Furanofuran lignans from Vitex negundo seeds

A new furanofuran lignan, vitelignin A (1), together with eight known lignan derivatives, were isolated from the seeds of Vitex negundo. Their structures were identified as (+)-4-oxo-8-hydroxy-2,6-di(3,4-methylenedioxy)phenyl-3,7-dioxabicyclo[3.3.0]octane (1), 4-oxosesamin (2), (+)-sesamin (3), (+)-paulownin (4), 4-hydroxysesamin (5), 4,8-dihydroxysesamin (6), 4-oxopaulownin (7), (+)-2-(3-methoxy-4-hydroxyphenyl)-6-(3,4-methylenedioxy)phenyl-3,7-dioxabicyclo[3.3.0]octane (8), and (+)-pinoresinol (9), respectively, based on extensive NMR and MS spectroscopic studies. Compounds 1, 2, and 7 showed moderate antifungal activity in vitro.     

Inhibition of Sporulation of Genus Bacillus by Various Microbial Protease Inhibitors

Several analogs modifying the 6-methoxy-2-methoxymethyl-3-(3,4-methyienedioxyphenyl)-1,4-benzodioxan-7-yl group of haedoxans were synthesized and their insecticidal activity was examined. 2-(2,6-Dimethoxyphenoxy)-1-hydroxy-6-(2-methoxy-5-methoxyethoxyphenyl)-3,7-dioxabicyclo-[3.3.0]octane, which lacked the 3-(3,4-methylenedioxybenzyloxy) moiety of the benzodioxanyl group, was not insecticidal, but caused prolonged paralysis of the housefly. A compound replacing the 6-(2-methoxy-5-methoxyethoxyphenyl) by 6-(5-butoxy-2-methoxyphenyl) exhibited insecticidal activity comparable to one thirty-thousandth of that of haedosan A. It became evident that the 1,4-benzodioxane framework charging the 3-(3,4-methylenedioxy)phenyl group is important for the insecticidal activity of haedoxans.     

毛头鬼伞子实体化学成分及抗糖尿病活性初探

从毛头鬼伞子实体中萃取得到乙醇、乙酸乙酯、石油醚3种有机提取物,采用α-葡萄糖苷酶活性抑制实验对3种有机提取物的抗糖尿病活性进行评价,结果显示,乙酸乙酯提取物对α-葡萄糖苷酶有较强的抑制活性。采用柱层析技术从乙酸乙酯提取物中分离纯化出10种化合物,经核磁等方法鉴定为：（1）顺,顺-9,12-十八(碳)二烯酸;（2）顺式-9-十八烯酸;（3）(22E,24R)-麦角甾烷-5,7,22-三烯-3β醇;（4）3β-5α-6α-22E-麦角甾-7,22-双烯-3,5,6-三醇-6-亚油酸酯;（5）3β-5α-6α-22E-麦角甾-7,22-双烯-3,5,6-三醇-6-油酸酯;（6）邻苯二甲酸二异丁酯;（7）对羟基苯乙醇;（8）4-羟基苯乙基乙酸酯;（9）3-(4-羟基-3-甲氧苯基)败脂酸;（10）N-反式-3,4亚甲二氧基肉桂酰基-3-甲氧基酪胺。对分离化合物的α-葡萄糖苷酶活性抑制实验结果显示,N-反式-3,4亚甲二氧基肉桂酰基-3-甲氧基酪胺对α-葡萄糖苷酶具有较强的抑制活性,其IC₅₀值为4.17mg/mL。     

Optical Resolution and Determination of Absolute Configurations of α-Isopropyl-4-substituted Phenylacetic Acids and Insecticidal Activities of Their 5-Benzyl-3-furylmethyl Esters

In connection with disclosure of a new class of insecticides, the modified phenylacetates, six new optically active α-isopropy-4-substituted phenylacetic acids whose substituents are respectively 4-methyl,4-methoxy, 4-fluoro, 4-chloro, 4-bromo and 3,4-methylenedioxy group were prepared by optical resolution and their absolute configurations were determined by comparative ORD with α-isopropylphenylacetic acid derivatives whose absolute configuration is known as (S)-(²). Esters of the (S)-(²)-acids with 5-benzyl-3-furylmethanol were nearly twice toxic to Musca domestica than those of the racemic esters. Optical purities of the resolved acids were determined by GLC and NMR (with Eu-FOD) as (?)-methyl esters.     

Thonningine-A and thonningine-B: two 3-phenylcoumarins from the seeds of Millettia thonningii

The seeds of Millettia thonningii have yielded four isoflavones and three 4-hydroxy-3-phenylcoumarins, of which two are novel. On the basis of spectral analyses the novel compounds have been identified as 4-hydroxy-5,8-dimethoxy-3-(3′,4′-methylenedioxy)phenyl-2″-isopropenylfurano (4″,5″:6,7)coumarin (thonningine-A) and 4-hydroxy-5,8-dimethoxy-3-(4′-methoxy)phenyl-2″-isopropenylfurano(4″, 5″: 6,7)coumarin (thonningine-B).     

Synthesis and Insecticidal Activity of Lignan Analogs (III)

Ten haedoxan analogs with the bond split between 2C and 3C of the 6-methoxy-2-methoxymethyl-3-(3,4-methylenedioxy)phenyl-1,4-benzodioxan-7-yl group of haedoxans were synthesized, and their insecticidal activity was assessed on the housefly. The inactivity of an analog having a 2-methoxy-5-(2-methoxyethoxy)-4-(3,4-methylenedioxybenzyloxy)phenyI instead of the 1,4-benzodioxan-7-yl group made it evident that the benzodioxane framework is essential for the activity of haedoxans.     

2,3-Dimethoxybenzo[i]phenanthridines: topoisomerase I-targeting anticancer agents

Appropriately substituted benzo[i]phenanthridines structurally related to nitidine, a benzo[c]phenanthridine alkaloid with antitumor activity, are active as topoisomerase I-targeting agents. Studies on benzo[i]phenanthridines have indicated analogues that possess a 2,3-methylenedioxy moiety and at least one and preferably two methoxyl groups at the 8- and 9-positions, such as 8,9-dimethoxy-2,3-methylenedioxybenzo[i]phenanthridine, 2, are active as topoisomerase I-targeting agents. Tetramethoxylated benzo[i]phenanthridines, wherein the 2,3-methylenedioxy moiety is replaced with methoxyl groups at the 2- and 3-position, are inactive as a topoisomerase I-targeting agent. These results initially suggested that the 2,3-methylenedioxy moiety was critical to the retention of potent activity. Further studies revealed that 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine, 7a, is more potent than 2 as a topoisomerase I-targeting agent. The observation that 2,3-dimethoxylated benzo[i]phenanthridines can actually exhibit enhanced activity prompted the present study in which several 8-substituted 2,3-dimethoxybenzo[i]phenanthridines were prepared and their pharmacological activities evaluated. The influence of NH(2), CN, CH(2)OH, OBn, OCH(3), OH, and NHCOCH(3 )substituents at the 8-position on the relative activity of these 2,3-dimethoxybenzo[i]phenanthridines was examined. Relative to these derivatives, 7a was the most potent topoisomerase I-targeting agent, possessing similar cytotoxicity to that of nitidine in the human lymphoblast tumor cell line, RPMI8402.     

Structure-Antibacterial Activity Relationship for 9-O,9′-O-Demethyl (+)-virgatusin

The relationship between the antibacterial activity and structure of 9-O,9′-O-demethyl (+)-virgatusin (Virg 3) was examined. The conversion of hydroxy groups on the 9 and 9′ positions to amino groups increased the activity. It was found that the 3′-methoxy group was more important for higher activity than the 4′-methoxy group on the 7′-phenyl group, and that the 3,4-methylenedioxy group on the 7-phenyl group was necessary for activity.     

Astraciceran: a new isoflavan phytoalexin from Astragalus cicer

A new phytoalexin isolated from the fungus-inoculated leaflets of Astragalus cicer has been identified as 7-hydroxy-2′-methoxy-4′,5′-methylenedioxyisoflavan (astraciceran). The synthesis of astraciceran and its 3′,4′-methylenedioxy analogue is described.     

天山棱子芹化学成分的研究

从天山棱子芹中首次分离得到15个已知化合物,通过NMR、MS及IR等波谱数据,分别鉴定为6,7-二羟基香豆素(1),( )-marmesin(2),marmesinin(3),5,7,4'-三羟基黄酮(4),莰非醇3-O-α-L-吡喃鼠李糖甙(5),藤黄菌素3'-O-β-D-吡喃葡萄糖甙(6),(R)-6-hydroxy-3-(2-hydroxypropan-2-yl)-6-methylcyclohex-2-enone(7),4-羟基苯甲酸(8),3-甲氧基4羟基苯甲酸(9),3-甲氧基-4,5-亚甲二氧基苯甲酸(10),丁香酸甲酯(11),丁香酸甲酯4-O-β-D-吡喃葡萄糖甙(12),姜油酮4’-O-β-D-吡喃葡萄糖甙(13),2-(4-羟基苯基)-乙醇(14)和正二十八醇(15)。其中化合物7为一新的天然产物。     

Synthesis and antiproliferative activity of benzyl and phenethyl analogs of makaluvamines

Analogs of marine alkaloid, makaluvamine, bearing substituted benzyl and substituted phenethyl side chains have been synthesized and their antiproliferative activities have been evaluated. 4-Methyl, 4-chloro, and 4-fluoro substituted benzyl analogs possessed pronounced antiproliferative effects on the breast cancer cell line, MCF-7 at IC(50) values of 2.3 microM, 1.8 microM, and 2.8 microM, respectively. 4-Methyl, 4-chloro, and 3,4-methylenedioxy derivatives showed the best activity against MCF-7 among the phenethyl analogs with IC(50) values of 2.3 microM, 2.8 microM, and 2.4muM, respectively. In general, methoxy substitutions resulted in slight loss in activity in both benzyl and phenethyl series. Benzyl, 4-fluorobenzyl, 3,4-dimethoxyphenethyl, and 3,4-methylenedioxyphenethyl analogs were tested by NCI in their 60 cell lines in vitro human cancer cell screen. All four compounds showed excellent inhibition against several tested cancer cell lines. Benzyl and 4-fluorobenzyl analogs were relatively more active than 3,4-dimethoxy phenethyl and 3,4-methylenedioxy phenethyl analogs. In NCI assays, the best LogGI(50) values were shown by the fluorobenzyl analog against the renal cancer cell line RXF-393 (<-8.0M) and dimethoxy phenethyl analog against the CNS cancer cell line, SF-268 (<-8.0M). The best LogLC(50) value was shown by the fluorobenzyl analog against the breast cancer cell line MCF-7 (-6.01 M).     

E-Combretastatin and E-resveratrol structural modifications: Antimicrobial and cancer cell growth inhibitory β-E-nitrostyrenes

As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three β-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The β-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy-4,5-methylenedioxy derivatives. Two of the β-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v). All except four (4r, 4s, 4t, 4u) of the series significantly inhibited a minipanel of human cancer cell lines. All but eight led to an IC₅₀ of <10 μM for inhibition of tubulin polymerization, and all except three (4l, 4t, 4v) displayed antimicrobial activity.     

长形肉豆蔻Myristica argentea Warb.化学成分研究(英文)

从长形肉豆蔻Myristica argentea乙醇提取物乙酸乙酯部分分离得到12个化合物,经理化和波谱分析分别鉴定为黄樟醚(1)、甲基丁香酚(2)、异甲基丁香酚(3)、3′-羟基异黄樟醚(4)、7-羟基-3′,4′-亚甲二氧基黄烷(5)、1,4-苯二甲酸二甲酯(6)、内消旋-二氢愈创木脂酸(7)、赤式-1-(4-羟基-3-甲氧基苯基)-4-(3,4-亚甲二氧基苯基)-2,3-二甲基丁烷(8)、赤式-1-(4-羟基-3-甲氧基苯基)-2-(2-甲氧基-4-(1(E)-丙烯基)苯氧基)-丙烷-1-醇(9)、nectandrin B(10)、β-谷甾醇(11)和胡萝卜苷(12)。化合物4~6和8~12为首次自该植物中分离得到,化合物4~6为首次从该属植物中分离得到。     

Synthesis,topoisomerase-targeting activity and growth inhibition of lycobetaine analogs

The plant alkaloid lycobetaine has potent topoisomerase-targeting properties and shows anticancer activity. Based on these findings, several lycobetaine analogs were synthesized mainly differing in their substituents at 2, 8 and 9 position and their biological activities were evaluated. The topoisomerase-targeting properties and cytotoxicity of these structural analogs were assessed in the human gastric carcinoma cell line GXF251L. Performing a plasmid relaxation assay, an increased inhibition of topoisomerase I was found with N-methylphenanthridinium chlorides bearing a 8,9-methylenedioxy moiety or a methoxy group in 2-position. Furthermore, quaternized phenanthridinium derivatives bearing either a 2-methoxy or a 8,9-methylenedioxy moiety in conjunction with a 2-hydroxy or 2-methoxy group display potent topoisomerase II inhibition as shown by decatenation of kinetoplast DNA. In general, the N-methylphenanthridinium chlorides possess more potency in inhibiting topoisomerase I than topoisomerase II. All quaternized derivatives also exhibited potent inhibition of tumor cell growth in the low micromolar concentration range. Hence, N-methylphenanthridinium compounds were found to represent a promising class of compounds, potently inhibiting both, topoisomerases I and II, and may be further developed into clinically useful topoisomerase inhibitors.     

Zanthomamide: An aromatic amide from Zanthoxylum thomense

From the stem bark of Zanthoxylum thomense a new amide, zanthomamide has been isolated and characterized as N-methyl, N-cinnamyl-(3′,4′-methylenedioxy)-phenylethylamine. Other constituents identified are the known benzophenanthridines, decarine, norchelerythrine and angoline.     

Alkaloids of Litsaea laeta and L. salicifolia

The structure for laetine (2-hydroxy-1-methyl 10,11-methylenedioxy noraporphine), a new alkaloid from the bark of Litsaea laeta has been established. N,O-Dimethylharnovine and glaucine were also isolated from the same source. C-2 hydroxy aporphines are characteristic of L. laeta. Two known alkaloids, dicentrinone and nordicentrine, have also been isolated from the leaves of L. salicifolia.     

Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 8. High affinity ligands for opioid receptors in the picomolar Ki range: Oxygenated N-(2-[1,1′-biphenyl]-4-ylethyl) analogues of 8-CAC

N-[2-(4′-methoxy[1,1′-biphenyl]-4-yl)ethyl]-8-CAC (1) is a high affinity (K_i = 0.084 nM) ligand for the μ opioid receptor and served as the lead compound for this study. Analogues of 1 were made in hopes of identifying an SAR within a series of oxygenated (distal) phenyl derivatives. A number of new analogues were made having single-digit pM affinity for the μ receptor. The most potent was the 3′,4′-methylenedioxy analogue 18 (K_i = 1.6 pM).     

经皮给药载体载MD-CPT透明质酸纳米乳的细胞吞噬与体内药代动力学研究

本文在研究制备了包载10,11-亚甲二氧基喜树碱(MD-CPT)的透明质酸纳米乳(HANs)经皮给药系统的基础上,进一步研究了载MD-CPT透明质酸纳米乳的细胞吞噬,并进行了体内药代动力学分析.通过优化制备条件,得到了皮肤渗透性良好的缓释剂型.从CLSM观察到药物被细胞摄入并传递入细胞核,同时,载药纳米乳的细胞吞噬效率呈时间依赖性,不同细胞株HSF、HUVES、MCF-7、KF的细胞吞噬率略有不同.用Rhodanmine B标记HANs,通过荧光显微镜观察到载药纳米乳透过角质层到达真皮层的拟动态过程.利用HPLC检测MD-CPT血药浓度,测得经皮给药半衰期T1/2是静脉注射的3.6倍,肌肉注射的1.6倍,体内药物滞留时间显著增加;血药浓度峰谷值差异小,曲线平缓,说明经皮给药能保证血药浓度呈现可控的持续性.最终通过活体成像系统和组织切片荧光显微镜,直观地反映出经皮给药后药物在大鼠体内的分布情况和各组织器官药物含量,确定载药纳米乳主要采取胞间渗透的扩散方式,在局部给药的区域滞留时间较长,有利于对浅表性的病灶区持续给药,延长药效,而剩余的MD-CPT和解离的HANs都进入了血液循环,最终通过新陈代谢被排出体外.为无创型HANs经皮给药系统应用于浅表性肿瘤治疗提供了理论基础.     

A benzil and isoflavone from Iris tenuifolia

Two compounds, tenuifodione (1) and tenuifone (2), and 12 known compounds, izalpinin (3), alpinone (4), arborinone (5), irilin B (6), irisone A (7), irisone B (8), betavulgarin (9), beta-sitosterol (10), 5,7-dihydroxy-2',6-dimethoxyisoflavone (11), 2',5-dihdroxy-6,7-methylenedioxy flavanone (12), irisoid A (13) and ethyl-beta-d-glucopyranoside (14) were isolated from the whole plant of Iris tenuifolia Pall. All compounds, except 12, were isolated for the first time from this plant. Compounds 2, 3 and 11 have shown a considerable DPPH radical scavenging activity. Structures of these compounds were identified on the basis of spectroscopic techniques, including 2D NMR. Compounds 3, 5 and 7 were also subjected to single-crystal X-ray diffraction analysis and their structures were unambiguously deduced.     

An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists

The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.