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Several fluorinated derivatives of the anti-HIV maturation agent bevirimat ( 1 ) were synthesized and evaluated for anti-HIV replication activity. The modified positions were the C-2, C-3, C-28, and C-30 positions, either directly on the betulinic acid ( 2 ) skeleton or in the attached side chains. Compound 18 , which has a trifluoromethyl group added to C-30 of its isopropenyl group, exhibited similar potency to 1 against HIV-1 NL4-3 . In total, our current studies support our prior conclusion that C-30 allylic modification is unlikely to be a pharmacophore for anti-HIV activity, but could be a meaningful route to manipulate other properties of 2 -related compounds. [ABSTRACT FROM AUTHOR]

One new eremophilane-type sesquiterpene (1, citreopenin) was isolated fromPenicillium citreonigrum(HQ738282), and the structure was elucidated by a combination of spectroscopic data interpretation and single-crystal X-ray diffraction analysis using Cu Kα radiation (CCDC 1030588). Compound1showed weak activity against KB-VIN (IC50 = 11.0 ± 0.156 μM), while the known compound3exhibited selective cytotoxicity against MDA-MB-231 triple-negative breast cancer (TNBC) (IC50 = 5.42 ± 0.167 μM). [ABSTRACT FROM PUBLISHER]

Twenty-five amide alkaloids ( 1 – 25 ) from Piper boehmeriifolium and 10 synthetic amide alkaloid derivatives ( 39 – 48 ) were evaluated for antiproliferative activity against eight human tumor cell lines, including chemosensitive and multidrug-resistant (MDR) cell lines. The results suggested tumor type-selectivity. 1-[7-(3,4,5-Trimethoxyphenyl)heptanoyl]piperidine ( 46 ) exhibited the best inhibitory activity (IC 50 = 4.94 μM) against the P-glycoprotein (P-gp)-overexpressing KBvin MDR sub-line, while it and all other tested compounds, except 9 , were inactive (IC 50 >40 μM) against MDA-MB-231 and SK-BR-3. Structure–activity relationships (SARs) indicated that (i) 3,4,5-trimethoxy phenyl substitution is critical for selectivity against KBvin, (ii) the 4-methoxy group in this pattern is crucial for antiproliferative activity, (iii) double bonds in the side chain are not needed for activity, and (iv), in arylalkenylacyl amide alkaloids, replacement of an isobutylamino group with pyrrolidin-1-yl or piperidin-1-yl significantly improved activity. Further study on Piper amides is warranted, particularly whether side chain length affects the ability to overcome the MDR cancer phenotype. [ABSTRACT FROM AUTHOR]

Meiosis is a special form of nuclear division to generate eggs, sperm and spores in eukaryotes. Meiosis consists of the first (MI) and the second (MII) meiotic divisions, which occur consecutively. MI is reductional, in which homologous chromosomes derived from parents segregate. MI is supported by an elaborate mechanism involving meiosis-specific cohesin and its protector. MII is equational, in which replicated sister-chromatids separate as in mitosis. MII is generally considered to mimic mitosis in mechanism. However, fission yeast Mes1p is essential for MII but dispensable for mitosis. The mes1-B44 mutant arrests before MII. Transcription of mes1 is low in vegetative cells and boosted in a narrow window between late MI and late MII. The mes1 mRNA undergoes meiosis-specific splicing. Here we show that Mes1p is a factor that suppresses the degradation of cyclin Cdc13p at anaphase I. Mes1p binds to Slp1p, an activator of APC/C (anaphase promoting complex/cyclosome), and counteracts its function to engage Cdc13p in proteolysis. Inhibition of APC/C-dependent degradation of Cdc13p by Mes1p was reproduced in a Xenopus egg extract. We therefore propose that Mes1p has a key function in saving a sufficient level of MPF (M-phase-promoting factor) activity required for the execution of MII. [ABSTRACT FROM AUTHOR]

The fundamental mechanisms of mitosis are conserved throughout evolution in eukaryotes, including ubiquitin-mediated proteolysis of cell cycle regulators by the anaphase-promoting complex/cyclosome. The spindle checkpoint protein Cdc20 activates the anaphase-promoting complex/cyclosome in a substrate-specific manner. It is present in the cytoplasm and concentrated in the centrosomes throughout the cell cycle, accumulates at the kinetochores in metaphase, and is no longer detected following anaphase. However, it is unknown whether Cdc20 has the same activities and distribution during meiosis in male germ cells. We found that in mice, Cdc20 accumulates in the cytoplasm of pachytene spermatocytes during meiosis I, is distributed throughout spermatocytes undergoing meiotic division, and is present in the cytoplasm of postmeiotic spermatids. Several proteins bind to and regulate the function of Cdc20 during mitosis. We identified speriolin and determined that it is a novel spermatogenic cell-specific Cdc20-binding protein, is present in the cytoplasm, and is concentrated at the centrosomes of spermatocytes and spermatids and that a leucine zipper domain is required to target speriolin to the centrosome. The seven tandem WD motifs of Cdc20 probably fold into a seven-blade E-propeller structure, and we determined that they are required for speriolin binding and for localization of Cdc20 to the centrosomes and nucleus, suggesting that speriolin might regulate or stabilize the folding of Cdc20 during meiosis in spermatogenic cells. [ABSTRACT FROM AUTHOR]

With the recent increase in demand, power system have become large and complex and generation plants are located far from the load center. As a result, power system instability has become more serious. On the other hand, the active and reactive powers are controlled rapidly and flexibly by the superconducting magnetic energy storage (SMES) system. This paper proposes a practical method to suppress power oscillation in a multimachine power system by using SMES wherein its active power is controlled by the signal derived from a bus frequency derivation. This controlled scheme is conducted easily only by detecting the frequency deviation on the state. The proposed method is examined on a 4-machine miniature power system connecting a 1-MU SMES as well as another digital simulation using the same model. The effectiveness of the proposed method is shown. [ABSTRACT FROM AUTHOR]

The digital simulation method has been utilized to analyze phenomena in power systems. Since different algorithms can be applied, depending on the phenomena to be analyzed, digital simulation allows for high-precision analysis. However, it also has a disadvantage: it produces continuous phenomena which occur in actual systems only fragmentarily. Thus, when discussing important projects at research centers such as IREQ in Canada, an analog simulator issued to continously analyze the phenomena from the moment the fault occurs until steady state. These analog simulators, however, consist of only a few generator models. They are only effective for analyzing phenomena in small-scale systems and do not allow for analysis of phenomena in large-scale systems over a long period of time. For this reason, the Kansai Electric Power Company (KEPCO) in cooperation with Hitachi, Ltd., and Fuji Electric Co., Ltd., has developed the world's largest power system simulator (APSA: Advanced Power System Analyzer). The simulator will be used to analyze the evolution of accidents in actual systems and to analyze continuous system phenomena over a long period. This paper describes an outline of the simulator. [ABSTRACT FROM AUTHOR]

The article discusses delayed current zero phenomenon. When a fault occurs on a transmission line, it is sometimes possible for the fault current not to become zero for several cycles. This phenomenon is called the delayed current zero phenomenon. Whether the circuit breaker is able to interrupt such a current raises a serious problem. The most important problem of delayed current zero phenomena is the delay time. Delay time is greatly affected by many factors such as the type of fault, fault conditions, etc. and in particular by the arc resistance at fault point.

Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1–14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC50 values ranging from 0.5–0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site. [ABSTRACT FROM AUTHOR]

Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC 50 , 67.0 nM) and 19b (IC 50 , 99.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives. [ABSTRACT FROM AUTHOR]

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel 7-substituted CPT derivatives incorporating piperazinyl-sulfonylamidine moieties were designed, synthesized and evaluated for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB, and KB-VIN). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Remarkably, most of the compounds exhibited comparable cytotoxicity against the multidrug-resistant (MDR) KB-VIN and parental KB tumor cell lines, while irinotecan lost activity completely against KB-VIN. Especially, compounds 13r and 13p (IC 50 0.38 and 0.85 μM, respectively) displayed the greatest cytotoxicity against the MDR KB-VIN cell line and merit further development into preclinical and clinical drug candidates for treating cancer, including MDR phenotype. [ABSTRACT FROM AUTHOR]

In the course of our continuing studies on the 2-(benzo[ b ]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (TEDB-TB) series, we designed and synthesized nine amino-TEDB-TB derivatives to improve pharmaceutical properties, identify structure activity relationships, and discover novel antitubulin agents. Among all newly synthesized amino-TEDB-TBs, the 5′- and 6′-amino derivatives, 6 and 7 , exhibited significant antiproliferative activity against five human tumor cell lines, including an MDR subline overexpressing P-gp. The IC 50 values of 0.50–1.01 µM were 3–6 times better than those of previously reported hydroxy-TEDB-TBs. Compounds 6 and 7 inhibited tubulin polymerization, induced both depolymerization of interphase microtubules and multiple spindle formations, and caused cell arrest at prometaphase. Among all compounds, compound 7 scored best pharmaceutically with LogP 2.11 and biologically with greater antiproliferative activity and induction of cell cycle arrest at prometaphase. [ABSTRACT FROM AUTHOR]

In an effort to discover potent camptothecin-derived antitumor agents, novel camptothecin analogues with sulfonylpiperazinyl motifs at position-7 were designed and synthesized. They were evaluated for in vitro cytotoxicity with the sulforhodamine-B (SRB) method in five types of human tumor cell lines, A-549, MDA-MB-231, KB, KB-VIN and MCF-7. With IC 50 values in the low μM to nM level, most of the new analogues showed greater cytotoxicity activity than the reference compounds irinotecan and topotecan. Furthermore, compounds 12l (IC 50 , 1.2 nM) and 12k (IC 50 , 20.2 nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that integration of sulfonylpiperazinyl motifs into position-7 of camptothecin is an effective strategy for discovering new potent cytotoxic camptothecin derivatives. [ABSTRACT FROM AUTHOR]

Several neo-tanshinlactone derivatives with fluorine or the trifluoromethyl group were synthesized and their antiproliferative activities were evaluated. Compared with neo-tanshinlactone, fluorinated derivatives showed a broad activity spectrum against human tumor lines. For a neo-tanshinlactone chemical skeleton, these results also indicated that the hydrophobic group (methyl) at C-4 position and the carbon–carbon double bond of ring-D might play a crucial role in selective antibreast cancer activity. In addition, the synthesized compounds 10 and 17 showed a broad range of antiproliferative activity with IC50 values of 15–40 μM. [ABSTRACT FROM AUTHOR]

TaxchininA, with a 11(15→1)-abeo-taxaneskeleton, is a major, but inactive taxoid contained in leaves of Taxus chinensis. In our design of dual-functionalantitumor abeo-taxane derivatives, two fragmentsfrom antitumor agents with different molecular targets (the N-acyl-3′-phenylisoserine side chain from the antimitoticagent paclitaxel and an α,β-unsaturated carbonyl systemfrom NF-κB inhibitors) were incorporated into the scaffold oftaxchinin A. The resulting compounds displayed broad inhibitory effectsagainst proliferation of tumor cell lines, with notable selectivitytoward colon cancer, melanoma, and renal cancer, when evaluated inthe NCI-60 human tumor cell line screening panel. On the basis ofthe NCI-60 assay data, structure–activity relationship (SAR)correlations were elucidated. Mechanistic studies indicated that thisnew compound type can both destabilize microtubules and inhibit NF-κBactivation, thereby inducing tumor cell apoptosis. This first reportof the dual-functional taxoid-core compounds thus provides new opportunitiesfor future drug development based on natural axoid scaffolds. [ABSTRACT FROM AUTHOR]

Abstract: 1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, which share a fragment from (±)-3′-O-4′-O-bis(3,4-dimethoxycinnamoyl)-cis-khellactone (DMDCK) and 3′R,4′R-disubstituted-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DSP), exhibited remarkable chemoreversal activity on multidrug resistant human nasopharyngeal carcinoma (KB) when combined with three anticancer drugs, paclitaxel, vincristine and doxorubicin. Among 15 novel synthesized analogs, bis-trimethoxybenzoyl derivative 15 was the most active (340-fold more active than verapamil when used with vincristine) followed by two di-cinnamoyl derivatives, 10 and 11, and then di-cyclohexanecarbonyl derivative 9. All aliphatic chain derivatives, 3–5, showed no activity. Structure-activity relationship study indicated that a di-ester structure was critical to enhance the activity resulting from the maintenance of the spatial arrangement proposed by the pharmacophore based on the verapamil-binding site. Further mechanism of action study showed 15 inhibited mainly P-glycoprotein efflux pump function, while 13 exhibited an additional multidrug resistance-associated protein efflux pump function. [Copyright &y& Elsevier]

Novel dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate(DDB) analogues were designed and synthesized to improve their chemosensitizingaction on KBvin (vincristine-resistant nasopharyngeal carcinoma) cells,a multidrug resistant cell line overexpressing P-glycoprotein (P-gp).Structure–activity relationship analysis showed that aromaticand bulky aliphatic side chains at the 2,2′-positions effectivelyand significantly sensitized P-gp overexpressing multidrug resistant(MDR) cells to anticancer drugs, such as paclitaxel (TAX), vincristine(VCR), and doxorubicin (DOX). DDB derivatives 16and 23showed 5–10 times more effective reversal abilitythan verapamil (VRP) for TAX and VCR. Analogue 6alsoexhibited five times greater chemosensitizing effect against DOX thanVRP. Importantly, no cytotoxicity was observed by the active DDB analoguesagainst both non-MDR and MDR cells, suggesting that DDB analoguesserve as novel lead compounds for the development of chemosensitizersto overcome the MDR phenotype. The mechanism of action studies demonstratedthat effective inhibition of P-glycoprotein by DDB analogues dramaticallyelevated the cellular concentration of anticancer drugs. [ABSTRACT FROM AUTHOR]

A new matrine alkaloid derivative (+) -(14 β)-14-ethylmatridin-15-one ( 1) was isolated from the poisonous plant Oxytropis ochrocephala B unge. The structure was established by spectroscopic methods, including extensive 1D- and 2D- NMR experiments. [ABSTRACT FROM AUTHOR]

Ten alkaloids ( 1 – 10 ), with sophoridine ( 1 ) as the most abundant component, were obtained from the whole plants of Oxytropis ochrocephala Bunge. Furthermore, eight new sophoridine derivatives ( 11 – 16 , 20 , 21 ), with modification on the C-14 position of 1 were synthesized. All compounds ( 1 – 16 , 20 , 21 ) were evaluated for antiproliferative activity against five human tumor cell lines. Among them, the newly synthesized derivative 20 exhibited the best inhibitory activity against the tested cell lines. Its activity was increased by more than fourfold as compared with parent compound 1 . [ABSTRACT FROM AUTHOR]

The Asian plant Kalimeris shimadai has been used as food and ethnologic medicine for over a thousand years. In this study, we isolated and identified one new lignan, kalshiolin A (1), and 12 known lignans (2–13). The structures were characterized by the comprehensive analyses of spectroscopic data (HR-ESI-MS, IR, 1D, and 2D-NMR) and the absolute configuration of 1 was determined from ECD calculations. The new compound 1 was also screened for cytotoxic activity but did not show significant potency (IC50 35.9–43.3 μM) against A549, MDA-MB-231, MCF7, KB, and KB-VIN cell lines. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA's pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the impact of these groups on antiproliferative activity against five human tumor cell lines. A racemic 2-F-BA (compound 6) showed significantly improved antiproliferative activity, while each diastereomer exhibited similar effects. We also demonstrated that 2-F-BA is a topoisomerase (Topo) I and IIα dual inhibitor in cell-based and cell-free assays. A hypothetical mode of binding to the Topo I-DNA suggested a difference between the hydrogen bonding of BA and 2-F-BA to DNA, which may account for the difference in bioactivity against Topo I. [ABSTRACT FROM AUTHOR]

The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them ( 1c and 1h ) showed IC 50 values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c . Furthermore, immunocytochemical examination of 1c suggested a destabilization of microtubules, which was significantly different from the effect of IM , an indirubin derivative. [ABSTRACT FROM AUTHOR]

Six new Pd(II), Pt(II) and Ag(I) complexes, (1);{Pd (L 1)]2C 6 H 4 } 2 Cl 4 } (2); Pt(L 2)(DMSO)Cl; 3; {PtL 5 ] 2 C 6 H 4 } 2 ·PhCOO-⋅11NO 3 -; 4; {[Pt(L 4)] 2 C 6 H 4 }; the binuclear cyclometalated complex the polymer chain (5); {[PtL 5 ]C 6 H 4 }·NO 3 -}; and the polymeric silver species (6); Zn(L 6) 2 ·AgNO 3 ·CHCl 3 were synthesized and thoroughly characterized using X-ray diffraction and spectroscopic techniques (L 1 =(S,S)-1,4-i-PrOx] 2 C 6 H 4 } 2 Cl 4 , L 2 =Di(2,2-bis(4R-isopropyl-4,5-dihydro-oxazol-2-yl)acetonitrile) zinc (II) (B R1);L 3 = 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene (A R2); L 4 = 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene，L 5 =1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)-benzene，L 6 =Di(2,2-bis(4S-isopropyl-4,5-dihydrooxazol-2-yl)acetonitrile) zinc (II). Complexes 1-6 showed cytotoxic effects against human tumour cell lines, including a multidrug-resistant subline. Oxazoline and Pd complex 1 induced apoptosis in A549 cells. DFT calculations were also performed to exhibit the excellent bioactivity of complex 1 against A549, MDA-MB-231, and KB cells. Complex 1, with the best docking score and a stable interaction network within the binding site of the G-quadruplex, could stably interact with the G-quadruplex. Additionally, complex 1 was further used in the animal experiment of human lung adenocarcinoma cells in nude mice. By comparing with the model control group, the tumour volume, relative tumour volume and relative tumour proliferation rate T/C decreased significantly in the cisplatin group and compound 1 (complex 1) group. [Display omitted] • Six novel mononuclear, dinuclear and one-dimensional Pd(II), Pt(II) and Ag(I) complexes related with oxazoline ligands have been easily prepared in good yields from 68% to 92%. • Pd(II), Pt(II) and Ag(I) complexes showed different cytotoxic effects against human tumour cell lines, especially complex 1 could induce an apoptosis in cell A549. • DFT calculations and molecular docking simulations were performed to explore the possible interaction mechanism between these complexes and the binding pocket of G-quadruplex. • Comparing with the control group, the tumour volume, relative tumour volume and relative tumour proliferation rate T/C decreased significantly in the animal experiment by using complex 1. [ABSTRACT FROM AUTHOR]

Previously synthesized 2-(benzo[ b ]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B ( 1 , TEDB-TB) and 2-(naphth-1′-yl)-6,8,8-triethyldesmosdumotin B ( 2 ) showed potent activity against multiple human tumor cell lines, including a multidrug-resistant (MDR) subline, by targeting spindle formation and/or the microtubule network. Consequently, ester analogues of hydroxylated naphthyl substituted TEBDs ( 3 – 5 ) were prepared and evaluated for their effects on tumor cell proliferation and on tubulin assembly. Among all new compounds, compound 6 , a 4′-acetoxynaphthalen-1′-yl derivative, displayed the most potent antiproliferative activity (IC 50 0.2–5.7 μM). Selected analogues were confirmed to be tubulin assembly inhibitors in cell-free and cell-based assays using MDR tumor cells. The new analogues partially inhibited colchicine binding to tubulin, suggesting their binding mode would be different from that of colchicine. This observation was supported by computational docking model analyses. Thus, the newly synthesized triethylated chromones with esterified naphthalene groups have good potential for development as a new class of mitotic inhibitors that target tubulin. [ABSTRACT FROM AUTHOR]

The new quinolizidine alkaloid (+)-(14β)-14-ethylmatridin-15-one (I) is isolated from the poisonous plant Oxytropis ochrocephala. [ABSTRACT FROM AUTHOR]

Ten known alkaloids are isolated from Oxytropis ochrocephala with sophoridine (I) as the most abundant component. [ABSTRACT FROM AUTHOR]

Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4-disubstituted quinazolines (series 4 – 7 ) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b , was discovered with a good balance between high potency (IC 50 0.68 μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI 50 8.54 μM), as well as other human tumor cell lines (GI 50 < 20 μM), and a desirable druglike property profile with low log P value (2.54) and high aqueous solubility (95.6 μg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound. [ABSTRACT FROM AUTHOR]

In an ongoing investigation of 20-sulfonylamidine derivatives ( 9 , YQL-9a) of camptothecin ( 1 ) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan ( 3 ). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1 , 3 , and 9 . Novel key structural features related to the antiproliferative activities were identified by structure–activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π–π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity. [ABSTRACT FROM AUTHOR]

Thirteen new N -aryl 1,2,3,4-tetrahydroquinoline compounds ( 4a – f , 6a – c , and 8a – d ) were synthesized and evaluated for antitumor activity and drug-like properties. Compound 4a exhibited high inhibitory potency with low nanomolar GI 50 values of 16–20 nM in cellular assays, including excellent activity against the P-glycoprotein overexpressing cell line KBvin. Compound 4a inhibited colchicine binding to tubulin and tubulin assembly with an IC 50 value of 0.85 μM, superior to the reference compound CA4 (1.2 μM) in the same assay. In addition, 4a also exhibited highly improved water solubility (75 μg/mL) and a suitable log P value (3.43) at pH 7.4. With a good balance between antitumor potency and drug-like properties, compound 4a could be a new potential drug candidate for further development. Current results on SAR studies and molecular modeling provided more insight about this class of compounds as tubulin polymerization inhibitors targeting the colchicine site. [ABSTRACT FROM AUTHOR]

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel structurally diverse PEG-based 20( S )-CPT sulfonylamidine derivatives were designed, synthesized via a Cu-multicomponent reaction (MCR), and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Significantly, these derivatives exhibited comparable cytotoxicity against KBvin, while irinotecan was less active against this cell line. With a concise efficient synthesis and potent cytotoxic profiles, especially significant activity towards KBvin, these compounds merit further development as a new generation of CPT-derived PEG-conjugated drug candidates. [ABSTRACT FROM AUTHOR]

Curcumin ( 1 ) down-regulates the expression as well as phosphorylation of epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells expressing gefitinib-resistant EGFR. Thirty-seven newly synthesized curcumin analogues including dimethoxycurcumin ( 2 , DMC) were evaluated for their effects on EGFR expression as well as phosphorylation in two gefitinib-resistant lung adenocarcinoma cell lines, CL1-5 (EGFR wt ) and H1975 (EGFR L858R+T790M ). Based on the identified structure–activity relationships, methoxy substitution at C-3′, C-4′, or both positions favored inhibitory activity (compounds 1 , 2 , 5 , 8 – 15 , 17 , 36 ), while compounds with more polar substituents were generally less active in both cell lines. Compound 36 with a fluorine substituent at C-6′ and its protonated counterpart 2 did not lose activity, suggesting halogen tolerance. In addition, a conjugated linker was essential for activity. Among all evaluated curcumin derivatives, compound 2 showed the best inhibitory effects on both wild-type and mutant EGFR by efficiently inducing gefitinib-insensitive EGFR degradation. Compound 23 also reduced gefitinib-induced gastrointestinal damage in the non-transformed intestinal epithelial cell line IEC-18. [ABSTRACT FROM AUTHOR]

Little information has been reported on the antitumor effects of the diterpenoid alkaloid constituents of Aconitum plants, used in the herbal drug ‘bushi’. This study was aimed at determining the antitumor activities of Aconitum C 19 -and C 20 -diterpenoid alkaloids and synthetic derivatives against lung (A549), prostate (DU145), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines. Newly synthesized C 20 -diterpenoid alkaloid derivatives showed substantial suppressive effects against all human tumor cell lines tested. In contrast, natural and derivatized C 19 -diterpenoid alkaloids showed only a slight or no effect. Most of the active compounds were hetisine-type C 20 -diterpenoid alkaloids, specifically kobusine and pseudokobusine analogs with two different substitution patterns, C-11 and C-11,15. Notably, several C 20 -diterpenoid alkaloids were more potent against multidrug-resistant KB subline KB-VIN cells. Pseudokobusine 11-3′-trifluoromethylbenzoate ( 94 ) is a possible promising new lead meriting additional evaluation against multidrug-resistant tumors. [ABSTRACT FROM AUTHOR]

In our continuing search for natural product-based spin-labeled antitumor drugs, 20 novel spin-labeled camptothecin derivatives were synthesized via a Cu-catalyzed one pot reaction and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). Eighteen of the target compounds ( 9a , 9b , 9d – 9k , 9m – 9t ) exhibited significant in vitro antiproliferative activity against these four tested tumor cell lines. Compounds 9e and 9j (IC 50 0.057 and 0.072 μM, respectively) displayed the greatest cytotoxicity against the multidrug-resistant (MDR) KBvin cell line and merit further development into preclinical and clinical drug candidates for treating cancer including MDR phenotype. [ABSTRACT FROM AUTHOR]

One dimeric matrine-type alkaloid, ochrocephalamine A ( 1 ), was isolated from the poisonous plant Oxytropis ochrocephala Bunge. Its structure was elucidated by spectroscopic data and single-crystal X-ray diffraction. The insecticidal and cytotoxic activities of 1 were evaluated. [ABSTRACT FROM AUTHOR]

Twelvenovel 20-sulfonylamidine derivatives (9a–9l) of camptothecin (1) were synthesized viaa Cu-catalyzed three-component reaction. They showed similar or superiorcytotoxicity compared with that of irinotecan (3) againstA-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor celllines. Compound 9ademonstrated better cytotoxicity againstMDR cells compared with that of 1and 3.Mechanistically, 9ainduced significant DNA damage byselectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chkrelated DNA damage-response pathway. In xenograft models, 9ademonstrated significant activity without overt adverse effectsat 5 and 10 mg/kg, comparable to 3at 100 mg/kg. Notably, 9aat 300 mg/kg (i.p.) showed no overt toxicity in contrastto 1(LD5056.2 mg/kg, i.p.) and 3(LD50177.5 mg/kg, i.p.). Intact 9ainhibitedTopo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9ais a new class of TopoI inhibitor. 20-Sulfonylamidine 1-derivative 9amerits development as an anticancer clinical trial candidate. [ABSTRACT FROM AUTHOR]

Selective inhibition of cyclin-dependent kinase 8 (CDK8) has been recently regarded as a potential approach for cancer therapy. A series of novel CDK8 inhibitors with the pyridine core was identified via scaffold hopping from the known CDK8 inhibitor A-7. The new inhibitors were designed to improve the ligand efficiency so as to enhance drug-likeness. Most of the compounds showed significant inhibition against CDK8/cyclin C, and the most active compounds (5d , 5e and 7′) displayed IC 50 values of 2.4 nM, 5.0 nM and 7.7 nM, respectively. Preliminary kinase profiling of selected compounds against a panel of kinases from different families indicated that this compound class might selectively inhibit CDK8 as well as its paralog CDK19. Some compounds exhibited cellular activity in both MTT and SRB assays against a variety of tumor cells, including HCT-116, A549, MDA-MB-231, KB, KB-VIN and MCF-7. Further flow cytometry analysis revealed a dose-dependent G2/M phase arrest in MDA-MB-231 cells treated with compounds 6'a , 6'b , 6'j and 6'k. In addition, compound 6'k demonstrated moderate antitumor efficacy in HCT-116 mouse models, although unfavorable pharmacokinetic profiles were suggested by preliminary study in mice. The results provided a new structural prototype for the search of selective CDK8 inhibitors as antitumor agents. [Display omitted] • Potent CDK8 inhibitors with the pyridine core were identified. • Some compounds showed inhibitory activities against a panel of tumor cells. • Several compounds induced G2/M arrest in MDA-MB-231 cells. • Compound 6'k showed moderate antitumor efficacy in HCT-116 mouse models. [ABSTRACT FROM AUTHOR]

Abstract: The natural diterpenoid andrographolide (1) exhibits various biological activities. Seventeen derivatives of 1 were prepared via esterification and etherification of 14-dehydroxy-11,12-didehydroandrographolide (2). Most derivatives demonstrated significant inhibition against tumor cell growth. The most active compounds, 3b and 3c, had GI50 values of 1.46–9.19μM against A549, DU145, KB and KB-Vin tumor cells. In an immunocytochemical study, treatment with compound 3c disrupted microtubule dynamics in PC-3 cells, but caused no accumulation of metaphase cells, which is a phenotype dissimilar from that of 1. This difference suggests that structural modification of 1 resulted in a shift in the underlying molecular mechanism. [Copyright &y& Elsevier]

Abstract: In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (5–12, 15, 16, 19, and 20) are conjugates of curcumin (1) or methyl curcumin (2) with a flutamide- or bicalutamide-like moiety. Two compounds (22 and 23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, 21). Among the newly synthesized conjugates compound 15, a conjugate of 2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with 1 and 2 against both prostate tumor cell lines with IC50 values of 41.8μM (for LNCaP) and 39.1μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin–anti-androgen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that 1 accumulated mainly in the nuclei, while conjugate 6 was distributed in the cytosol. At the tested conditions, anti-androgens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression. [Copyright &y& Elsevier]

Abstract: In our ongoing study of the desmosdumotin C (1) series, twelve new analogues, 21–32, mainly with structural modifications in ring-A, were prepared and evaluated for in vitro antiproliferative activity against several human tumor cell lines. Among them, the 4′-iodo-3,3,5-tripropyl-4-methoxy analogue (31) showed significant antiproliferative activity against multiple human tumor cell lines with ED50 values of 1.1–2.8μM. Elongation of the C-3 and C-5 carbon chains reduced activity relative to propyl substituted analogues; however, activity was still better than that of natural compound 1. Among analogues with various ether groups on C-4, compounds with methyl (2) and propyl (26) ethers inhibited cell growth of multiple tumor cells lines, while 28 with an isobutyl ether showed selective antiproliferative activity against lung cancer A549 cells (ED50 1.7μM). The gene expression profiles showed that 3 may modulate the spindle assembly checkpoint (SAC) and chromosome separation, and thus, arrest cells at the G2/M-phase. [Copyright &y& Elsevier]

[Display omitted] Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials. [ABSTRACT FROM AUTHOR]

A new biological scaffold was produced by replacing the 6π-electron phenyl ring-B of a natural flavone skeleton with a 10π-electron benzothiophene (BT). Since aromatic rings are important for ligand protein interactions, this expansion of the π-electron system of ring-B might change the bioactivity profile. One of the resulting novel natural product-inspired compounds, 2-(benzo[ b ]thiophen-3-yl)-5-hydroxy-7-isopropoxy-6-methoxyflavone (6), effectively arrested the cell cycle at the G2/M phase and displayed significant antiproliferative effects with IC 50 values of 0.05–0.08 μM against multiple human tumor cell lines, including a multidrug resistant line. A structure-activity relationship study revealed that a 10π-electron system with high aromaticity, juxtaposed 4-oxo and 5-hydroxy groups, and 7-alkoxy groups were important for potent antimitotic activity. Interestingly, two BT-flavonols (3-hydroxyflavone), 16 and 20 , with 3-hydroxy and 5-alkoxy groups, induced distinct biological profiles affecting the cell cycle at the G1/S phase by inhibition of DNA replication through an interaction with topoisomerase I. [Display omitted] • Benzo[ b ]thiophenyl(BT) chromone was discovered as a new antitumor scaffold. • Small changes of functional groups induced distinct biological profiles. • 5-OH BT-chromone derivatives arrested cell cycle progression at the G2/M phase by inhibition of tubulin assembly. • 3-OH BT-chromone derivatives affected the G1/S phase by inducing DNA damage through inhibition of Topo I. • The binding mode to the target protein was discussed by a docking model. [ABSTRACT FROM AUTHOR]

In this paper, it was assumed that a synchronous generator in a customer system was connected to a distribution system via the fault current limiter (FCL). We theoretically investigated the influence of the output power of the generator on the limiting effect of the fault current when a three-phase short-circuit fault occurs. It was shown that the fault current out of the customer system, limited by the FCL, rises with the output power of the generator. It was found that the larger the output, the higher the fault current at the fault point is when the limiting resistance is less than 15 Ω in the case of the resistive-type FCL. On the other hand, the fault current at the fault point decreases with an increase in the output power for a limiting resistance more than 15 Ω. In contrast, it was found that the suppressing effect on the fault current at the fault point due to the inductive-type FCL hardly depends on the output power. © 2004 Wiley Periodicals, Inc. Electr Eng Jpn, 148(3): 15–24, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.10357 [ABSTRACT FROM AUTHOR]

A novel nonlinear decentralized robust governor control for hydroturbine-generator sets in multi-machine power systems is suggested in this paper. The nonelastic water hammer effect and disturbances are considered in the modeling. The advanced differential geometry theory, nonlinear robust control theory and the dynamic feedback method are combined to solve the problem. The nonlinear decentralized robust control law for the speed governor of hydroturbine-generators has been derived. The input signals to the proposed controller are all local measurements and independent to the system parameters. The derived control law guarantees the integrated system stability with disturbance attenuation, which is significant to the real power system application. Computer tests on an 8-machine, 36-bus power system show clearly the effectiveness of the new control strategy in transient stability enhancement and disturbance attenuation. The computer test results based on the suggested controller are compared favorably with those based on the conventional linear governor control. [Copyright &y& Elsevier]

This paper presents an integrated linear and nonlinear control for a unified power flow controller (UPFC). Three Pulse-Width Modulation (PWM) parameters of the UPFC are controlled by Proportional-Integral-Differential (PID) laws, and an analytic expression of the nonlinear control law for the UPFC phase angle ρ 2 is obtained by a feedback linearization method. This combined linear and nonlinear control strategy enables the UPFC to improve power system transient stability and dynamic performance effectively. Simulation results illustrate the effectiveness of the developed control strategy. [ABSTRACT FROM AUTHOR]

A multi-target oriented optimal control strategy for FACTS devices installed in multi-machine power systems is presented in this paper, which is named the intelligent optimal sieving control (IOSC) method. This new method divides the FACTS device output region into several parts and selects one typical value from each part, which is called output candidate. Then, an intelligent optimal sieve is constructed, which predicts the impacts of each output candidate on a power system and sieves out an optimal output from all of the candidates. The artificial neural network technologies and fuzzy methods are applied to build the intelligent sieve. Finally, the real control signal of FACTS devices is calculated according to the selected optimal output through inverse system method. Simulation has been done on a three-machine power system and the results show that the proposed IOSC controller can effectively attenuate system oscillations and enhance the power system transient stability. [Copyright &y& Elsevier]

α-Trifluoromethyl chalcones were prepared and evaluated for their antiproliferative activities against androgen-independent prostate cancer cell lines as well as five additional types of human tumor cell lines. The most potent chalcone 5 showed superior antitumor activity in vivo with both oral and intraperitoneal administration at 3 mg/kg. Cell-based mechanism of action studies demonstrated that 5 induced cell accumulation at sub-G1 and G2/M phases without interfering with microtubule polymerization. Furthermore, several cancer cell growth-related proteins were identified by using chalcone 5 as a bait for the affinity purification of binding proteins. [ABSTRACT FROM AUTHOR]

This paper describes power swing damping control by HVDC power modulation. In a hybrid system (where the ac transmission system and the HVDC system compose a loop transmission system), damping control of power swing by control of HVDC power is called power modulation control. The new HVDC link between the Shikoku and Kansai power systems forms a loop transmission system consisting of the existing ac transmission system and the new HVDC transmission system; therefore, power modulation control can be applied for stabilization of the ac system. This paper deals with a newly developed power modulation control system to damp two power-swing modes occurring in a 60-Hz interconnected system and the neighboring power system to the HVDC converter station. Characteristics of power swings in an ac system, principles of power swing damping control by power modulation, the control system design method, and the results of verification tests by digital and analog simulators are described. It is shown that the developed power modulation system applied to the HVDC link is effective for damping two power swing modes. © 1998 Scripta Technica, Electr Eng Jpn, 124(3): 10–18, 1998 [ABSTRACT FROM AUTHOR]

Large-capacity adjustable speed machines (ASMs) at pumped storage power stations have been put into full operation and their operating characteristics have been highly evaluated from the viewpoint of power system operation. The output power (input power) of ASMs can be controlled very quickly by applying a vector control scheme to the excitation control. This quick responsive feature of ASMs can make it possible to improve the stability of the neighbor subpower system. For improvement of transient stability, the output power of ASMs is reduced very quickly in order to control the acceleration of neighbor generators during and after transmission line faults. For improvement of dynamic stability, the output power of ASMs is modulated in accordance with the stabilizing signals detected from the swing of generator rotor or the power flow fluctuation on the transmission line. This paper describes the design concepts and method of control system for improving the transient and dynamic stability and proposes a power system stabilizing control system. The effects of the proposed stabilizing control system have been verified by a power system simulator. © 1997 Scripta Technica, Inc. Electr Eng Jpn, 121(2): 27–36, 1997 [ABSTRACT FROM AUTHOR]

Recently, power systems have become larger and more complex. Particularly, the looping of power systems is becoming highly desirable to improve the stability. The main features of such looped power systems are: (i) comparatively fewer losses; and (ii) improved angle stability as well as voltage stability. However, these systems have demerits, such as, in case of route off fault in a loop power system, power disturbances increase more and more, etc. If these demerits are overcome, the loop power systems are going to be more beneficial. In an attempt to obtain a solution to such problems, this paper describes several results of applying a high-speed phase shifter in the control system of a loop power system. [ABSTRACT FROM AUTHOR]