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3.
Drug Discov Today ; 25(6): 956-958, 2020 06.
Article in English | MEDLINE | ID: mdl-32325124

ABSTRACT

This article examines three aspects of antivirals, such as hydroxychloroquine, chloroquine, and remdesvir, as they might relate to the treatment of a viral infection such as COVID-19: (i) the use of vaporization for the delivery of antivirals, with the bulk constituents having mild antiviral efficacy; (ii) the application of a marine natural product extract as opposed to a single molecule as an antiviral agent; and (iii) a counter intuitive approach to formulation that is, in part, based on delivering multiple species that fall into three categories: building blocks for the virus to accelerate replication; an energy source for the infected cell to boost its immune response; and the species that antagonize or provide toxicity to the virus.


Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Aquatic Organisms/chemistry , Biological Products/administration & dosage , Biological Products/chemistry , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/chemistry , COVID-19 , Chloroquine/administration & dosage , Chloroquine/chemistry , Coronavirus Infections/drug therapy , Drug Compounding , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/chemistry , Models, Molecular , Pandemics , Pneumonia, Viral/drug therapy , Volatilization
4.
Genome Announc ; 5(43)2017 Oct 26.
Article in English | MEDLINE | ID: mdl-29074662

ABSTRACT

Seven mycobacteriophages from distinct geographical locations were isolated, using Mycobacterium smegmatis mc2155 as the host, and then purified and sequenced. All of the genomes are related to cluster A mycobacteriophages, BobSwaget and Lokk in subcluster A2; Fred313, KADY, Stagni, and StepMih in subcluster A3; and MyraDee in subcluster A18, the first phage to be assigned to that subcluster.

5.
Tuberculosis (Edinb) ; 107: 149-155, 2017 12.
Article in English | MEDLINE | ID: mdl-29050764

ABSTRACT

The frontline tuberculosis (Tb) antibiotic isoniazid has been repurposed using a three component complex aimed at increasing the delivery efficiency and adding new avenues to its mechanism of action. This study focuses on pharmacokinetic studies of the isoniazid-sucrose-copper (II)-PEG-3350 complex. The assays include the Plasma Protein Binding Assay (85.8%), Caco-2 Permeability Assay (B→APapp, 0.13 × 10-6 cm/s), Cytochrome P450 Inhibition Assay (i.e. CYP2B6, IC50 = 7.26 µM), In vitro microsomal Stability Assay (t1/2 NADPH-Dependent > 240 min), and HepG2 Cytotoxicity (no toxicity). The National Cancer Institute's 60 cell line panel is used to measure activity against cancer cells. The percent growth values averaged over all 60 cell lines indicates the complex has no anti-cancer activity, which also suggests a lack of general toxicity. It also provides data for the complexes specificity against Mycobacterium tuberculosis.


Subject(s)
Antitubercular Agents/pharmacokinetics , Coordination Complexes/pharmacokinetics , Copper/chemistry , Cytochrome P-450 CYP2B6 Inhibitors/pharmacokinetics , Intestinal Mucosa/metabolism , Isoniazid/pharmacokinetics , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/chemistry , Antitubercular Agents/toxicity , Caco-2 Cells , Cell Survival/drug effects , Coordination Complexes/toxicity , Cytochrome P-450 CYP2B6 Inhibitors/chemistry , Cytochrome P-450 CYP2B6 Inhibitors/toxicity , Drug Compounding , Half-Life , Hep G2 Cells , Humans , Intestinal Absorption , Isoniazid/analogs & derivatives , Isoniazid/chemistry , Isoniazid/toxicity , Permeability
6.
Bioorg Med Chem Lett ; 24(1): 371-7, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24269164

ABSTRACT

A number of delivery agents, such as proteins, liposomes, micelles, and nanoparticles, are utilized for transporting pharmaceutical agents in a physiological environment. This Letter focuses on the use of the copper(II) ion and its potential role as a delivery agent for the taxanes and taxol couple to a malaria drug. Nuclear magnetic resonance (NMR, (1)H, (13)C, (15)N), Mass Spectrometry (LC-MS, MALDI-TOF, FT-ICR) and computational methods are used to examine the structure of the complex. The National Cancer Institute's benchmark 60 cell line panel is used to compare the efficacy of the copper-taxol and copper-taxol-hydroxychloroquin complexes to that of iron-taxol and pure taxol.


Subject(s)
Antimalarials/chemistry , Antineoplastic Agents/chemistry , Copper/chemistry , Drug Carriers/chemistry , Organometallic Compounds/chemistry , Taxoids/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Delivery Systems , Drug Screening Assays, Antitumor , Humans , Hydroxychloroquine/chemistry , Ions/chemistry , Molecular Structure , Organometallic Compounds/chemical synthesis , Paclitaxel/chemistry , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 23(15): 4453-8, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23777781

ABSTRACT

In the first phase of this study, the binding of hydroxychloroquine to the copper(II) cation is examined using liquid chromatography-mass spectrometry (LC-MS), matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS), Fourier transform-ion cyclotron resonance spectrometry (FT-ICR) and nuclear magnetic resonance ((1)H and (13)C NMR) in one and two dimensions. The data suggest the metal-ligand complex is a polarity adaptive molecule. In the second phase of the study, the complexes activity is tested against the National Cancer Institute's 60 cell line panel. Its anti-cancer activity is compared to quinine, Cu(II)-quinine and hydroxychloroquine. It serves as a base line for future anti-cancer complexes in which hydroxychloroquine is utilized for its ability to impact cell autophagy.


Subject(s)
Copper/chemistry , Hydroxychloroquine/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/toxicity , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
8.
Acta Pharm ; 62(2): 201-9, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22750818

ABSTRACT

Laser light scattering and scanning electron microscopy (SEM) are used to study hemoglobin in the aqueous phase. The impact that salts [NaCl, Ca3(PO4)2] and iron oxide nanoparticles have on the hemoglobin size are also studied. The first set of experiments examined hemoglobin aggregates in the aqueous phases in the presence of salts and nanoparticles. Aqueous phase samples were then dehydrated and examined using SEM. The resulting structures resemble those observed in nanobacteria studies conducted in other labs. This study demonstrates that aggregates of hemoglobin and various salts found in a physiological environment can produce structures that resemble nanobacteria.


Subject(s)
Hemoglobins/chemistry , Metal Nanoparticles/chemistry , Calcifying Nanoparticles/chemistry , Calcium Phosphates/chemistry , Chemical Precipitation , Ferric Compounds/chemistry , Hemoglobins/ultrastructure , Metal Nanoparticles/ultrastructure , Microscopy, Electron, Scanning , Osmolar Concentration , Particle Size , Sodium Chloride/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
9.
Mar Drugs ; 8(1): 1-23, 2010 Jan 04.
Article in English | MEDLINE | ID: mdl-20161968

ABSTRACT

The natural products kahalalide F, halichondrin B, and discodermolide are relatively large structures that were originally harvested from marine organisms. They are oxygen rich structures that, to varying degrees, should have the ability to bind iron (II or III) by Fe-O and/or Fe-N bonds. In this semi empirical study, the binding of these natural products to iron (II) is studied and the aqueous stability factor (ASF) is used to determine which bonding configuration is most stable. The energy, the complex charge (+1), the average Fe-O (or Fe-N) bond distances and the dipole moments are used to calculate the ASF. The ASF provides insight to which complex will be the most stable and water soluble, important for a medicinal application. The ability of a molecule with a more than six oxygen and/or nitrogen atoms to bind iron (hexavalent, octahedral) by shifting which six atoms (O/N) are bound to the iron qualifies it as a polarity adaptive molecule.


Subject(s)
Alkanes/chemistry , Biological Products/chemistry , Carbamates/chemistry , Depsipeptides/chemistry , Ethers, Cyclic/chemistry , Iron/chemistry , Lactones/chemistry , Oxygen/chemistry , Pyrones/chemistry , Siderophores/chemistry , Alkanes/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Carbamates/pharmacology , Cell Line, Tumor , Chemical Phenomena , Computational Biology , Depsipeptides/pharmacology , Ethers, Cyclic/pharmacology , Humans , Inhibitory Concentration 50 , Lactones/pharmacology , Macrolides , Models, Molecular , Molecular Conformation , Neoplasms/drug therapy , Pyrones/pharmacology , Siderophores/pharmacology , Structure-Activity Relationship
10.
Nat Prod Res ; 22(10): 865-78, 2008.
Article in English | MEDLINE | ID: mdl-18626821

ABSTRACT

Bryostatin structures share a commonality of a central bryophan ring, but each differs due to two groups (R(1) and R(2)) that are attached to the bryophan ring via ester bonds. This research examines the impact that conditions such as UV light, acidic and basic conditions can have on the bryostatin structure in the presence of octanoic acid and water. Mass spectrometry (MS) measurements suggest that bryostatin can easily rearrange into various structures under natural conditions by reacting with carboxylates that are ubiquitous in nature. A second set of measurements suggest bryostatin can be hydrolyzed by water, a reaction that has significant implications in both medicinal applications and extraction procedures.


Subject(s)
Bryostatins/chemistry , Tandem Mass Spectrometry/methods , Carboxylic Acids/chemistry , Esterification , Hydrolysis , Molecular Structure , Water/chemistry
11.
Nat Prod Res ; 22(5): 399-413, 2008 Mar 20.
Article in English | MEDLINE | ID: mdl-18404560

ABSTRACT

In this computational study, geometric factors are calculated by applying semi-empirical methods (PM3) that support experimental evidence from this lab where bryostatins can bind trivalent iron with six Fe-O bonds forming an octahedral geometry. The geometric factors are calculated for all 20 structures (Fe3+ bound to bryostatin 1-20) as a neutral, monovalent, and divalent species. The average Fe-O bond distances and bond angles are compared to those of known marine and terrestrial siderophores. From these two data sets, we then examined other known marine natural products (MNPs) that can form a hexavalent complex with six Fe-O bonds and draw conclusions about their potential biological role as marine siderophores. This computational data indicates that Fe(III) strongly bonds to a host of MNPs, increasing their water solubility, contracting their structure, hence allowing transport through cell membranes more readily, and in some cases, stabilizing ester bonds that are susceptible to hydrolysis. It is argued that administering medicinally bryostatin, its analogs or other MNPs as a ferric complex, holds some fundamental chemical advantages compared to its administration as a neutral uncomplexed species.


Subject(s)
Biological Products/chemistry , Bryostatins/chemistry , Ferric Compounds/chemistry , Organometallic Compounds/chemistry , Siderophores/chemistry , Animals , Bryozoa/chemistry , Models, Molecular , Molecular Conformation , Thermodynamics
12.
Nat Prod Res ; 20(6): 611-28, 2006 May 20.
Article in English | MEDLINE | ID: mdl-16835096

ABSTRACT

Marine Natural Products (MNPs), such as bryostatin 1, are exposed to a range of physical and chemical conditions through the life cycle of the host organism. These include exposure to sunlight, oxidizing and reducing agents, cation binding, and adsorption to reactive metal oxide surfaces. Using Fourier Transform-Ion Cyclotron Resonance (FT-ICR), Matrix Assisted Laser Desorption Ionization Mass Spectrometry (MALDI-MS), UV/Vis absorbance spectroscopy, and molecular modeling, we studied the impact of UV light, TiO2, I2, and reaction with FeCl3 on the structure of bryostatin 1. Our results demonstrate that natural conditions transform bryostatin to a number of structures, including one with a molar mass of 806 Da, which we have previously identified in the sediment collected from the Gulf of Mexico. To date, at least 20 different structures of bryostatin have been reported in the literature. This work suggests that these variations may be products of the chemical environment in which the bryozoa Bugula neritina resides and are not the result of genetic variations within Bugula.


Subject(s)
Bryozoa/chemistry , Ecosystem , Macrolides/chemistry , Animals , Bryostatins , Bryozoa/metabolism , Chlorides , Computer Simulation , Ferric Compounds/chemistry , Iodine/chemistry , Macrolides/metabolism , Molecular Structure , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Spectrophotometry, Ultraviolet , Titanium/chemistry , Ultraviolet Rays
13.
Nat Prod Res ; 19(5): 467-91, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15938194

ABSTRACT

The bryozoan species Bugula neritina contains the anticancer agent bryostatin. Bryostatin has been extracted from these sessile marine invertebrates since the late 1960s from the Gulf of California, Gulf of Mexico, as well as various locations on the eastern and western rims of the Pacific Ocean. In this work we are focusing on animals harvested in the Gulf of Mexico near Alligator Point (Florida). Using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) we measure the concentration of 70 elements in B. neritina, a sea squirt, and the sediment from the point of harvesting. This data has helped us generate an extraction process for marine natural products. Combining UV/VIS absorbance measurements with Matrix Assisted Laser Desorption Ionization-Time of Flight-Mass Spectrometer (MALDI-TOF-MS), we demonstrated that the specific form of bryostatin extracted is a function of the solvent. A 9.4T Fourier Transform-Ion Cyclotron Resonance (FT-ICR) mass spectrometer, whose sensitivity, mass accuracy, and resolving power allowed the exact empirical formulas of potential precursors of bryostatin to be identified, was employed. Finally we examine extracts of 14 marine species of the Gulf of Mexico, from the sand trout (Cynoscion arenarius) to chicken liver sponge (Chrondrilla nucula), all recently collected, which had shown some medicinal activity thirty years ago in a National Cancer Institute study. By the MALDI-TOF-MS, we were able to identify mass spectral features that correspond to different variations of the basic bryostatin structure, which raises the question if the bryozoans are the original source of bryostatin.


Subject(s)
Bryozoa/chemistry , Macrolides/chemistry , Animals , Bryostatins , Fishes , Mass Spectrometry/methods , Molecular Structure , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
14.
J Nanosci Nanotechnol ; 5(1): 167-74, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15762175

ABSTRACT

We have completed a preliminary series of experiments that compare the silicate shells of the marine organism diatoms to Single-Wall NanoTubes (SWNT), Multi-Wall NanoTubes (MWNT), Exfoliated Graphite (EG), and silica as templates for producing nanostructures of the manganese acetate cluster Mn12 (Mn12[CH3(COO)16(H2O)4O12].(2)CH3COOH.4H2O). Mn12 exhibits magnetic properties because of the molecular arrangement within the cluster and exhibits no exchange couplings between the individual clusters. Data from scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), and laser diffraction are discussed in terms of research that can expand the use of diatoms and other materials as templates for nanostructures.


Subject(s)
Crystallization/methods , Diatoms/chemistry , Graphite/chemistry , Magnetics , Manganese/chemistry , Nanotubes/chemistry , Silicon Dioxide/chemistry , Diatoms/ultrastructure , Materials Testing , Nanotechnology/methods , Nanotubes/ultrastructure , Particle Size , Surface Properties
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