P388 Murine Leukemia Cell Line Research Articles

Ciliatonoids D–M, highly modified limonoids from the twigs of Toona ciliata

A new ring-intact limonoid, ciliatonoid D (1), five new 7,8-seco limonoids, ciliatonoids E–I (2–6), three new 7,8-seco-29-nor limonoids, ciliatonoids J–L (7–9), and a new 7,8:9,11-diseco limonoid, ciliatonoid M (10), together with eleven known limonoids were isolated from the twigs of Toona ciliata. Their structures were established by comprehensive analyses of spectroscopic, electronic circular dichroism, single-crystal X-ray diffraction data. Compound 6 bears an uncommon 1,30-oxygen bridge. Compound 10 represents a rare example of a structure with 9,11-seco limonoid from Meliaceae. The orientation of the 14,15-epoxy moiety in a known limonoid, toonayunnanae C (12), was revised as in a β-orientation by quantum NMR calculations with ML-J-DP4 probability analysis. Compound 9 and a known analogue, toonanoronoid C (11), were found to show modest in vitro cytotoxicity against HL-60 (human premyelocytic leukemia) and P-388 (murine leukemia) cell lines.

Antiproliferative Activity of Triterpenoid and Steroid Compounds from Ethyl Acetate Extract of Calotropis gigantea Root Bark against P388 Murine Leukemia Cell Lines

Calotropis gigantea has been known to produce bioactive secondary metabolites with antiproliferative activities against cancer cells. Herein, we extracted the secondary metabolites using ethyl acetate from its root bark and further tested its antiproliferative activities against P388 murine leukemia cell lines. The subfractions from the ethyl acetate extract was obtained from Vacuum Liquid Column Chromatography (VLCC), and followed by Gravity Column Chromatography (GCC). The subfraction C2 and D1 were identified to contain triterpenoids and steroids with the most potent cytotoxicity against Brine Shrimp Lethality Test (BSLT). A 3-(4,5-dimethylthiazol-2-yl) -2-5 diphenyl tetrazolium bromide (MTT) assay suggested that ethyl acetate extract has the highest antiproliferative activities against P388 murine leukemia cell lines (IC50 = 21.79 μg/mL), as opposed to subfraction C2 (IC50 = 50.64 µg/mL) and subfraction D1 (IC50 = 49.33 µg/mL). The compound identified in subfraction C2 and D1 are taraxerol acetate and calotropone, respectively. Though taraxerol acetate and calotropone were active in inhibiting the leukemic cell lines, their IC50s were lower than the ethyl acetate extract, which is probably due to the synergism of the secondary metabolites.

Activity of Cytotoxic Flavanoids against a P-388 Murine Leukemia Cell Line from the Stem Bark of Aglaia elliptica (Meliaceae)

800x600 Two mixture s of flavanoid compounds ( 1 and 2 ), a mixture of catechin ( 1a ) and epicatechin ( 1b ) , and a mixture of gallocatechin ( 2a ) and epigallocatechin ( 2b ) , were isolated from the active fraction of the stem bark of Aglaia elliptica methanol extract. The chemical structure of the compounds w as identified with spectroscopic data , including UV, IR, NMR ( 1 H, 13 C, DEPT 135°, HMQC, HMBC, 1 H- 1 H COSY) , and MS, and additionally compared with previously reported spectral data. All compounds were evaluated for their cytotoxic effects against P-388 murine leukemia cells. Compound 2 showed cytotoxicity against the P-388 murine leukemia cell , with an IC 50 value of 7.79 µg/mL, but compound 1 wa s found not to be active ( more than 100 µg/mL ) . Normal 0 false false false EN-ID X-NONE X-NONE

7α-Hydroxyfriedelan-3-one-26-ol-29-oic acid and other Constituents from Pileostegia viburnoides var. glabrescens

Phytochemical investigation of the roots and rhizomes of Pileostegia viburnoides var. glabrescens led to the isolation and identification of 31 compounds (1-31), 25 of which (1-2, 4-7, 9-12, 15-18, 21-31) were isolated from the Pileostegia genus for the first time. 7α-Hydroxyfriedelan-3-one-26-ol-29-oic acid (1) is a new friedelane-type triterpene. The structure of n-butyl-β-D-fructopyranoside (2) was determined by single-crystal X-ray diffraction. Compounds 4 and 12 displayed marginal cytotoxicity against the P388 murine leukemia cell line with IC₅₀ values of 13.4 μM and 25.0 μM, respectively. Compound 23 exhibited marginal anti-inflammatory activity by the inhibition of lipopolysaccharide induced nitric oxide production in RAW 264.7 macrophage cells, with an IC₅₀ value of 32.0 μM. Compounds 3, 8-10, 25, and 27 were phytotoxic to the dicot Lactuca sativa (lettuce) and/or the monocot Agrostis stolonifera (bentgrass).

Concise Synthesis and Biological Assessment of (+)‐Neopeltolide and a 16‐Member Stereoisomer Library of 8,9‐Dehydroneopeltolide: Identification of Pharmacophoric Elements

We describe herein a concise synthesis of (+)-neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond-forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross-metathesis reaction directed by H-bonding, and a ring-closing metathesis conducted under non-high dilution conditions. Moreover, we developed a 16-member stereoisomer library of 8,9-dehydroneopeltolide to systematically explore the stereostructure-activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HT-1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure-activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency.

Synthesis and characterization of new trimetallic complexes with {Pt2Au(μ-S)2}n+ (n = 2, 3) cores containing C, N and N, N donor ligands

Reactions of the dinuclear platinum(II) sulfide complex [Pt2(μ-S)2(PPh3)4] with a range of gold(III) dichloride complexes [AuLCl2] containing C, N- or N, N-cycloaurated ligands L gives a new series of dicationic adducts [Pt2(μ-S)2(PPh3)4AuL]2+, isolated as their PF6− salts. The complexes investigated are [Au{C6–H4(CH2NMe2)-2}Cl2], [Au{C6H3(CH2NMe2)-2-(OMe)-5}Cl2], [Au{NC5H4(CH2C6H4)-2}Cl2], [Au{NC5H4(COC6H4)-2}Cl2] and [Au{NC5H4(CONH)-2}Cl2]. An X-ray structure determination on the picolinamide-derived complex [Pt2(μ-S)2(PPh3)4Au{NC5H4(CONH)-2}](PF6)2 was not of sufficiently high quality for detailed discussion, but confirmed the atom connectivity. Reactions of [Pt2(μ-S)2(PPh3)4] with [AuCl2(bipy)]PF6 (L=bipy=2,2’-bipyridine) and [AuCl2(phen)]Cl (L=phen=1,10-phenanthroline) gives the corresponding tricationic adducts [Pt2(μ-S)2(PPh3)4AuL]3+, also isolated as their PF6− salts. The complexes are characterised by NMR spectroscopy, electrospray mass spectrometry and microelemental analyses. Biological assay data of a selection of these new complexes towards the P388 murine leukemia cell line, as well as a range of antimicrobial tests, reveals overall low activity compared to other cycloaurated gold(III) complexes.

Antioxidant, antibacterial and cytotoxic activities of essential oils and ethanol extracts of selected South East Asian herbs

Antioxidant, antibacterial and cytotoxic activities of essential oils and ethanol extracts of four South East Asian traditional herbs were investigated. Their essential oils were analyzed byGas chromatography mass spectrometry (GC-MS) and a total of 57 types of volatile organics were identified. Artemisia argyi, Centella asiatica, Cosmos caudatus, and Polygonum hydropiper contained 30, 20, 19 and 21 types of volatiles, respectively. The major volatile hydrocarbon for A. argyi, C. asiatica and C. caudatus was a-cadinene while dodecanal was the major component for P. hydropiper. Total phenolic content of ethanol extracts analyzed by Folin-Ciocalteu method were in the range of 31.58±3.08 to 84.03±8.15 mg GAE/100 g. Free radical-scavenging activity of the four ethanol extracts were in the range of 654.43±17.22 to 5857.54±164.13 mg AA/100 g; while ferric-reducing antioxidant power were in the range of 26.58±1.10 to 50.08±0.71 mg AAE/g. Essential oils of all four species were inactive for both these assays. Ethanol extracts of these herbs were active against 60 to 80% of ten strains of human pathogenic bacteria tested, compared to 20 to 50% inhibition for essential oils. Only ethanol extracts of A. argyi and C. caudatus showed activity against P388 murine leukemia cell line, while all the essential oils were inactive. Key words: Antimicrobial, antioxidant, cytotoxicity, ethanol extracts, essential oils, total phenolic content.

Lagunamides A and B: Cytotoxic and Antimalarial Cyclodepsipeptides from the Marine Cyanobacterium Lyngbya majuscula

Lagunamides A (1) and B (2) are new cyclic depsipeptides isolated from the marine cyanobacterium Lyngbya majuscula obtained from Pulau Hantu Besar, Singapore. The planar structural characterization of these molecules was achieved by extensive spectroscopic analysis, including 2D NMR experiments. In addition to Marfey's method and (3)J(H-H) coupling constant values, a modified method based on Mosher's reagents and analysis using LC-MS was deployed for the determination of the absolute configuration. Lagunamides A and B displayed significant antimalarial properties, with IC(50) values of 0.19 and 0.91 μM, respectively, when tested against Plasmodium falciparum. Lagunamides A and B also possessed potent cytotoxic activity against P388 murine leukemia cell lines, with IC(50) values of 6.4 and 20.5 nM, respectively. Furthermore, these cyanobacterial compounds exhibited moderate antiswarming activities when tested against Pseudomonas aeruginosa PA01.

Vanchrobactin and anguibactin siderophores produced by Vibrio sp. DS40M4.

The marine bacterium Vibrio sp. DS40M4 has been found to produce a new triscatechol amide siderophore, trivanchrobactin (1), a related new biscatecholamide compound, divanchrobactin (2), and the previously reported siderophores vanchrobactin (3) and anguibactin (4). Vanchrobactin is comprised of l-serine, d-arginine, and 2,3-dihydroxybenzoic acid, while trivanchrobactin is a linear trimer of vanchrobactin joined by two serine ester linkages. The cyclic trivanchrobactin product was not detected. In addition to siderophore production, extracts of Vibrio sp. DS40M4 were screened for biologically active molecules; anguibactin was found to be cytotoxic against the P388 murine leukemia cell line (IC(50) < 15 microM).

Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of Norzoanthamine and Zoanthamine

The zoanthamine alkaloids, a type of heptacyclic marine alkaloid isolated from colonial zoanthids of the genus Zoanthus sp., have distinctive biological and pharmacological properties in addition to their unique chemical structures with stereochemical complexity. Namely, norzoanthamine (1) can suppress the loss of bone weight and strength in ovariectomized mice and has been expected as a promising candidate for a new type of antiosteoporotic drug, while zoanthamine (2) has exhibited potent inhibitory activity toward phorbol myristate-induced inflammation in addition to powerful analgesic effects. Recently, norzoanthamine derivatives were demonstrated to inhibit strongly the growth of P-388 murine leukemia cell lines, in addition to their potent antiplatelet activities on human platelet aggregation. Their distinctive biological properties, combined with novel chemical structures, make this family of alkaloids extremely attractive targets for chemical synthesis. However, the chemical synthesis of the zoanthamine alkaloids has been impeded owing to their densely functionalized complex stereostructures. In this paper, we report the first and highly efficient total syntheses of norzoanthamine (1) and zoanthamine (2) in full detail, which involve stereoselective synthesis of the requisite triene (18) for an intramolecular Diels-Alder reaction via the sequential three-component coupling reactions, the key intramolecular Diels-Alder reaction, and subsequent crucial bis-aminoacetalization as the key steps. Ultimately, we achieved the total synthesis of norzoanthamine (1) in 41 steps with an overall yield of 3.5 % (an average of 92 % yield each step) and that of zoanthamine (2) in 43 steps with an overall yield of 2.2 % (an average of 91 % yield each step) starting from (R)-5-methylcyclohexenone (3), respectively.

Tetranortriterpenoids from the Leaves of Cipadessa cinerascens

Seven known and six new tetranortriterpenoids, cineracipadesins A-F (1-6), were isolated from the leaves of Cipadessa cinerascens. Compound 1 has a mexicanolide-type structural skeleton with a rare 9alpha,11alpha-epoxide ring; compound 2 has a methyl angolensate-type structure with 9,11-dihydroxy groups, representing the first example of a precursor of a trijugin-type limonoid; and 3 is the first reported methyl angolensate-type limonoid with a ketone group at ring C. Their structures were determined with extensive spectroscopic analysis. X-ray crystallography confirmed the structure of 1. The ability of compounds 1-7 to inhibit the growth of the P-388 murine leukemia cell line was evaluated.

Synthesis of (+)-Neopeltolide

The marine macrolide neopeltolide shows cytotoxicity against A-549 human lung ­adenocarcinoma, the NCI-ADR-RES human ovarian sarcoma and P388 murine leukemia cell lines. It also inhibits the growth of the fungal pathogen Candida albicans.

Evolving Trends in the Dereplication of Natural Product Extracts. 2. The Isolation of Chrysaibol, an Antibiotic Peptaibol from a New Zealand Sample of the Mycoparasitic Fungus Sepedonium chrysospermum

By the application of an HPLC bioactivity profiling/microtiter technique in conjunction with capillary NMR instrumentation and access to the AntiMarin database the conventional evaluation/isolation dereplication/characterization procedures can be dramatically truncated. This approach is illustrated using the isolation of a new peptaibol, chrysaibol (1), from a New Zealand isolate of the mycoparasitic fungus Sepedonium chrysospermum. The unique nature of chrysaibol was recognized by bioactivity-guided fractionation using HPLC bioactivity profiling/microtiter plate analysis in conjunction with capillary NMR instrumentation and the AntiMarin database. 2D NMR techniques, in combination with MS fragmentation experiments, determined the planar structure of chrysaibol (1), while the absolute configurations of the amino acid residues were defined by Marfey's method. Chrysaibol (1) was cytotoxic against the P388 murine leukemia cell line (IC50 6.61 microM) and showed notable activity against Bacillus subtilis (IC50 1.54 microM).

Synthesis and Evaluation of Novel N-Substituted-6-methoxynaphthalene-2-Carboxamides as Potential Chemosensitizing Agents for Cancer

A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6-methoxynaphthalene-2-carboxamides 8-13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2-7. Compounds 8-12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Compounds 8-12 were non-toxic at lower dose of 20 microg/ml, and effectively reversed adriamycin resistance. However, at higher doses (40, 80 microg/ml) they showed significant cytotxicity and hence reversal potency was not determined at these concentrations.

Recent Progress in the Synthesis of Bioactive Polycyclic Natural Products

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Neopeltolide, a Macrolide from a Lithistid Sponge of the Family Neopeltidae

A new marine-derived macrolide designated as neopeltolide (1) has been isolated from a deep-water sponge of the family Neopeltidae. Its structure was elucidated on the basis of spectroscopic data interpretation. Neopeltolide (1) is a potent inhibitor of the in vitro proliferation of the A-549 human lung adenocarcinoma, the NCI-ADR-RES human ovarian sarcoma, and the P388 murine leukemia cell lines, with IC50's of 1.2, 5.1, and 0.56 nM, respectively. Neopeltolide (1) also inhibited the growth of the fungal pathogen Candida albicans with a minimum inhibitory concentration of 0.62 microg/mL.

Recent progress in the synthesis of bioactive polycyclic natural products

Abstract The zoanthamine alkaloids, a type of heptacyclic marine alkaloid isolated from colonial zoanthids of the genus Zoanthus sp., have distinctive biological and pharmacological properties as well as their unique chemical structures with stereochemical complexity. Namely, norzoanthamine can suppress the loss of bone weight and strength in ovariectomized mice and has been considered a promising candidate for an antiosteoporotic drug, whereas zoanthamine has exhibited potent inhibitory activity toward phorbol myristate-induced inflammation in addition to powerful analgesic effects. Recently, norzoanthamine derivatives were demonstrated to inhibit strongly the growth of P-388 murine leukemia cell lines, in addition to their potent antiplatelet activities on human platelet aggregation. These distinctive biological properties, combined with novel chemical structures, make this family of alkaloids extremely attractive targets for chemical synthesis. However, the chemical synthesis of the zoanthamine alkaloids has been impeded owing to their densely fuctionalized complex stereostructures. We report here the first and highly stereoselective total syntheses of norzoanthamine and zoanthamine, which involves stereoselective synthesis of the requisite triene for intramolecular Diels-Alder reaction via three-component coupling reactions, a key intramolecular Diels-Alder reaction, and subsequent crucial bis-aminoacetalization as the key steps.

Pteratides I—IV, New Cytotoxic Cyclodepsipeptides from the Malaysian Basidiomycete Pterula sp.

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Pteratides I−IV, New Cytotoxic Cyclodepsipeptides from the Malaysian Basidiomycete Pterula sp.

Four new cyclodepsipeptides, pteratides I-IV (1-4), have been isolated from the extract of a Pterula species collected from a Malaysian tropical forest. Homonuclear and heteronuclear 2D NMR techniques as well as MS fragmentation experiments, in combination with methanolysis, determined the gross structures of the peptides and showed that pteratides I and II each contained the nonproteinogenic amino acid 4-methylproline. The absolute configurations of the amino acids in pteratides I-IV were established using Marfey's method. Pteratides I and II are each potently cytotoxic against the P388 murine leukemia cell line (IC50 values of 41 and 40 nM, respectively). Pteratides III and IV show weaker, but still notable, activity with IC50 values of 7.4 and 2.9 microM, respectively.

Design, synthesis and evaluation of naphthalene-2-carboxamides as reversal agents in MDR cancer

A novel class of molecules with structure N-[3-(4-substituted-1-piperazinyl) propyl]-6-methoxy naphthalene-2-carboxamides were designed by generating a pharmacophore for potent MDR reversal activity, using Elacridar (GF 120918) as a query molecule and using MOE software. They were synthesized by condensing 6-methoxynaphthalene-2-carboxylic acid with N-[3-(4-substituted-1-piperazinyl) propyl] amines in the presence of DCC in DMF. They were evaluated in P388 murine lymphocytic leukemia cell line (P388) in vitro using SRB assay for cytotoxicity and in adriamycin-resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Test compounds were non-toxic at the doses studied (upto 80 μg/ml). They effectively reversed adriamycin resistance at the doses studied (40 and 80 μg/ml). The percentage enhancement in adriamycin activity was in the range 33.58 −90.67 (at 40 μg/ml) and 8.80–46.04 (at 80 μg/ml) and the corresponding reversal potency values were in the range 1.33–1.90 and 1.08–1.46, respectively. Test compounds 2, 3, and 5 exhibited better activity as compared to the standard resistant reversal agent (Verapamil), at same concentration.