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Biomedical subjects

M R Boyd

Publications and source records attributed to M R Boyd.

At least 145 records · Page 8Linked to original sources
PubMed1995

Activity of penciclovir against Epstein-Barr virus.

Penciclovir inhibited the productive replication cycle of Epstein-Barr virus (EBV) in assays measuring infectious virus production, viral antigen expression, and viral DNA synthesis. In the test measuring inhibition of EBV DNA synthesis, 50% effective concentrations of penciclovir and acyclovir were 2.3 +/- 0.8 and 2.2 +/- 0.6 micrograms/ml, respectively. The 50% cell growth inhibitory concentration of penciclovir was > 100 micrograms/ml for both P3HR-1 and Raji cells. Penciclovir is a selective inhibitor of EBV in cell culture.

Acyclovir↗
PubMed1995

Antineoplastic agents 337. Synthesis of dolastatin 10 structural modifications.

New structural modifications of the marine shell-less mollusk peptide constituent dolastatin 10 (1) have been synthesized, and evaluated against a variety of cancer cell lines and for their ability to inhibit tubulin polymerization. A number of useful structure-activity relationships were uncovered. The most important observation was that the dolaphenine unit of dolastatin 10 could be satisfactorily replaced with a phenethylamine. Peptide 11C, designated auristatin PE, was found to exhibit inhibition of cancer cell growth and tubulin assembly comparable to that of dolastatin 10.

Amino Acid Sequence↗
PubMed1995

Rat brain cytochrome P450. Reassessment of monooxygenase activities and cytochrome P450 levels.

There have been considerable interlaboratory variations in the reported levels of rat brain microsomal cytochrome P450 and associated monooxygenase activities. To ascertain if the variability could be accountable, at least in part, to different methodologies used for microsome preparation, cytochrome P450 monooxygenase components and activities were directly compared herein using brain microsome prepared by various methods. Rat brain microsome isolated using a calcium aggregation method in the presence of dithiothreitol and glycerol contained approximately 100 pmol of cytochrome P450/mg protein. Considerably lower cytochrome P450 levels (e.g. 20-40 pmol/mg protein) were found in brain microsome prepared in a more conventional manner using Tris or phosphate buffers without glycerol and dithiothreitol. The NADPH cytochrome c reductase activity was consistently approximately 23-25 nmol of cytochrome c reduced/min/mg protein, whatever the method of preparation of the brain microsome. Cytochrome P450-associated monooxygenase activities, namely morphine N-demethylase and ethoxycoumarin O-deethylase, were dependent on the amount of protein in the incubation medium, the length of incubation, and the ratio of the concentration of the substrate to the amount of protein in the incubation mixture. The specific activity of morphine N-demethylase was constant over a range of protein concentration, if the ratio of the concentration of the substrate to the protein was kept constant.

Animals↗
PubMed1995

Organomercury (II) complexes with anti-carcinogenic agents. II. Anti-neoplastic activity.

Organomercury(II) complexes of the type, p-MeOC6H4HgL1 (I), p-NO2C6H4HgL2 (II), p-MeOC6H4HgL3 (III) and p-MeC6H4HgL4 (IV) (HL1-6-mercaptopurine, HL2-6-thioguanine, HL3-5-fluorouracil, L4-phenyldithiocarbazate) have been screened against the following cell panels: leukemia, non-small cell lung cancer, small cell lung cancer, brain cancer, melanoma, ovarian cancer and renal cancer. The variation in anti-neoplastic activity has been correlated with the structural parameters of the complexes.

Antineoplastic Agents↗
PubMed1995

Antineoplastic agents 320: synthesis of a practical pancratistatin prodrug.

Owing to its sparingly soluble properties, the potential anticancer drug pancratistatin (1) resisted conventional drug formulation procedures and the synthesis of a water-soluble prodrug became necessary. That important objective for further pre-clinical development was met by devising a route to a disodium phosphate derivative (5). The key step in the synthesis of the phenolic phosphate was phosphorylation of 1,2,3,4-tetraacetoxy-pancratistatin (2) with dibenzyloxy(N,N-diisopropylamido)-phosphine. Subsequent oxidation with m-chloroperbenzoic acid afforded phosphate 4a. Hydrogenolysis of the benzyl esters followed by base-catalysed hydrolysis of the acetate groups led to the water-soluble prodrug 5 in high yield.

Amaryllidaceae Alkaloids↗
PubMed1995

Antineoplastic agents 322. synthesis of combretastatin A-4 prodrugs.

Combretastatin A-4 (1a), the principal cancer cell growth-inhibitory constituent of the Zulu medicinal plant Combretum caffrum, has been undergoing preclinical development. However, the very limited water solubility of this phenol has complicated drug formation. Hence, derivatives of the combretastatin A-4 (1a) 3'-phenol group were prepared for evaluation as possible water-soluble prodrugs. As observed for combretastatin A-4, the sodium salt (1b), potassium salt (1c) and hemisuccinic acid ester (1e) derivatives of phenol 1a were essentially insoluble in water. Indeed, these substances regenerated combretastatin A-4 upon reaction with water. A series of other simple derivatives (1d, 1f-j) proved unsatisfactory in terms of water solubility or stability, or both. The most soluble derivatives evaluated included the ammonium (1l), potassium (1m) and sodium (1n) phosphate salts, where the latter two proved most stable and suitable. Both the potassium (1m) and sodium (1n) phosphate derivatives of combretastatin A-4 were also found to exhibit the requisite biological properties necessary for a useful prodrug. Sodium salt 1n was selected for drug formulation and further pre-clinical development.

Animals↗
PubMed1994

Preparative separation of naphthyltetrahydroisoquinoline alkaloids from Ancistrocladus korupensis by centrifugal partition chromatography.

Crude extracts of Ancistrocladus korupensis contain a complex mixture of naphthyltetrahydroisoquinoline alkaloids, including the human immunodeficiency virus-inhibitory dimeric alkaloids michellamines A and B and the antimalarial monomeric korupensamines A-D. The efficient separation of michellamines A and B from these extracts has been accomplished by centrifugal partition chromatography. The chromatographic conditions used on a multi-channel cartridge unit (Sanki LLN) have been successfully scaled up with a newly developed, stacked-disk type centrifugal partition chromatography unit (Sanki NMF) for separating larger amounts of alkaloid mixtures with similar resolution. A refined, three-step process (solvent-solvent partitioning, centrifugal partition chromatography and HPLC) has been developed and applied to the scaled-up production of michellamine B for preclinical drug development.

Alkaloids↗
PubMed1994

Anticancer specificity of some ellipticinium salts against human brain tumors in vitro.

Novel structure-activity relationships (SAR) distinct from known SAR for ellipticines have been revealed for certain ellipticinium salts. In particular, ellipticiniums such as the prototypical 9-methoxy-2-methylellipticinium (I- or OAc-) were found to be preferentially cytotoxic to the brain tumor cell line subpanel of the NCI 60 cell-line screening panel. Similar specificity also was apparent with 9-unsubstituted ellipticiniums, or others bearing 9-methyl or 9-chloro substituents. In contrast, 9-hydroxy-substituted ellipticiniums, as well as all nonquaternized ellipticines tested, were devoid of brain tumor specificity. Therefore, it did not appear that this unusual preference was correlated with the relative availability of redox cycling mechanisms, since redox cycling presumably is blocked in 9-methyl- and 9-chloroellipticiniums. Indeed, related investigations have indicated that the brain tumor specificity is mediated by preferential uptake and intracellular accumulation of the specific ellipticiniums. The present study further supports that the NCI in vitro "disease-oriented" primary screen can facilitate the discovery of novel, selectively cytotoxic leads for in vivo and mechanistic investigations.

Brain Neoplasms↗
PubMed1994

Anti-HIV michellamines from Ancistrocladus korupensis.

Here we report details of the isolation and determination of the absolute configurations and comparative anti-HIV activities of novel, atropisomeric naphthylisoquinoline alkaloid dimers, michellamines A, B, and C, from a newly described species of Ancistrocladus from the Korup rainforest of Cameroon. We further provide a more extensive analysis of the range of anti-HIV activity of michellamine B, the most potent and abundant member of the series. Michellamine B inhibited HIV-induced cell killing and viral replication in a variety of human cell lines, as well as in cultures of human peripheral blood leukocytes and monocytes. Michellamine B was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6 and the pyridinone-resistant strain A17; the compound also inhibited several strains of HIV-2.

Africa↗
PubMed1994

Cellular uptake as a determinant of cytotoxicity of quaternized ellipticines to human brain tumor cells.

The quaternized ellipticine derivative, 9-methoxy-N2-methylellipticinium acetate (MMEA), is representative of a group of ellipticinium compounds found preferentially cytotoxic to human brain tumor cell lines comprising a subpanel of the U.S. National Cancer Institute (NCI)'s in vitro "disease-oriented" anticancer drug discovery screen. The present studies indicate that the accumulation and cytotoxicity of MMEA in these susceptible cells are mediated in part by a cellular transport process having substrate and inhibitor specificities similar to those found in glial-derived cells which presumably comprise part of the structural (non-neuronal) elements of normal brain.

Antineoplastic Agents↗
PubMed1994

Ethnobotany and drug discovery: the experience of the US National Cancer Institute.

Between 1960 and 1981 the National Cancer Institute (NCI) screened 114,000 extracts of 35,000 plants, mainly collected in temperate regions. Of the three clinically active anticancer drugs so far discovered in that programme, none was isolated from a plant collected on an ethnobotanical basis, though various Taxus species, which are the source of taxol, are reported to have been used medicinally. Since 1986, the NCI has focused its collections in tropical and subtropical regions worldwide; collections cover a broad taxonomic range, though priority is given to medicinal plants when relevant information is available. As of August 1993, 21,881 extracts derived from over 10,500 samples had been tested in a screen for activity against the human immunodeficiency virus (HIV); 2320 of these extracts were of medicinal plant origin. Approximately 18% of both the total number of extracts and the medicinal plant-derived extracts showed significant anti-HIV activity; in each instance about 90% of the active extracts were aqueous. The activity of the aqueous extracts has been attributed mainly to the presence of polysaccharides or tannins. Four plant-derived compounds are in preclinical development at the NCI; only one of the four sources plants, obtained from a noncontract source, was collected on an ethnobotanical basis. At this stage the results indicate that the current NCI collection policy offers the best chances for the discovery and development of agents for the treatment of AIDS (acquired immune deficiency syndrome) and cancer.

Drug Screening Assays, Antitumor↗
PubMed1994

Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors.

A series of benzothiadiazine derivatives were screened against the human immunodeficiency virus (HIV) and certain structure-activity relationships were defined for anti-HIV activity in this chemical class. The selected representative NSC 287474 was a highly potent inhibitor of HIV-induced cell killing and HIV replication in a variety of human cell lines, as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2, and also against both nevirapine- and pyridinone-resistant strains (N119 and A17) of HIV-1, which are cross-resistant to several structurally diverse nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase, but not HIV-2 reverse transcriptase. Combination of NSC 287474 with AZT synergistically inhibited HIV-1-induced cell killing in vitro. The compound did not inhibit the replication of the Rauscher murine leukemia retrovirus or the simian immunodeficiency virus. The benzothiadiazine class of compounds represents a new active anti-HIV-1 chemotype within the diverse group of nonnucleoside reverse transcriptase inhibitors.

Antiviral Agents↗
PubMed1994

Isolation and structure of cephalostatins 10 and 11.

Further investigation of antineoplastic constituents from the marine worm Cephalodiscus gilchristi, employing a 450 kg re-collection from the Indian Ocean (Southeast Africa), has led to isolation and structural determination of two previously undetected members of the cephalostatin series, designated cephalostatins 10 [4] and 11 [5]. Structural analyses were conducted primarily employing high field 2D nmr and high resolution mass spectral techniques. All the stereochemical assignments were deduced using the original X-ray crystal structure of cephalostatin 1 and ROESY 2D nmr methods. Both cephalostatins 10 and 11 strongly inhibited growth of a series of important human cancer cell lines.

Animals↗
PubMed1994

Koumbalones A and B, new casbane diterpenes from Maprounea africana.

The organic extract of Maprounea africana yielded koumbalones A [1] and B [2], defined by spectral methods as new variations on the casbane ring system. The gross structures, relative configurations, and solution conformations were determined by a combination of spectral analyses and molecular modeling. Because koumbalone A spontaneously converts to koumbalone B at room temperature, koumbalone B may be an artifact of isolation.

Diterpenes↗
PubMed1994

Cucurbitacins: differential cytotoxicity, dereplication and first isolation from Gonystylus keithii.

A characteristic pattern of differential cytotoxicity of extracts of Iberis amara seeds, predominantly toward renal tumor, brain tumor, and melanoma cell lines in the NCI human disease-oriented tumor screening panel, was traced to cucurbitacins E [1] and I [2]. This same differential cytotoxicity profile was detected in extracts of Begonia plebeja and Gonystylus keithii. Computer-assisted recognition of these profiles was followed by a rapid chemical fractionation, thus permitting the efficient dereplication of those extracts containing cucurbitacins B [3] and D [4], respectively. This is the first report of cucurbitacins from the genus Gonystylus.

Antineoplastic Agents, Phytogenic↗
PubMed1994

Novel naphthoquinones from Conospermum incurvum.

During the reisolation of the trimeric naphthoquinone derivative conocurvone [1] from an extract of the Australian shrub Conospermum incurvum, six monomeric naphthoquinones were isolated. These include three novel 1,4-naphthoquinone derivatives: 3-methyl-14,15-dihydro-15-hydroxyteretifolione B [3], 3-methyl-14,15-dihydro-15-hydroxyteretifolione B methyl ether [4], and 2,3-dimethyl-6-hydroxy-7-methoxy-1,4-naphthoquinone [5]. In addition, the previously reported compounds 3-methylteretifolione B [6], 3-methylteretifolione B methyl ether [7], and 8-geranyl-2,7-dihydroxy-3-methyl-1,4-naphthoquinone [8] were isolated and identified. The structures of the novel 1,4-naphthoquinones were elucidated by spectral methods. While conocurvone [1] is a potent inhibitor of HIV-1-induced cell killing, all of the monomeric naphthoquinone derivatives were inactive against HIV-1.

Antiviral Agents↗
PubMed1994

Depressive symptoms in young women of the Piedmont: prevalence in rural women.

Depression rates in women are twice that of men. In certain groups of women depression exceeds 40 percent. These groups include urban, poor, young mothers, and women who use primary health care facilities. We hypothesized that rates of depressive symptoms in rural women users of primary care would exceed those reported in population studies. Depressive symptoms were expected to be associated with common risk factors for depression. To test these hypotheses, 181 rural women, ages 18 to 52, were interviewed by telephone using the Center for Epidemiologic Studies Depression Scale (CES-D). Of these, 41.4 percent reported depressive symptoms exceeding the cutoff score of 16 on the CES-D. The mean CES-D score for the entire sample was 15.3 and was 27.6 for women scoring over 16 on the CES-D. Young, unemployed, and poorly educated women were most likely to report depressive symptoms. These findings suggest that many rural women are at-risk for depression. High mean CES-D scores in women scoring above the cutoff indicate that rural women experience multiple and persistent depressive symptoms. These findings also show that women with fewer educational and economic resources report more depressive symptoms. Rural health professionals can increase detection of women at risk for depression by considering their age, and their education, and employment status.

Adult↗