Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Jamie Horn is active.

Publication


Featured researches published by Jamie Horn.


MedChemComm | 2013

Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents

Narsimha Reddy Penthala; Vijayakumar N. Sonar; Jamie Horn; Markos Leggas; Jai Shankar K. Yadlapalli; Peter A. Crooks

A new library of small molecules with structural features resembling combretastatin analogs was synthesized and evaluated for anticancer activity against a panel of 60 human cancer cell lines. Three novel acrylonitrile analogs (5, 6 and 13) caused a significant reduction in cell growth in almost all the cell lines examined, with GI50 values generally in the range 10-100 nM. Based on the structural characteristics of similar drugs, we hypothesized that the cytotoxic activity was likely due to interaction with tubulin. Furthermore, these compounds appeared to overcome cell-associated P-glycoprotein (P-gp)-mediated resistance, since they were equipotent in inhibiting OVCAR8 and NCI/ADR-Res cell growth. Given that antitubulin drugs are among the most effective agents for the treatment of advanced prostate cancer we sought to validate the results from the 60 cell panel by studying the representative analog 6 utilizing prostate cancer cell lines, as well as exploring the molecular mechanism of the cytotoxic action of this analog.


Journal of Molecular Structure-theochem | 1996

Benzylic carbonium ions as ultimate carcinogens of polynuclear aromatic hydrocarbons

Andreas F. Lehner; Jamie Horn; James W. Flesher

Abstract Perturbational molecular orbital calculations were applied to a series of polynuclear aromatic hydrocarbons (PAH) to assess the energetics involved in generating electrophilic carbonium ions of two types, triol and benzylic carbonium ions. ΔE β , an index of carbonium ion formation and stability, was nearly always higher for benzylic carbonium ions attached to mesoanthracenic positions of PAHs than for terminal ring triol carbonium ions. Furthermore, the reactivity index N t for substitution reactions leading to benzylic carbonium ions was lowest in each molecule at the site corresponding to the most favorable ΔE β value. No similar relationship existed for ortholocalization energies of bonds at which addition reactions generate triol carbonium ions. Statistical analysis revealed that Iball indices for carcinogenicity showed higher correlation with both benzylic-relevant ΔE β and N t values than with triol carbonium ion ΔE β or ortholocalization energies. Various authors claim correlation between the energetics of triol carbonium ion generation and carcinogenicity, yet our observations along similar lines of reasoning demonstrate even stronger correlation and more favorable energetics for benzylic carbonium ions that require initial methylation at an exceptionally reactive center. Based on our calculations, we predict that animal tests, such as repeated application to mouse skin or repeated subcutaneous injection in mice or rats, should reveal benzylic carbonium ions arising from hydroxymethyl sulfate ester metabolites to be endowed with more complete carcinogenic potency than triol carbonium ions arising from dihydrodiol epoxide metabolites.


Journal of Molecular Structure-theochem | 1996

MOLECULAR MODELING OF CARCINOGENIC POTENTIAL IN POLYCYCLIC HYDROCARBONS

James W. Flesher; Jamie Horn; Andreas F. Lehner

Abstract The generality and validity of rules of molecular geometry for predicting the carcinogenic potential of unsubstituted polynuclear aromatic hydrocarbons (PAHs) were further tested. These rules are based on the number and location of sites for the electrophilic substitution in unsubstituted PAHs. When the rules of molecular geometry are applied in the absence of specific theoretical or experimental information, they have been shown to predict carcinogenic potential with a high degree of accuracy. However, the accuracy of the rules is even further improved when additional information about the number and location of sites for electrophilic substitution is examined. A theoretical method that probes for such exceptionally reactive centers has been provided by the molecular orbital calculations of Dewar and Dennington. Calculations of this sort have been applied with the rules in order to make predictions of carcinogenic potential in 90 alternant and nonalternant PAHs. These predictions, with very few exceptions, were in good agreement with currently available carcinogenicity test data. It is concluded that a relationship exists between carcinogenic potential, molecular geometry, and the relative energies for electrophilic substitution of the individual carbons in unsubstituted PAHs.


Journal of Natural Products | 2015

Cytotoxic Indolocarbazoles from Actinomadura melliaura ATCC 39691

Khaled A. Shaaban; Sherif I. Elshahawi; Xiachang Wang; Jamie Horn; Madan K. Kharel; Markos Leggas; Jon S. Thorson

Actinomadura melliaura ATCC 39691, a strain isolated from a soil sample collected in Bristol Cove, California, is a known producer of the disaccharide-substituted AT2433 indolocarbazoles (6-9). Reinvestigation of this strain using new media conditions led to >40-fold improvement in the production of previously reported AT2433 metabolites and the isolation and structure elucidation of the four new analogues, AT2433-A3, A4, A5, and B3 (1-4). The availability of this broader set of compounds enabled a subsequent small antibacterial/fungal/cancer SAR study that revealed disaccharyl substitution, N-6 methylation, and C-11 chlorination as key modulators of bioactivity. The slightly improved anticancer potency of the newly reported N-6-desmethyl 1 (compared to 6) contrasts extensive SAR of monoglycosylated rebeccamycin-type topoisomerase I inhibitors where N-6 alkylation has contributed to improved potency and ADME. Complete 2D NMR assignments for the known metabolite BMY-41219 (5) and (13)C NMR spectroscopic data for the known analogue AT2433-B1 (7) are also provided for the first time.


Journal of Pharmaceutical Analysis | 2012

Validated LC-MS/MS method for simultaneous determination of SIM and its acid form in human plasma and cell lysate: Pharmacokinetic application

Tamer A. Ahmed; Jamie Horn; John Hayslip; Markos Leggas

Simvastatin (SIM) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LC–MS/MS method was developed to measure SIM and its acid form (SIMA) in plasma and peripheral blood mononuclear cells (PBMCs) obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75:25 (% v/v) acetonitrile:ammonium acetate (0.1 M, pH 5.0) mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5–500 ng/mL for SIM and 5–500 ng/mL for SIMA in plasma and 2.5–250 ng/mL for SIM and 5–250 ng/mL for SIMA in cell lysate. Recovery was >58% for SIM and >75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients.


Chemico-Biological Interactions | 2003

The metabolism of formyl-substituted benzanthracenes to hydroxymethyl metabolites in rat liver in vitro and in vivo.

Jamie Horn; James W. Flesher; Andreas F. Lehner

Hydroxylation of benzylic methyl carbon atoms on drugs and carcinogenic polycyclic aromatic hydrocarbons (PAHs) forms benzylic alcohols. Many carcinogenic and mutagenic PAHs bear a primary or secondary benzylic hydroxyl group attached to the meso-region of the molecule. According to the unified theory, PAHs bearing a benzylic hydroxyl group are proximate carcinogenic metabolites. This paper demonstrates that carcinogenic benz[a]anthracenes bearing a formyl group at the meso-region undergo enzymatic reductive metabolism to the corresponding carcinogenic benzylic alcohol in vitro and in vivo. The unified theory would then predict sulfuric acid esterification of such benzylic alcohols as the final common step in their metabolic activation to generate ultimate electrophilic benzylic carbocations. Finally, oxidative metabolism of 7-formylbenz[a]anthracenes gives rise to corresponding carboxylic acids and other oxygenated metabolites that are carcinogenically inert. Thus, oxidative metabolism of meso-region formyl compounds represents an avenue for the elimination of the carcinogen in a detoxified form.


Polycyclic Aromatic Compounds | 2002

The Meso-Region Theory of Aromatic Hydrocarbon Carcinogenesis

James W. Flesher; Jamie Horn; Andreas F. Lehner

Structure-activity relationships (SAR) demonstrate the importance, for carcinogenic activity in polycyclic aromatic hydrocarbons (PAHs), of substituents at meso-regions of exceptional reactivity whether located in an aromatic nucleus or on a side chain. The simplest SAR is that a majority of carcinogenic hydrocarbons can be classified as anthracene derivatives. The meso-region theory proposes that the chemical and biochemical pathways of activation of both unsubstituted and meso-substituted PAHs are essentially the same. The first biochemical step, in a chain of three substitution reactions, involves the methylation of unsubstituted PAHs, at a meso-center of exceptional reactivity. Hydroxylation of a meso-region methyl group is followed by the formation of a reactive ester (e.g., sulfuric acid ester) bearing a good leaving group, which would be expected to generate a highly reactive carbonium ion. The carbonium ion would be expected to react with critical nucleophiles to initiate the chain of cellular events which results in cancer. When a substituent blocks a meso-region of exceptional reactivity, carcinogenic activity is reduced or abolished.


Journal of Lipid Research | 2015

The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination

Yuhuan Wang; Xiaoxi Liu; Sonja S. Pijut; Jianing Li; Jamie Horn; Emily M. Bradford; Markos Leggas; Terrence A. Barrett; Gregory A. Graf

Previous studies suggest an interdependent relationship between liver and intestine for cholesterol elimination from the body. We hypothesized that a combination of ursodiol (Urso) and ezetimibe (EZ) could increase biliary secretion and reduce cholesterol reabsorption, respectively, to promote cholesterol excretion. Treatment with Urso increased hepatic ABCG5 ABCG8 (G5G8) protein and both biliary and fecal sterols in a dose-dependent manner. To determine whether the drug combination (Urso-EZ) further increased cholesterol excretion, mice were treated with Urso alone or in combination with two doses of EZ. EZ produced an additive and dose-dependent increase in fecal neutral sterol (FNS) elimination in the presence of Urso. Finally, we sequentially treated wide-type and G5G8-deficient mice with Urso and Urso-EZ to determine the extent to which these effects were G5G8 dependent. Although biliary and FNS were invariably lower in G5G8 KO mice, the relative increase in FNS following treatment with Urso alone or the Urso-EZ combination was not affected by genotype. In conclusion, Urso increases G5G8, biliary cholesterol secretion, and FNS and acts additively with EZ to promote fecal sterol excretion. However, the stimulatory effect of these agents was not G5G8 dependent.


Drug Metabolism and Disposition | 2011

Metabolic pathways of the camptothecin analog AR-67.

Jamie Horn; Marta Milewska; Susanne M. Arnold; Markos Leggas

7-tert-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67; also known as DB-67) is a novel lipophilic camptothecin analog in early-phase anticancer clinical trials. In support of these studies, we evaluated the metabolism of AR-67 in vitro and identified potential metabolites in patient samples. The lactone form of AR-67 was found to be preferentially metabolized over AR-67 carboxylate in human microsomes. Subsequently, the lactone form was tested as a substrate in a panel of CYP450 and UDP-glucuronosyltransferase (UGT) enzymes known to metabolize the majority of clinically approved molecules. AR-67 was metabolized by CYP3A5, CYP3A4, CYP1A1, and CYP1A2, in order of activity. Extrahepatic UGT1A8 and UGT1A7 possessed at least 6-fold higher metabolizing activity than UGT1A1 and other UGT enzymes tested. CYP1A1 and UGT1A7 displayed Michaelis-Menten kinetics, whereas CYP3A4, CYP3A5, and UGT1A8 displayed kinetics consistent with substrate inhibition. Chromatographic analysis of representative patient plasma and urine samples demonstrated the presence of AR-67 glucuronides and oxidized products in the urine but only in very minimal amounts. We conclude that limited in vivo metabolism of AR-67 by UGT1A1 may partly explain the absence of AR-67 glucuronides in plasma and hypothesize that UGT1A8- and CYP3A-mediated biotransformation within the gastrointestinal epithelium may provide protective mechanisms against AR-67 gastrointestinal toxicity.


Biomedical Chromatography | 2010

An HPLC assay for the lipophilic camptothecin analog AR-67 carboxylate and lactone in human whole blood.

Eleftheria Tsakalozou; Jamie Horn; Mark Leggas

AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin, DB-67) is a camptothecin analog currently in early stage clinical trials. The lactone moiety of camptothecins hydrolyzes readily in blood to yield the pharmacologically inactive carboxylate form. However the lactone form of third-generation lipophilic congeners, such as AR-67, is more stable, possibly due to partitioning into red cell membranes. This prompted us to develop a reverse-phase HPLC method with fluorescence detection (excitation 380 nm/emission 560 nm), which could quantitate the concentration of AR-67 lactone and carboxylate in whole blood. Samples were prepared by red cell lysis, protein precipitation with methanol and centrifugation to remove denatured materials. Recovery was estimated to be >85%. Analytes were eluted isocratically with 0.15 m ammonium acetate buffer containing 10 mm TBAP (pH 6.5) and acetonitrile (65:35, v/v) on a Nova-Pak C(18) column (4 µm; 3.9 × 150 mm). The assay was linear in the ranges 0.5-300 and 2.5-300 ng/mL for carboxylate and lactone, respectively. Accuracy and precision were acceptable. AR-67 forms were stable in whole blood and in methanolic supernatants. This assay has been successfully applied to measure AR-67 concentrations in whole blood of patients enrolled in a phase I study.

Collaboration


Dive into the Jamie Horn's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Narsimha Reddy Penthala

University of Arkansas for Medical Sciences

View shared research outputs
Researchain Logo
Decentralizing Knowledge