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Biomedical subjects

J L McLaughlin

Publications and source records attributed to J L McLaughlin.

At least 19 recordsLinked to original sources
PubMed2003

Determination of huperzine A in formulated products by reversed-phase-liquid chromatography using diode array and electrospray ionization mass spectrometric detection.

A precise and selective high-performance liquid chromatographic (HPLC) method with diode-array detection for quantifying huperzine A in formulated products was developed and validated. A liquid chromatographic-mass spectrometric (LC/MS) procedure was devised to confirm the HPLC method. Huperzine A was dissolved in 1,2-dichloroethane, chromatographed on a YMCBasic C18 column, and detected at 308 nm. A gradient mobile phase of 10 mM ammonium acetate (pH = 3.5)--methanol was used. Identification was based on retention time, UV spectra and mass spectra by comparison with a commercial standard. The UV peak areas were used for quantitation of huperzine A content. The correlation coefficient (R2) of the calibration curve was 1 over the range 0.8-11.6 microg/ml. Overall recovery of huperzine A was 103.9% +/- 1.8 (mean +/- SD). Relative standard deviations for intra- and interday precision were < 2%.

Alkaloids↗
PubMed2002

Development of a paw paw herbal shampoo for the removal of head lice.

The development and clinical testing of an herbal lice removal shampoo, containing a standardized extract of paw paw, thymol, and tea tree oil, are described. All of these ingredients were selected for their ability to deplete adenosine triphosphate (ATP) levels and, thus, prevent ATP-dependent pesticide resistance. Optimum concentrations of the ingredients, treatment times, and dosing schedules were established through in vitro tests with head lice. In addition to pilot studies involving 21 participants, a final clinical trial, using the optimum shampoo formulation in 16 participants, demonstrated 100% effectiveness in removing head lice and nits.

Adult↗
PubMed2001

MtrC, an outer membrane decahaem c cytochrome required for metal reduction in Shewanella putrefaciens MR-1.

Shewanella putrefaciens is a facultative anaerobe that can use metal oxides as terminal electron acceptors during anaerobic respiration. Two proteins, MtrB and Cct, have been identified that are specifically involved in metal reduction. Analysis of S. putrefaciens mutants deficient in metal reduction led to the identification of two additional proteins that are involved in this process. MtrA is a periplasmic decahaem c-type cytochrome that appears to be part of the electron transport chain, which leads to Fe(III) and Mn(IV) reduction. MtrC is an outer membrane decahaem c-type cytochrome that appears to be required for the activity of the terminal Fe(III) reductase. Membrane fractions of mutants deficient in MtrC exhibited a decreased level of Fe(III) reduction compared with the wild type. We suggest that MtrC may be a component of the terminal reductase or may be required for its assembly.

Anaerobiosis↗
PubMed1999

Two bioactive mono-tetrahydrofuran acetogenins, annoglacins A and B, from Annona glabra.

Two new bioactive mono-THF Annonaceous acetogenins, annoglacins A and B, have been isolated from the fractionated ethanolic extracts of the leaves of Annona glabra, directing the fractionation with the brine shrimp lethality test (BST). Their structures were elucidated based on spectroscopic and chemical methods and the absolute stereochemistries were determined by the advanced Mosher ester method. Annoglacins A and B were selectively 1000 and 10,000 times, respectively, more potent than adriamycin against the human breast carcinoma (MCF-7) and pancreatic carcinoma (PACA-2) cell lines in our panel of six human solid tumor cell lines.

Animals↗
PubMed1999

Asitrilobins A and B: cytotoxic mono-THF annonaceous acetogenins from the seeds of Asimina triloba.

The seeds of Asimina triloba have yielded two novel cytotoxic mono-tetrahydrofuran (THF) Annonaceous acetogenins, asitrilobins A (1) and B (2). In addition, annonacin, asimin and asiminacin, which are known, and annomontacin and xylomaticin, which are known but are new in this species, were obtained. Compounds 1 and 2 have a relative stereochemical relationship of erythro/cis/threo across the mono-THF ring with its two flanking hydroxyls and they, thus, represent a new type of acetogenin. Their structures were established on the basis of chemical and spectral evidence. 1 and 2 showed potent bioactivities in the brine shrimp lethality test (BST) and among six human solid tumor cell lines with notable selectivity for the pancreatic cell line (MIA PaCa-2) at ten to one-hundred times the potency of adriamycin.

Animals↗
PubMed1999

Goniotriocin and (2,4-cis- and -trans)-xylomaticinones, bioactive annonaceous acetogenins from Goniothalamus giganteus.

Goniotricin (1) and a mixture of (2,4-cis and -trans)-xylomaticinones (2), new bioactive annonaceous acetogenins, were isolated from the bark of Goniothalamus giganteus (Annonaceae) by activity-directed fractionation using the brine shrimp lethality test. Compound 1 is the first nonadjacent ring-hydroxylated bis-tetrahydrofuran (THF) acetogenin to be reported. Compound 2 is the cis- and trans-ketolactone mixture of xylomaticin, a known compound whose absolute stereochemistry has not been previously determined. The absolute stereochemistry of 2 was determined by the advanced Mosher's ester method. Both 1 and 2 showed significant and selective cytotoxicities among the six tumor cell lines in our seven-day MTT human solid tumor panel. In the yellow fever mosquito larvae microtiter assay, 1 was quite active, with an ED50 value of 3. 5 microg/mL.

Animals↗
PubMed1999

Chemical defense in the zebra swallowtail butterfly, Eurytides marcellus, involving annonaceous acetogenins.

Few herbivores feed on the foliage of the North American paw paw tree, Asimina triloba; notable exceptions are the larvae of the zebra swallowtail butterfly, Eurytides marcellus. Toxic annonaceous acetogenins, produced by A. triloba, are responsible for the relative unpalatability of the leaves. Acetogenins found in A. triloba extracts are potent pesticidal and antineoplastic agents and have emetic activity in vertebrates. In this study, partitioned aqueous MeOH fractions of the bioactive CH2Cl2 extracts, of freeze-dried and pulverized larvae, and of mature butterflies revealed acetogenin content through the use of HPLC coupled to tandem MS (LC-MS/MS). This sensitive technique provides an uncomplicated method for the detection of trace compounds and, in this instance, has confirmed tissue presence of acetogenins that serve a probable role as chemical defense agents against bird predation in zebra swallowtail larvae and adults.

Animals↗
PubMed1999

Annonaceous acetogenins: recent progress.

The Annonaceous acetogenins are promising new antitumor and pesticidal agents that are found only in the plant family Annonaceae. Chemically, they are derivatives of long-chain fatty acids. Biologically, they exhibit their potent bioactivities through depletion of ATP levels via inhibiting complex I of mitochondria and inhibiting the NADH oxidase of plasma membranes of tumor cells. Thus, they thwart ATP-driven resistance mechanisms. This review presents the progress made in the chemistry, biology, and development of these compounds since December 1995.

Animals↗
PubMed1999

Two novel acetogenins, annoglaxin and 27-hydroxybullatacin, from Annona glabra.

Two new bioactive Annonaceous acetogenins, annoglaxin (1) and 27-hydroxybullatacin (2), have been isolated from the fractionated ethanolic extracts of the leaves of Annona glabra, directing the fractionation with the brine shrimp lethality test (BST). The structures of 1 and 2 were elucidated on the basis of spectroscopic and chemical methods, and the absolute stereochemistries were determined by the advanced Mosher ester method. 1 presents unusual features of an OH at C-8 and a carbonyl at C-12 and, while less potent than 2, shows interesting selectivity for the human breast carcinoma (MCF-7) cell line. Compound 2 was at least 100 000 times more potent than adriamycin against the human kidney carcinoma (A-498), prostate carcinoma (PC-3), and pancreatic carcinoma (PACA-2) cell lines in our panel of six human solid tumor cell lines.

4-Butyrolactone↗
PubMed1999

Annocherin and (2,4)-cis- and trans-annocherinones, monotetrahydrofuran Annonaceous acetogenins with a C-7 carbonyl group from Annona cherimolia seeds.

The new cytotoxic monotetrahydrofuran Annonaceous acetogenins, annocherin (1) and a mixture of (2,4)-cis- and trans-annocherinones (2 and 3), were isolated from the bioactive methanolic extract of Annonacherimolia seeds. Compounds 1-3 each possess an unusual 7-carbonyl group. Their structures were established on the basis of chemical and spectral evidence. Compounds 1-3 showed significant toxicity in the brine shrimp lethality test and cytotoxicity for six human solid tumor cell lines, with selectivity for the renal cell line (A-498) at potencies equivalent to Adriamycin.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I.

The annonaceous acetogenins are the most potent of the known inhibitors of bovine heart mitochondrial complex I. These inhibitors act, at the terminal electron transfer step of the enzyme, in a similar way to the usual complex I inhibitors, such as piericidin A and rotenone; however, structural similarities are not apparent between the acetogenins and these known complex I inhibitors. A systematic set of isolated natural acetogenins was prepared and examined for their inhibitory actions with bovine heart mitochondrial complex I to identify the essential structural factors of these inhibitors for the exhibition of potent activity. Despite their very potent activity, the structural requirements of the acetogenins are not particularly rigid and remain somewhat ambiguous. The most common structural units, such as adjacent bis-tetrahydrofuran (THF) rings and hydroxyl groups in the 4- and/or 10-positions, were not essential for exhibiting potent activity. The stereochemistry surrounding the THF rings, surprisingly, seemed to be unimportant, which was corroborated by an exhaustive conformational space search analysis, indicating that the model compounds, with different stereochemical arrangements around the THF moieties, were in fairly good superimposition. Proper length and flexibility of the alkyl spacer moiety, which links the THF and the alpha, beta-unsaturated gamma-lactone ring moieties, were essential for the potent activity. This probably results from some sort of specific conformation of the spacer moiety which regulates the two ring moieties to locate into an optimal spatial position on the enzyme. It is, therefore, suggested that the structural specificity of the acetogenins, required for optimum inhibition, differs significantly from that of the common complex I inhibitors in which essential structural units are compactly arranged and conveniently defined. The structure-activity profile for complex I inhibition is discussed in comparison with those for other biological activities.

Animals↗
PubMed1998

Cytotoxic and insecticidal constituents of the unripe fruit of Persea americana.

Unripe avocado fruit (Persea americana) was subjected to a bioactivity-directed fractionation, as monitored via the brine shrimp lethality assay, to isolate three major bioactive constituents (1-3). Compounds 1-3 all have a 1,2,4-triol moiety and a long aliphatic chain that terminates as either an alkane, alkene, or alkyne, respectively; 1 is new, while 2 and 3 have been described previously but not as cytotoxic or pesticidal agents. All have activity against six human tumor cell lines in culture and show selectivity for human prostate adenocarcinoma (PC-3) cells with 3 being nearly as potent as adriamycin. Also, when tested against yellow fever mosquito larva, 3 was more effective than rotenone, a natural botanical insecticide and positive control.

Aedes↗
PubMed1998

Membrane conformations and their relation to cytotoxicity of asimicin and its analogues.

Certain plant species belonging to the family Annonaceae produce Annonaceous acetogenins, which are a unique class of long-chain fatty acid derivatives with potent cytotoxicity. Putative protein targets of the acetogenins are membrane-associated proteins, including complex I. Asimicin and its analogues constitute a class of Annonaceous acetogenins containing two tetrahydrofuran (THF) rings with hydrocarbon chains tethered to each ring; an alpha,beta-unsaturated gamma-lactone ring is terminal to one of the alkyl chains. The compounds examined in this study differ in the length of the alkyl chain between the THF rings and the lactone ring. The positions of both the THF and the lactone rings within liposomal membranes were determined by proton (1H) nuclear magnetic resonance spectroscopy. The depth of membrane penetration of acetogenins, coupled to membrane diffusion, controls the conformation of acetogenins as they diffuse to an active site. Based on 1H intermolecular nuclear Overhauser effects (NOEs), the THF rings of all acetogenins studied reside near the polar interfacial head group region of the DMPC. This was corroborated by 1H two-dimensional NOE spectroscopy and differential scanning calorimetry studies. The 1H difference NOE spectra indicated that the lactone rings of asimicin and parviflorin, the latter of which has two fewer carbons in its alkyl chain, are located below the glycerol backbone in the membrane. In contrast with asimicin and parviflorin, the lactone ring of longimicin B, an asimicin analogue with an alkyl chain four carbons shorter, resides close to the midplane in the membrane. This was corroborated by manganese-induced broadening studies. Since the THF rings are located near the center of the acetogenin molecules and the lactone ring is terminal to a long alkyl chain, these observations indicate that an asimicin-type acetogenin can be in either sickle-shaped or U-shaped conformations, depending on the length of the alkyl chain between the THF rings and the lactone ring. Interestingly, longimicin B does not exhibit significant cytotoxicity, but parviflorin is as cytotoxic as asimicin. The cytotoxicity of the asimicin-type of acetogenins would seem to be strongly related to the membrane conformation. This is the first report elucidating the conformation of Annonaceous acetogenins in membranes.

Calorimetry, Differential Scanning↗
PubMed1998

Mono-THF ring annonaceous acetogenins from Annona squamosa.

Continuing work on the bark of Annona squamosa Rich. (Annonaceae), directed by the brine shrimp lethality test (BST), has resulted in the isolation of three new Annonaceous acetogenins, 4-deoxyannoreticuin, cis-4-deoxyannoreticuin, and (2,4-cis and trans)-squamoxinone. The first two are additional examples of acetogenins isolated from this plant species which contain the unusual feature of an oxygen functionality at the C-9 position. They have a hydroxylated mono-THF ring with respective threo/trans/threo and threo/cis/threo relative stereochemistries. The latter compound is a ketolactone mixture which has the same relative stereochemistry around the THF ring and the same spatial relationship between the THF ring and the hydroxyl group along the aliphatic chain as 4-deoxyannoreticuin, but is two methylene units longer. Additionally, the isolated hydroxyl group is at C-11, while the THF ring starts at C-17, instead of at C-9 and C-15, respectively, as for the first two compounds. All three compounds showed moderate, but significant, cytotoxicities against a panel of six human tumor cell lines with (2,4 cis and trans)-squamoxinone showing promising selectivity against the pancreatic cell line (PACA-2).

4-Butyrolactone↗
PubMed1998

Mono-tetrahydrofuran acetogenins from Goniothalamus giganteus.

Goniotetracin and a mixture of (2,4-cis and trans)-gonioneninone, new, bioactive, mono-tetrahydrofuran (THF) gamma-lactone and ketolactone acetogenins, were isolated from the bark of Goniothalamus giganteus (Annonaceae) by activity-directed fractionation using the brine shrimp lethality test (BST). The structures were elucidated based on spectroscopic and chemical methods. Their absolute stereochemistries were determined by the advanced Mosher ester method. Both showed selective and significant cytotoxicities, comparable to the potency of adriamycin, to the human pancreatic tumour cell line (PACA-2), while goniotetracin and goniothalamicin were comparable to the activity of rotenone against yellow fever mosquito larvae.

4-Butyrolactone↗
PubMed1998

Muricoreacin and murihexocin C, mono-tetrahydrofuran acetogenins, from the leaves of Annona muricata.

Bioactivity-directed fractionation of the leaves of Annona muricata L. (Annonaceae) resulted in the isolation of two new Annonaceous acetogenins, muricoreacin (1) and murihexocin C (2). Compounds 1 and 2 showed significant cytotoxicities among six human tumor cell lines with selectivities to the prostate adenocarcinoma (PC-3) and pancreatic carcinoma (PACA-2) cell lines.

4-Butyrolactone↗
PubMed1998

Annojahnin from Annona jahnii: a possible precursor of mono-tetrahydrofuran acetogenins.

A new cytotoxic Annonaceous acetogenin, annojahnin (1), was isolated from the twigs of Annona jahnii (Annonaceae) by bioactivity-directed fractionation using lethality to brine shrimp. Compound 1 represents an unusual type of C-37 Annonaceous acetogenin, lacking either tetrahydrofuran (THF) or epoxide rings, bearing a keto group at C-10, and possessing a double bond located two methylenes away from a vicinal diol. The structure and absolute configuration of 1 were elucidated by 1H and 13C NMR, COSY, and single-relayed COSY and from chemical derivatives. 4-Deoxy-18/21-trans-annomontacin 10-one (4) and 4-deoxy-18/21-cis-annomontacin-10-one (5), two semisynthetic mono-THF acetogenins, were prepared from 1 by reactions that mimic the biogenetic pathways. These acetogenins showed selective cytotoxicities, comparable or superior to adriamycin, among six human solid tumor cell lines. Reduction of the 10-keto of 1, to the racemic 10-OH derivative (3), retained the bioactivities as did the conversion of 1 to 4 and 5.

4-Butyrolactone↗