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1.
Mol Ecol ; 30(11): 2626-2640, 2021 06.
Article in English | MEDLINE | ID: mdl-33219558

ABSTRACT

Most retroviral endogenization and host adaptation happened in the distant past, with the opportunity to study these processes as they occurred lost to time. An exception exists with the discovery that koala retrovirus (KoRV) has recently begun its endogenization into the koala (Phascolarctos cinereus) genome. What makes this opportunity remarkable is the fact that Northern Australian koalas appear to be undergoing endogenization with one KoRV subtype (KoRV-A), while all subtypes (KoRV-A-I) coexist exogenously, and Southern Australian koalas appear to carry all KoRV subtypes as an exogenous virus. To understand the distribution and relationship of all KoRV variants in koalas, the proviral KoRV envelope gene receptor binding domain was assessed across the koala's natural range. Examination of KoRV subtype-specific proviral copy numbers per cell found that KoRV-A proviral integration levels were consistent with endogenous incorporation in Northern Australia (southeast Queensland and northeast New South Wales) while revealing lower levels of KoRV-A proviral integration (suggestive of exogenous incorporation) in southern regions (southeast New South Wales and Victoria). Phylogeographical analysis indicated that several major KoRV-A variants were distributed uniformly across the country, while non-KoRV-A variants appeared to have undergone lineage diversification in geographically distinct regions. Further analysis of the major KoRV-A variants revealed a distinct shift in variant proportions in southeast New South Wales, suggesting this as the geographical region where KoRV-A transitions from being predominantly endogenous to exogenous in Australian koalas. Collectively, these findings advance both our understanding of KoRV in koalas and of retroviral endogenization and diversification in general.


Subject(s)
Phascolarctidae , Retroviridae Infections , Animals , New South Wales , Phylogeny , Queensland , Retroviridae/genetics , Victoria
2.
Pharmaceutics ; 12(2)2020 Feb 21.
Article in English | MEDLINE | ID: mdl-32098214

ABSTRACT

Mannitol infusion is commonly used in the treatment of intracranial hypertension following traumatic brain injury. It has long been known to have stability issues, specifically, mannitol recrystallises from solutions greater than 10% w/v in ambient conditions. This can happen at any time, whether on the pharmacy shelf or during a medical procedure. This study describes the stability limits of 20% w/v mannitol infusion (the most common strength used clinically) and proposes a number of safer, stable and tuneable hyperosmotic formulations of mannitol in combination with clinically acceptable osmotic agents (NaCl, sorbitol and glycerol).

3.
J Nat Prod ; 79(6): 1598-603, 2016 06 24.
Article in English | MEDLINE | ID: mdl-27214528

ABSTRACT

The Zimbabwean medicinal plant Monadenium lugardae was evaluated as a potential source of new anticancer constituents. Four new tetracyclic triterpene (1-4) were isolated, accompanied by four previously known triterpenes (5-8). Against a panel of human tumor cell lines, lugardstatins 1 (1) and 2 (2) had good cancer cell growth inhibitory activity. All of the triterpene structures (1-8) were established by 1D and 2D NMR spectrometric and HR mass spectrometric analysis.


Subject(s)
Antineoplastic Agents, Phytogenic/isolation & purification , Euphorbia/chemistry , Plants, Medicinal/chemistry , Triterpenes/isolation & purification , Triterpenes/pharmacology , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Drug Screening Assays, Antitumor , Humans , Leukemia P388 , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Triterpenes/chemistry , Zimbabwe
4.
Mol Ecol Resour ; 13(4): 634-41, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23582171

ABSTRACT

The koala, an Australian icon, has been added to the threatened species list. Rationale for the listing includes proposed declines in population size, threats to populations (e.g. disease) and loss and fragmentation of habitat. There is now an urgent need to obtain accurate data to assess the status of koala populations in Australia, to ensure the long-term viability of this species. Advances in genetic techniques have enabled DNA analysis to study and inform the management of wild populations; however, sampling of individual koalas is difficult in tall, often remote, eucalypt forest. The collection of faecal pellets (scats) from the forest floor presents an opportunistic sampling strategy, where DNA can be collected without capturing or even sighting an individual. Obtaining DNA via noninvasive sampling can be used to rapidly sample a large proportion of a population; however, DNA from noninvasively collected samples is often degraded. Factors influencing DNA quality and quantity include environmental exposure, diet and methods of sample collection, storage and DNA isolation. Reduced DNA quality and quantity can introduce genotyping errors and provide inaccurate DNA profiles, reducing confidence in the ability of such data to inform management/conservation strategies. Here, we present a protocol that produces a reliable individual koala genotype from a single faecal pellet and highlight the importance of optimizing DNA isolation and analysis for the species of interest. This method could readily be adapted for genetic studies of mammals other than koalas, particularly those whose diet contains high proportions of volatile materials that are likely to induce DNA damage.


Subject(s)
DNA Fingerprinting/methods , DNA/genetics , DNA/isolation & purification , Feces/chemistry , Phascolarctidae/classification , Phascolarctidae/genetics , Animals , Australia , Genotype , Specimen Handling/methods
5.
J Nat Prod ; 75(6): 1063-9, 2012 Jun 22.
Article in English | MEDLINE | ID: mdl-22607450

ABSTRACT

Cephalostatin 1 (1), a remarkably strong cancer cell growth inhibitory trisdecacyclic, bis-steroidal pyrazine isolated from the marine tube worm Cephalodiscus gilchristi, continues to be an important target for practical total syntheses and a model for the discovery of less complex structural modifications with promising antineoplastic activity. In the present study, the cephalostatin E and F rings were greatly simplified by replacement at C-17 with an α-pyrone (in 12), typical of the steroidal bufodienolides, and by a dihydro-γ-pyrone (in 16). The synthesis of pyrazine 12 from 5α-dihydrotestosterone (nine steps, 8% overall yield) provided the first route to a bis-bufadienolide pyrazine. Dihydro-γ-pyrone 16 was synthesized in eight steps from ketone 13. While only insignificant cancer cell growth inhibitory activity was found for pyrones 12 and 16, the results provided further support for the necessity of more closely approximating the natural D-F ring system of cephalostatin 1 in order to obtain potent antineoplastic activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Phenazines/chemical synthesis , Pyrazines/chemical synthesis , Pyrones/chemical synthesis , Spiro Compounds/chemical synthesis , Steroids/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Chordata, Nonvertebrate , Humans , Marine Biology , Models, Molecular , Molecular Structure , Phenazines/chemistry , Phenazines/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrones/chemistry , Pyrones/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Steroids/chemistry , Steroids/pharmacology
6.
J Nat Prod ; 75(3): 385-93, 2012 Mar 23.
Article in English | MEDLINE | ID: mdl-22324723

ABSTRACT

Toward the objective of designing a structurally modified analogue of the combretastatin A-4 phosphate prodrug (1b) with the potential for increased specificity toward thyroid carcinoma, synthesis of a series of iodocombstatin phosphate (11a-h) and diiodocombstatin phosphate prodrugs (12a-h) has been accomplished. The diiodo series was obtained via 8a and 9c from condensation of 4 and 6, and the iodo sequence involved a parallel pathway. Both series of iodocombstatins were found to display significant to powerful inhibition of the growth of a panel of human cancer cell lines and of the murine P388 lymphocytic leukemia cell line. Of the diiodo series, 12a was also found to markedly inhibit growth of pediatric neuroblastoma, and monoiodocombstatin 9a strongly inhibited HUVEC growth. Overall, the strongest activity was found against the breast, CNS, leukemia, lung, and prostate cancer cell lines and the least activity against the pancreas and colon lines. Parallel biological investigations of tubulin interaction, antiangiogenesis, and antimicrobial effects were also conducted.


Subject(s)
Antineoplastic Agents/chemical synthesis , Hydrocarbons, Iodinated/chemical synthesis , Hydrocarbons, Iodinated/pharmacology , Organophosphorus Compounds/chemical synthesis , Prodrugs/chemical synthesis , Stilbenes/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Child , Drug Screening Assays, Antitumor , Female , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Hydrocarbons, Iodinated/chemistry , Male , Mice , Microbial Sensitivity Tests , Molecular Structure , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , Stilbenes/chemistry , Stilbenes/pharmacology
7.
J Nat Prod ; 74(5): 962-8, 2011 May 27.
Article in English | MEDLINE | ID: mdl-21534541

ABSTRACT

The dolastatin series of unique peptides, originally discovered as constituents of the sea hare Dolabella auricularia, is of increasing importance in providing biological leads, especially to new and useful anticancer drugs. Dolastatin 10 and three analogues, minor structural modifications designated auristatins, are currently in human cancer clinical trials. The present study was undertaken to explore delivery to the cancer sites by way of phosphate or quinoline modifications. The initial objectives, auristatin TP as sodium phosphate 3b (GI50 10(-2)-10(-4) µg/mL), auristatin 2-AQ (4, GI50 10(-2)-10(-3) µg/mL), and auristatin 6-AQ (5, GI50 10(-4) µg/mL), exhibited superior cancer cell growth inhibitory properties.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Depsipeptides/chemistry , Depsipeptides/pharmacology , Animals , Clinical Trials as Topic , Drug Screening Assays, Antitumor , Humans , Leukemia P388 , Mice , Molecular Structure
8.
Bioorg Med Chem ; 18(14): 4879-83, 2010 Jul 15.
Article in English | MEDLINE | ID: mdl-20598551

ABSTRACT

Bioassay-guided (murine P388 lymphocytic leukemia and human cancer cell lines) separation of an ethyl acetate extract prepared from the inky cap fungus Coprinus cinereus led to the isolation of three new sesquiterpenes, 7,7a-diepicoprinastatin 1 (1), 14-hydroxy-5-desoxy-2S,3S,9R-illudosin (2), and 4,5-dehydro-5-deoxyarmillol (3), together with the known armillol (4). The structure and relative configuration of 1 was determined by single-crystal X-ray diffraction experiments. The structures of compounds 2, 3, and 4 were each deduced by a combination of HRMS and 1D and 2D NMR techniques. Cyclobutane 2 led to modest inhibition of the murine P388 leukemia cell line.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coprinus/chemistry , Neoplasms/drug therapy , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Animals , Antineoplastic Agents/isolation & purification , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Cyclobutanes/chemistry , Humans , Mice , Models, Molecular , Sesquiterpenes/isolation & purification
9.
J Nat Prod ; 73(2): 164-6, 2010 Feb 26.
Article in English | MEDLINE | ID: mdl-20085286

ABSTRACT

Bioassay-guided separation of an extract of the wings from a Taiwan butterfly, Byasa polyeuctes termessa, allowed isolation of a new cancer cell growth inhibitor designated papilistatin (1a). The structure was determined by analysis of 1D and 2D NMR spectra and by HRMS. Against a panel of six human and the murine P388 leukemia cancer cell lines, papilistatin exhibited cancer cell growth inhibition with GI(50)'s of 0.093-3.5 microg/mL. Papilistatin was also found to have antibacterial activity.


Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Butterflies/metabolism , Dioxoles/isolation & purification , Dioxoles/pharmacology , Phenanthrenes/isolation & purification , Phenanthrenes/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Butterflies/chemistry , Dioxoles/chemistry , Drug Screening Assays, Antitumor , Enterococcus faecalis/drug effects , Humans , Inhibitory Concentration 50 , Leukemia P388 , Microbial Sensitivity Tests , Micrococcus luteus/drug effects , Molecular Structure , Phenanthrenes/chemistry , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects
10.
J Nat Prod ; 73(3): 399-403, 2010 Mar 26.
Article in English | MEDLINE | ID: mdl-20028026

ABSTRACT

Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [(11)C]-labeled derivative for positron emission tomography (PET). In order to obtain a suitable precursor for addition of a [(11)C]methyl group at the penultimate step, several new synthetic pathways to CA4P were evaluated. Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling.


Subject(s)
Bibenzyls/chemical synthesis , Stilbenes/chemical synthesis , Bibenzyls/chemistry , Isotope Labeling , Molecular Structure , Positron-Emission Tomography , Stereoisomerism , Stilbenes/chemistry
11.
Bioorg Med Chem ; 17(18): 6606-12, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19709889

ABSTRACT

As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three beta-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The beta-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy-4,5-methylenedioxy derivatives. Two of the beta-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v). All except four (4r, 4s, 4t, 4u) of the series significantly inhibited a minipanel of human cancer cell lines. All but eight led to an IC(50) of <10 microM for inhibition of tubulin polymerization, and all except three (4l, 4t, 4v) displayed antimicrobial activity.


Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Bibenzyls/chemistry , Stilbenes/chemistry , Styrenes/pharmacology , Tubulin Modulators/pharmacology , Anti-Infective Agents/chemistry , Antineoplastic Agents/chemistry , Bacteria/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Fungi/drug effects , Humans , Molecular Structure , Resveratrol , Structure-Activity Relationship , Styrenes/chemistry , Tubulin/metabolism , Tubulin Modulators/chemistry
12.
J Nat Prod ; 72(3): 366-71, 2009 Mar 27.
Article in English | MEDLINE | ID: mdl-19226154

ABSTRACT

Two new cyclodepsipeptides designated bacillistatins 1 (1) and 2 (2) have been isolated from cultures of a sample of Bacillus silvestris that was obtained from a Pacific Ocean (southern Chile) crab. Each 12-unit cyclodepsipeptide strongly inhibited growth of a human cancer cell line panel, with GI(50)'s of 10(-4)-10(-5) microg/mL, and each compound was active against antibiotic-resistant Streptococcus pneumoniae. The structures were elucidated by a combination of X-ray diffraction and mass and 2D NMR spectroscopic analyses, together with chemical degradation.


Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Bacillus/chemistry , Depsipeptides/isolation & purification , Depsipeptides/pharmacology , Animals , Antineoplastic Agents/chemistry , Crystallography, X-Ray , Depsipeptides/chemistry , Drug Resistance, Multiple, Bacterial/drug effects , Drug Screening Assays, Antitumor , Female , Humans , Male , Marine Biology , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Stereoisomerism
13.
J Nat Prod ; 71(9): 1561-3, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18729517

ABSTRACT

The very unstable (<10 min at rt) o-quinone 5 derived from the vicinal diphenol anticancer drug combretastatin A-1 (1) has been obtained by careful oxidation with NaIO4 and tetrabutylammonium bromide in water/dichloromethane. Immediate reaction with phenylenediamine (6) allowed o-quinone 5 to be trapped as the stable phenazine derivative 7. For further confirmation, 5 was also captured as a dimethoxyphenylenediamine-derived phenazine (11). Both phenazines 7 and 11 significantly inhibited (ED50 approximately 0.2 microg/mL) growth of the murine P388 lymphocytic leukemia cell line and provided a new SAR insight in the combretastatin series of naturally occurring anticancer drugs.


Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Biological Products/chemistry , Prodrugs/chemistry , Quinones/chemistry , Stilbenes/chemistry , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Biological Products/pharmacology , Drug Screening Assays, Antitumor , Leukemia P388 , Molecular Structure , Oxidation-Reduction , Prodrugs/pharmacology , Stilbenes/pharmacology , Structure-Activity Relationship
14.
J Nat Prod ; 71(3): 438-44, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18327911

ABSTRACT

Bioassay-guided fractionation of extracts of various plants, marine organisms, and microorganisms has led to the discovery of new natural sources of a number of known compounds that have significant biological activity. The isolation of interesting and valuable cancer cell growth inhibitors including majusculamide C ( 1), axinastatin 5 ( 5), bengazoles A ( 6), B ( 7), and E ( 8), manzamine A ( 10), jaspamide ( 11), and neoechinulin A ( 19) has been summarized.


Subject(s)
Antineoplastic Agents/pharmacology , Carbazoles/pharmacology , Depsipeptides/pharmacology , Indole Alkaloids/pharmacology , Oxazoles/pharmacology , Peptides, Cyclic/pharmacology , Piperazines/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Carbazoles/chemistry , Carbazoles/isolation & purification , Depsipeptides/chemistry , Depsipeptides/isolation & purification , Drug Screening Assays, Antitumor , Indole Alkaloids/chemistry , Indole Alkaloids/isolation & purification , Marine Biology , Molecular Structure , Oxazoles/chemistry , Oxazoles/isolation & purification , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Piperazines/chemistry , Piperazines/isolation & purification
15.
Mol Ecol Resour ; 8(3): 561-7, 2008 May.
Article in English | MEDLINE | ID: mdl-21585833

ABSTRACT

Shed feathers obtained by noninvasive genetic sampling (NGS) are a valuable source of DNA for genetic studies of birds. They can be collected across a large geographical range and facilitate research on species that would otherwise be extremely difficult to study. A limitation of this approach is uncertainty concerning the quality of the extracted DNA. Here we investigate the relationship between feather type, feather condition and DNA quality (amplification success) in order to provide a simple, cost-effective method for screening samples prior to genetic analysis. We obtained 637 shed feathers of the powerful owl (Ninox strenua) from across its range in southeastern Australia. The extracted DNA was amplified using polymerase chain reaction for a range of markers including mitochondrial DNA, ND3 and nuclear DNA, a simple sequence repeat (Nst02) and a portion of the CHD-1 gene (P2/P8). We found that feather condition significantly influenced the amplification success of all three loci, with feathers characterized as 'good' having greater success. Feather type was found to be of lower importance, with good quality feathers of all types consistently producing high success for all three loci. We also found that the successful amplification of multilocus genotypes was dependant on the condition of the starting material and was highly correlated with successful amplification of the sex-linked CHD-1 locus. Samples with low DNA quality have a higher probability of amplification failure and are more likely to produce incorrect genotypes; therefore, identifying samples with high DNA quality can save substantial time and cost associated with the genetic analysis of NGS. As a result, we propose a method for screening shed feathers in order to provide a subset of samples which will have a greater probability of containing high quality DNA suitable for the amplification of multilocus genotypes.

16.
J Nat Prod ; 69(5): 804-6, 2006 May.
Article in English | MEDLINE | ID: mdl-16724845

ABSTRACT

A Streptomyces sp. isolated from riverbank soil in Manitoba, Canada, was found to contain two cancer cell growth inhibitories: diazaanthraquinone 1 and 3-(hydroxyacetyl)indole (8). The structures were determined by interpretation of data from HRMS, UV, and high-field (400 MHz) NMR experiments. The red-colored diazaanthraquinone 1 and 3-(hydroxyacetyl)indole (8) were found to inhibit (0.1-3 microg/mL) growth of a minipanel of human cancer cell lines and P388 lymphocytic leukemia cells. Diazaanthraquinone 1 was also found to inhibit growth of the bacteria Streptococcus pneumoniae and Neisseria gonorrheae. However, three companion constituents, cyclo-Pro-Leu (5), cyclo-Pro-Phe (6), and cyclo-Pro-Val (7), did not inhibit cancer cell growth.


Subject(s)
Anti-Bacterial Agents/isolation & purification , Aza Compounds/isolation & purification , Indoles/isolation & purification , Quinones/isolation & purification , Streptomyces/chemistry , Amino Acid Sequence , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Aza Compounds/chemistry , Aza Compounds/pharmacology , Dipeptides/isolation & purification , Drug Screening Assays, Antitumor , Humans , Indoles/chemistry , Indoles/pharmacology , Leukemia P388 , Manitoba , Mice , Molecular Structure , Peptides, Cyclic/isolation & purification , Quinones/chemistry , Quinones/pharmacology , Streptococcus/drug effects , Streptomyces/isolation & purification , Tumor Cells, Cultured
17.
J Org Chem ; 69(12): 4019-22, 2004 Jun 11.
Article in English | MEDLINE | ID: mdl-15176826

ABSTRACT

A previously synthesized unit of dolastatin 10 (1), dolaphenine (Doe, 3), was converted in four steps to tripeptide 10. Subsequent condensation with carboxylic acid 11 (four steps from Meldrum's acid) provided a practical synthesis of the cancer cell growth inhibitor dolastatin 18 (2, Dhex-(S)-Leu-(R)-N-Me-Phe-Doe). The synthesis of dolastatin 18 (2) confirmed the R stereochemistry of the N-Me-Phe unit as originally assigned and unusual among amino acid components of the sea hare Dolabella auricularia. An X-ray crystal structure determination of dolastatin 18 was also completed.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Crystallography, X-Ray , Depsipeptides , Mollusca/chemistry , Oligopeptides/pharmacology , Peptides/chemistry , Structure-Activity Relationship
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