菌的抑菌活性为60%。     

Synthesis and biological evaluation of novel EG5 inhibitors

Human Eg5 is a mitotic kinesin that is essential for bipolar spindle formation and maintenance during mitosis. Recently, the discovery of compounds that inhibit Eg5 and cause mitotic arrest has attracted great interest, due to their potential use as the next generation of antimitotics. Here, we present the synthesis and biological investigation of 3,4-dihydrophenylquinazoline-2(1H)-thiones as selective and potent Eg5 inhibitors.     

Synthesis and biological activity of a novel inhibitor of dihydroceramide desaturase

A novel mechanism-based dihydroceramide desaturase inhibitor (XM462) in which the substrate C5 methylene group is replaced by a sulfur atom is reported. Dihydroceramide desaturase inhibition occurred both in vitro and in cultured cells with IC(50) values of 8.2 and 0.78 microM, respectively, at a substrate concentration of 10 microM. In vitro experiments showed that XM462 produced a mixed-type inhibition (K(i)=2 microM, alpha=0.83). LC-MS analyses showed that accumulation of endogenous dihydroceramides occurred in cells upon treatment with XM462 in serum-free medium, whereas ceramides built up in controls. In addition, XM462 was found to be metabolised to its 1-glucosyl and 1-phosphocholine derivatives, and to the products of N-deacylation and reacylation with palmitoyl and stearoyl groups. In Jurkat A3 cells cultured in serum-free medium, viability, as the percentage of trypan blue unstained cells in total cells, was reduced upon XM462 treatment (5 microM, 24 h), but not in controls. The interest of this compound is discussed.     

1,3-二氧环辛烷-2-羧酸类三环化合物的合成及其除草活性

二苯并1,3-二氧环辛烷-2-羧酸类三环化合物(见通式Ⅰ)(dibenzodioxocincarboxylic acid简称DBZ)的应用研究早期主要在医药方面(1977).Dow化学公司首先报道了此类化合物作为除草剂在农业上的应用(US 4976770 A,1990).1994年罗门哈斯公司的Lori Spangler博士注意到这类化合物结构新颖、公开专利较少(不超过10篇),开始了先导优化工作.沈阳院首先合成出专利中化合物(Ⅱ),经生测表明,化合物(Ⅱ)作用方式较慢、苗后活性高于苗前、杀草谱广、活性高(150g／ha),符合当前除草剂的发展方向.因此,双方成立了DBZ项目小组,其中包括合成人员、生测人…     

肿瘤靶向药物载体RGD与PEO-PPO-PEO偶合物的合成与表征

利用 PEO-PPO-PEO(pluronic P105)的生物可降解性、无免疫原性等特性将其作为药物载体,以减少化疗因子对全身的毒副作用.为了达到主动靶向治疗目的,将生物活性肽RGD(Arg-Gly-Asp) 接枝到PEO-PPO-PEO上,利用肿瘤组织特异表达的整合素与RGD的高亲和力结合,将药物特异性输送到肿瘤部位.将PEO-PPO-PEO羧基化接枝RGD,用FTIR、1H NMR 进行结构表征证实RGD的接枝是成功的.     

Synthesis, modeling, and biological evaluation of analogues of the semisynthetic brevetoxin antagonist beta-naphthoyl-brevetoxin

Brevetoxins are neurotoxic compounds produced by the dinoflagellate Karenia brevis. Extensive blooms induce neurotoxic shellfish poisoning (NSP) and asthma-like symptoms in humans. beta-naphthoyl-brevetoxin, the first semisynthetic brevetoxin antagonist, has been defined as the lead compound in the investigation of the mechanisms of bronchoconstriction induced by inhaled brevetoxins and relaxation or reversal of those effects by selected derivatives. In pursuit of more potent and effective brevetoxin antagonists, a series of beta-naphthoyl-brevetoxin analogues have been synthesized. Activities were determined by competitive displacement of tritiated brevetoxin-3 from rat brain synaptosomes and by lung resistance measurements in sheep. Additionally, preliminary computational structural studies have been performed. All analogues bound to rat brain synaptosomes with affinities similar to beta-naphthoyl-brevetoxin but exhibited very different responses in sheep. The biological evaluations along with computational studies suggest that the brevetoxin binding site in rat brain synaptosome might be different from the ones in lung tissue and both steric and electrostatic factors contribute to the efficacy of brevetoxin antagonism.     

Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage

One of the great challenges of medicinal chemistry is to create novel, effective, chemotherapeutic agents that show specificity for cancer cells combined with low systemic toxicity. A novel idea is to target the enzymes of the NAD biosynthesis and recycling pathways given that cancer cells display a higher NAD turnover rate than healthy cells. To this end, the compound FK866 (APO866; (E)-N-[4-(1-benzoylpiperidin-4-yl) butyl]-3-(pyridin-3-yl) acrylamide), which blocks nicotinamide phosphoribosyltransferase (NMPRTase) has entered clinical trials as a potential chemotherapeutic agent. Here we report the synthesis of analogues of FK866 synthesized by click chemistry.     

白藜芦醇类似物的合成研究

以对硝基甲苯、3,4-二甲氧基苯甲醛为起始原料,经过缩合、还原、重氮化、亲核取代反应和酰化反应,最终合成新的5种目标化合物。用元素分析、红外光谱1、HNMR1、3CNMR及多种二维核磁共振谱确定了目标化合物的结构。     

Synthesis and biological activity of metabolically stabilized cyclopentyl trisphosphate analogues of D-myo-Ins(1,4,5)P3

We describe the synthesis of four novel metabolically stabilized analogues of Ins(1,4,5)P(3) based on the known cyclopentane pentaol tris(phosphate) 2: tris(phosphorothioate) 3, tris(methylenephosphate) 4, tris(sulfonamide) 5, and tris(sulfate) 6. Of these analogues, only the tris(phosphorothioate) 3 and parent tris(phosphate) 2 bound to the type I InsP(3)R construct. In addition, both the tris(phosphorothioate) 3 and parent tris(phosphate) 2 elicited calcium release in MDA MB-435 breast cancer cells. The Ins(1,4,5)P(3) agonist activities of these two compounds can be rationalized on the basis of computational docking of the ligands to the binding domain of the type I InsP(3)R.     

N-取代去甲基斑蝥酰亚胺及其类似物的合成

合成了 N-取代去甲基斑蝥酰亚胺、去甲基斑蝥素等23种化合物,对其结构做了元素分析、红外光谱鉴定     

Synthesis, biological evaluation, and molecular modeling studies of rebeccamycin analogues modified in the carbohydrate moiety

A new series of indolocarbazole glycosides containing disaccharides were synthesized and their in vitro antiproliferative activity was evaluated against three human cancer cell lines (A2780, H460, and GLC4). Cytotoxicity appeared to be remarkably affected by the regio- and stereochemical features of the disaccharide moiety. In vivo antitumor activity of the compounds studied, two of which having IC(50)<100 nm, was determined using ovarian cancer cell line A2780 xenografted on nude mice. One compound showed an efficacy similar to that of the reference compound edotecarin, though with a lower long-lasting activity. The topoisomerase I inhibitory properties of some compounds were also examined. Molecular dynamics simulations of the ternary topoisomerase I-DNA-ligand complexes were performed to analyze the structural features of topoisomerase I poisoning with this class of indolocarbazoles. A plausible explanation of their biological behavior was provided. These theoretical results were compared with the recently published crystal structure of an indolocarbazole monosaccharide bound to the covalent human topoisomerase I-DNA complex.