Publications by authors named "Elaine Brown"

38 Publications

"A Woman in A Man's World": A Pilot Qualitative Study of Challenges Faced by Women Veterans During and After Deployment.

J Trauma Dissociation 2021 Mar-Apr;22(2):202-219. Epub 2021 Jan 20.

VISN17 Center of Excellence for Research on Returning War Veterans, Waco, Texas, USA.

Women Veterans face gender-specific challenges to military life and post-deployment readjustment, including gender-based discrimination and military sexual trauma. Despite recent military initiatives to address these issues, women still experience unique challenges during military service. This study examines spontaneous comments about gender-specific challenges to military life that were made by participants in a qualitative study of women's transitions to civilian life after deployment to Iraq or Afghanistan.

Methods: Women Veterans who were enrolled at a New England VA hospital and who had deployed to the U.S. conflicts in Iraq and Afghanistan participated in this qualitative study (N = 22). Interview queries and initial coding structure were developed through an extensive literature review. An iterative coding process generated additional themes identified in the data. For this project, codes regarding self-initiated reports of gender-specific challenges that fell outside the scope of the study's initial interview agenda were reviewed for thematic analysis.

Results: The following three self-initiated themes emerged among 12 respondents: 1) gender-based scrutiny and discrimination; 2) the military's inadequate position and response to military sexual trauma; and 3) disadvantages to women service members living in a male-dominated environment. Across all three themes emerged a sub-theme in which women perceived their unique needs to be inconvenient and/or disregarded. Respondents described how these challenges disrupted their lives during and after military service.

Conclusion: Results imply gender-specific challenges and military sexual trauma remain critical concerns for women Veterans well after deployment had ended, and that improved policy may have long-term health implications.
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http://dx.doi.org/10.1080/15299732.2020.1869068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933094PMC
January 2021

Control of protein palmitoylation by regulating substrate recruitment to a zDHHC-protein acyltransferase.

Commun Biol 2020 Jul 31;3(1):411. Epub 2020 Jul 31.

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Although palmitoylation regulates numerous cellular processes, as yet efforts to manipulate this post-translational modification for therapeutic gain have proved unsuccessful. The Na-pump accessory sub-unit phospholemman (PLM) is palmitoylated by zDHHC5. Here, we show that PLM palmitoylation is facilitated by recruitment of the Na-pump α sub-unit to a specific site on zDHHC5 that contains a juxtamembrane amphipathic helix. Site-specific palmitoylation and GlcNAcylation of this helix increased binding between the Na-pump and zDHHC5, promoting PLM palmitoylation. In contrast, disruption of the zDHHC5-Na-pump interaction with a cell penetrating peptide reduced PLM palmitoylation. Our results suggest that by manipulating the recruitment of specific substrates to particular zDHHC-palmitoyl acyl transferases, the palmitoylation status of individual proteins can be selectively altered, thus opening the door to the development of molecular modulators of protein palmitoylation for the treatment of disease.
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http://dx.doi.org/10.1038/s42003-020-01145-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395175PMC
July 2020

Targeting the trypanosome kinetochore with CLK1 protein kinase inhibitors.

Nat Microbiol 2020 10 13;5(10):1207-1216. Epub 2020 Jul 13.

Novartis Institute for Tropical Diseases, Emeryville, CA, USA.

The kinetochore is a macromolecular structure that assembles on the centromeres of chromosomes and provides the major attachment point for spindle microtubules during mitosis. In Trypanosoma brucei, the proteins that make up the kinetochore are highly divergent; the inner kinetochore comprises at least 20 distinct and essential proteins (KKT1-20) that include four protein kinases-CLK1 (also known as KKT10), CLK2 (also known as KKT19), KKT2 and KKT3. Here, we report the identification and characterization of the amidobenzimidazoles (AB) protein kinase inhibitors that show nanomolar potency against T. brucei bloodstream forms, Leishmania and Trypanosoma cruzi. We performed target deconvolution analysis using a selection of 29 T. brucei mutants that overexpress known essential protein kinases, and identified CLK1 as a primary target. Biochemical studies and the co-crystal structure of CLK1 in complex with AB1 show that the irreversible competitive inhibition of CLK1 is dependent on a Michael acceptor forming an irreversible bond with Cys 215 in the ATP-binding pocket, a residue that is not present in human CLK1, thereby providing selectivity. Chemical inhibition of CLK1 impairs inner kinetochore recruitment and compromises cell-cycle progression, leading to cell death. This research highlights a unique drug target for trypanosomatid parasitic protozoa and a new chemical tool for investigating the function of their divergent kinetochores.
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http://dx.doi.org/10.1038/s41564-020-0745-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610364PMC
October 2020

Essential roles for deubiquitination in Leishmania life cycle progression.

PLoS Pathog 2020 06 16;16(6):e1008455. Epub 2020 Jun 16.

York Biomedical Research Institute and Department of Biology, University of York, United Kingdom.

The parasitic protozoan Leishmania requires proteasomal, autophagic and lysosomal proteolytic pathways to enact the extensive cellular remodelling that occurs during its life cycle. The proteasome is essential for parasite proliferation, yet little is known about the requirement for ubiquitination/deubiquitination processes in growth and differentiation. Activity-based protein profiling of L. mexicana C12, C19 and C65 deubiquitinating cysteine peptidases (DUBs) revealed DUB activity remains relatively constant during differentiation of procyclic promastigote to amastigote. However, when life cycle phenotyping (bar-seq) was performed on a pool including 15 barcoded DUB null mutants created in promastigotes using CRISPR-Cas9, significant loss of fitness was observed during differentiation and intracellular infection. DUBs 4, 7, and 13 are required for successful transformation from metacyclic promastigote to amastigote and DUBs 3, 5, 6, 8, 10, 11 and 14 are required for normal amastigote proliferation in mice. DUBs 1, 2, 12 and 16 are essential for promastigote viability and the essential role of DUB2 in establishing infection was demonstrated using DiCre inducible gene deletion in vitro and in vivo. DUB2 is found in the nucleus and interacts with nuclear proteins associated with transcription/chromatin dynamics, mRNA splicing and mRNA capping. DUB2 has broad linkage specificity, cleaving all the di-ubiquitin chains except for Lys27 and Met1. Our study demonstrates the crucial role that DUBs play in differentiation and intracellular survival of Leishmania and that amastigotes are exquisitely sensitive to disruption of ubiquitination homeostasis.
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http://dx.doi.org/10.1371/journal.ppat.1008455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319358PMC
June 2020

Evaluation of clan CD C11 peptidase PNT1 and other Leishmania mexicana cysteine peptidases as potential drug targets.

Biochimie 2019 Nov 28;166:150-160. Epub 2019 Aug 28.

York Biomedical Research Institute, Department of Biology, University of York, Wentworth Way, Heslington, York, YO10 5DD, UK. Electronic address:

Leishmania mexicana is one of the causative agents of cutaneous leishmaniasis in humans. There is an urgent need to identify new drug targets to combat the disease. Cysteine peptidases play crucial role in pathogenicity and virulence in Leishmania spp. and are promising targets for developing new anti-leishmanial drugs. Genetic drug target validation has been performed on a number of cysteine peptidases, but others have yet to be characterized. We targeted 16 L. mexicana cysteine peptidases for gene deletion and tagging using CRISPR-Cas9 in order to identify essential genes and ascertain their cellular localization. Our analysis indicates that two clan CA, family C2 calpains (LmCAL27.1, LmCAL31.6) and clan CD, family C11 PNT1 are essential for survival in the promastigote stage. The other peptidases analysed, namely calpains LmCAL4.1, LmCAL25.1, and members of clan CA C51, C78, C85 and clan CP C97 were found to be non-essential. We generated a gene deletion mutant (Δpnt1) which was severely compromised in its cell growth and a conditional gene deletion mutant of PNT1 (Δpnt1: PNT1/Δ pnt1:HYG [SSU DiCRE]). PNT1 localizes to distinct foci on the flagellum and on the surface of the parasite. The conditional gene deletion of PNT1 induced blebs and pits on the cell surface and eventual cell death. Over-expression of PNT1, but not an active site mutant PNT1, was lethal, suggesting that active PNT1 peptidase is required for parasite survival. Overall, our data suggests that PNT1 is an essential gene and one of a number of cysteine peptidases that are potential drug targets in Leishmania.
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http://dx.doi.org/10.1016/j.biochi.2019.08.015DOI Listing
November 2019

A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis.

EBioMedicine 2018 Oct 27;36:83-91. Epub 2018 Sep 27.

Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom.; Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom.. Electronic address:

Background: Miltefosine has been used successfully to treat visceral leishmaniasis (VL) in India, but it was unsuccessful for VL in a clinical trial in Brazil.

Methods: To identify molecular markers that predict VL treatment failure whole genome sequencing of 26 L. infantum isolates, from cured and relapsed patients allowed a GWAS analysis of SNPs, gene and chromosome copy number variations.

Findings: A strong association was identified (p = 0·0005) between the presence of a genetically stable L. infantumMiltefosine Sensitivity Locus (MSL), and a positive response to miltefosine treatment. The risk of treatment failure increased 9·4-fold (95% CI 2·11-53·54) when an isolate did not have the MSL. The complete absence of the MSL predicted miltefosine failure with 0·92 (95% CI 0·65-0·996) sensitivity and 0·78 (95% CI 0·52-0·92) specificity. A genotyping survey of L. infantum (n = 157) showed that the frequency of MSL varies in a cline from 95% in North East Brazil to <5% in the South East. The MSL was found in the genomes of all L. infantum and L. donovani sequenced isolates from the Old World (n = 671), where miltefosine can have a cure rate higher than 93%.

Interpretation: Knowledge on the presence or absence of the MSL in L. infantum will allow stratification of patients prior to treatment, helping to establish better therapeutic strategies for VL treatment. FUND: CNPq, FAPES, GCRF MRC and Wellcome Trust.
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http://dx.doi.org/10.1016/j.ebiom.2018.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197651PMC
October 2018

Posttraumatic Stress Disorder and Mobile Health: App Investigation and Scoping Literature Review.

JMIR Mhealth Uhealth 2017 Oct 26;5(10):e156. Epub 2017 Oct 26.

VISN 17 Center of Excellence for Research on Returning War Veterans, Central Texas Veterans Health Care System, Waco, TX, United States.

Background: Posttraumatic stress disorder (PTSD) is a prevalent mental health issue among veterans. Access to PTSD treatment is influenced by geographic (ie, travel distance to facilities), temporal (ie, time delay between services), financial (ie, eligibility and cost of services), and cultural (ie, social stigma) barriers.

Objective: The emergence of mobile health (mHealth) apps has the potential to bridge many of these access gaps by providing remote resources and monitoring that can offer discrete assistance to trauma survivors with PTSD and enhance patient-clinician relationships. In this study, we investigate the current mHealth capabilities relevant to PTSD.

Methods: This study consists of two parts: (1) a review of publicly available PTSD apps designed to determine the availability of PTSD apps, which includes more detailed information about three dominant apps and (2) a scoping literature review performed using a systematic method to determine app usage and efforts toward validation of such mHealth apps. App usage relates to how the end users (eg, clinicians and patients) are interacting with the app, whereas validation is testing performed to ensure the app's purpose and specifications are met.

Results: The results suggest that though numerous apps have been developed to aid in the diagnosis and treatment of PTSD symptoms, few apps were designed to be integrated with clinical PTSD treatment, and minimal efforts have been made toward enhancing the usability and validation of PTSD apps.

Conclusions: These findings expose the need for studies relating to the human factors evaluation of such tools, with the ultimate goal of increasing access to treatment and widening the app adoption rate for patients with PTSD.
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http://dx.doi.org/10.2196/mhealth.7318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680516PMC
October 2017

Synthesis of Caffeine/Maleic Acid Co-crystal by Ultrasound-assisted Slurry Co-crystallization.

J Pharm Sci 2017 01 28;106(1):66-70. Epub 2016 Oct 28.

Centre for Pharmaceutical Engineering Science, University of Bradford, Bradford, West Yorkshire, UK. Electronic address:

A green approach has been used for co-crystallization of noncongruent co-crystal pair of caffeine/maleic acid using water. Ultrasound is known to affect crystallization; hence, the effect of high power ultrasound on the ternary phase diagram has been investigated in detail using a slurry co-crystallization approach. A systematic investigation was performed to understand how the accelerated conditions during ultrasound-assisted co-crystallization will affect different regions of the ternary phase diagram. Application of ultrasound showed considerable effect on the ternary phase diagram, principally on caffeine/maleic acid 2:1 (disappeared) and 1:1 co-crystal (narrowed) regions. Also, the stability regions for pure caffeine and maleic acid in water were narrowed in the presence of ultrasound, expanding the solution region. The observed effect of ultrasound on the phase diagram was correlated with solubility of caffeine and maleic acid and stability of co-crystal forms in water.
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http://dx.doi.org/10.1016/j.xphs.2016.09.009DOI Listing
January 2017

Near infra red spectroscopy as a multivariate process analytical tool for predicting pharmaceutical co-crystal concentration.

J Pharm Biomed Anal 2016 Sep 7;129:172-181. Epub 2016 Jun 7.

Centre for Pharmaceutical Engineering Science, University of Bradford, BD7 1DP, UK.

The use of near infra red spectroscopy to predict the concentration of two pharmaceutical co-crystals; 1:1 ibuprofen-nicotinamide (IBU-NIC) and 1:1 carbamazepine-nicotinamide (CBZ-NIC) has been evaluated. A partial least squares (PLS) regression model was developed for both co-crystal pairs using sets of standard samples to create calibration and validation data sets with which to build and validate the models. Parameters such as the root mean square error of calibration (RMSEC), root mean square error of prediction (RMSEP) and correlation coefficient were used to assess the accuracy and linearity of the models. Accurate PLS regression models were created for both co-crystal pairs which can be used to predict the co-crystal concentration in a powder mixture of the co-crystal and the active pharmaceutical ingredient (API). The IBU-NIC model had smaller errors than the CBZ-NIC model, possibly due to the complex CBZ-NIC spectra which could reflect the different arrangement of hydrogen bonding associated with the co-crystal compared to the IBU-NIC co-crystal. These results suggest that NIR spectroscopy can be used as a PAT tool during a variety of pharmaceutical co-crystal manufacturing methods and the presented data will facilitate future offline and in-line NIR studies involving pharmaceutical co-crystals.
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http://dx.doi.org/10.1016/j.jpba.2016.06.010DOI Listing
September 2016

Conditional gene deletion with DiCre demonstrates an essential role for CRK3 in Leishmania mexicana cell cycle regulation.

Mol Microbiol 2016 06 13;100(6):931-44. Epub 2016 Apr 13.

Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK.

Leishmania mexicana has a large family of cyclin-dependent kinases (CDKs) that reflect the complex interplay between cell cycle and life cycle progression. Evidence from previous studies indicated that Cdc2-related kinase 3 (CRK3) in complex with the cyclin CYC6 is a functional homologue of the major cell cycle regulator CDK1, yet definitive genetic evidence for an essential role in parasite proliferation is lacking. To address this, we have implemented an inducible gene deletion system based on a dimerised Cre recombinase (diCre) to target CRK3 and elucidate its role in the cell cycle of L. mexicana. Induction of diCre activity in promastigotes with rapamycin resulted in efficient deletion of floxed CRK3, resulting in G2/M growth arrest. Co-expression of a CRK3 transgene during rapamycin-induced deletion of CRK3 resulted in complementation of growth, whereas expression of an active site CRK3(T178E) mutant did not, showing that protein kinase activity is crucial for CRK3 function. Inducible deletion of CRK3 in stationary phase promastigotes resulted in attenuated growth in mice, thereby confirming CRK3 as a useful therapeutic target and diCre as a valuable new tool for analyzing essential genes in Leishmania.
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http://dx.doi.org/10.1111/mmi.13375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913733PMC
June 2016

PNT1 Is a C11 Cysteine Peptidase Essential for Replication of the Trypanosome Kinetoplast.

J Biol Chem 2016 Apr 3;291(18):9492-500. Epub 2016 Mar 3.

From the Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom, the Department of Biology, Centre for Immunology and Infection, University of York, Wentworth Way, Heslington, York YO10 5DD, United Kingdom,

The structure of a C11 peptidase PmC11 from the gut bacterium, Parabacteroides merdae, has recently been determined, enabling the identification and characterization of a C11 orthologue, PNT1, in the parasitic protozoon Trypanosoma brucei. A phylogenetic analysis identified PmC11 orthologues in bacteria, archaea, Chromerids, Coccidia, and Kinetoplastida, the latter being the most divergent. A primary sequence alignment of PNT1 with clostripain and PmC11 revealed the position of the characteristic His-Cys catalytic dyad (His(99) and Cys(136)), and an Asp (Asp(134)) in the potential S1 binding site. Immunofluorescence and cryoelectron microscopy revealed that PNT1 localizes to the kinetoplast, an organelle containing the mitochondrial genome of the parasite (kDNA), with an accumulation of the protein at or near the antipodal sites. Depletion of PNT1 by RNAi in the T. brucei bloodstream form was lethal both in in vitro culture and in vivo in mice and the induced population accumulated cells lacking a kinetoplast. In contrast, overexpression of PNT1 led to cells having mislocated kinetoplasts. RNAi depletion of PNT1 in a kDNA independent cell line resulted in kinetoplast loss but was viable, indicating that PNT1 is required exclusively for kinetoplast maintenance. Expression of a recoded wild-type PNT1 allele, but not of an active site mutant restored parasite viability after induction in vitro and in vivo confirming that the peptidase activity of PNT1 is essential for parasite survival. These data provide evidence that PNT1 is a cysteine peptidase that is required exclusively for maintenance of the trypanosome kinetoplast.
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http://dx.doi.org/10.1074/jbc.M116.714972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850289PMC
April 2016

An essential signal peptide peptidase identified in an RNAi screen of serine peptidases of Trypanosoma brucei.

PLoS One 2015 27;10(3):e0123241. Epub 2015 Mar 27.

Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

The serine peptidases of Trypanosoma brucei have been viewed as potential drug targets. In particular, the S9 prolyl oligopeptidase subfamily is thought to be a good avenue for drug discovery. This is based on the finding that some S9 peptidases are secreted and active in the mammalian bloodstream, and that they are a class of enzyme against which drugs have successfully been developed. We collated a list of all serine peptidases in T. brucei, identifying 20 serine peptidase genes, of which nine are S9 peptidases. We screened all 20 serine peptidases by RNAi to determine which, if any, are essential for bloodstream form T. brucei survival. All S9 serine peptidases were dispensable for parasite survival in vitro, even when pairs of similar genes, coding for oligopeptidase B or prolyl oligopeptidase, were targeted simultaneously. We also found no effect on parasite survival in an animal host when the S9 peptidases oligopeptidase B, prolyl oligopeptidase or dipeptidyl peptidase 8 were targeted. The only serine peptidase to emerge from the RNAi screen as essential was a putative type-I signal peptide peptidase (SPP1). This gene was essential for parasite survival both in vitro and in vivo. The growth defect conferred by RNAi depletion of SPP1 was rescued by expression of a functional peptidase from an RNAi resistant SPP1 gene. However, expression of catalytically inactive SPP1 was unable to rescue cells from the SPP1 depleted phenotype, demonstrating that SPP1 serine peptidase activity is necessary for T. brucei survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123241PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376731PMC
February 2016

Oral health care for underserved children in the United States.

J Community Health Nurs 2014 ;31(1):1-7

a Utica College , Utica , New York.

Dental caries is the most common chronic disease of childhood with approximately 25% of children from low-income families entering kindergarten without ever having seen a dentist ( Larsen, Larsen, Handwerker, Kim, & Rosenthal, 2009 ). Youth, poverty, and race are characteristics of populations susceptible to oral disease (Dye, Xianfen, & Thorton-Evans, 2012). Services delivering oral health care to underserved populations are referred to as dental safety-net clinics. This article explores the impact of the dental safety-net on improving access to oral health care for underserved children in the United States.
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http://dx.doi.org/10.1080/07370016.2014.868729DOI Listing
April 2015

Regulators of Trypanosoma brucei cell cycle progression and differentiation identified using a kinome-wide RNAi screen.

PLoS Pathog 2014 Jan 16;10(1):e1003886. Epub 2014 Jan 16.

Wellcome Trust Centre for Molecular Parasitology and Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom ; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

The African trypanosome, Trypanosoma brucei, maintains an integral link between cell cycle regulation and differentiation during its intricate life cycle. Whilst extensive changes in phosphorylation have been documented between the mammalian bloodstream form and the insect procyclic form, relatively little is known about the parasite's protein kinases (PKs) involved in the control of cellular proliferation and differentiation. To address this, a T. brucei kinome-wide RNAi cell line library was generated, allowing independent inducible knockdown of each of the parasite's 190 predicted protein kinases. Screening of this library using a cell viability assay identified ≥42 PKs that are required for normal bloodstream form proliferation in culture. A secondary screen identified 24 PKs whose RNAi-mediated depletion resulted in a variety of cell cycle defects including in G1/S, kinetoplast replication/segregation, mitosis and cytokinesis, 15 of which are novel cell cycle regulators. A further screen identified for the first time two PKs, named repressor of differentiation kinase (RDK1 and RDK2), depletion of which promoted bloodstream to procyclic form differentiation. RDK1 is a membrane-associated STE11-like PK, whilst RDK2 is a NEK PK that is essential for parasite proliferation. RDK1 acts in conjunction with the PTP1/PIP39 phosphatase cascade to block uncontrolled bloodstream to procyclic form differentiation, whilst RDK2 is a PK whose depletion efficiently induces differentiation in the absence of known triggers. Thus, the RNAi kinome library provides a valuable asset for functional analysis of cell signalling pathways in African trypanosomes as well as drug target identification and validation.
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http://dx.doi.org/10.1371/journal.ppat.1003886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894213PMC
January 2014

Long-term consequences of membership in trajectory groups of delinquent behavior in an urban sample: violence, drug use, interpersonal, and neighborhood attributes.

Aggress Behav 2013 Nov-Dec;39(6):440-52. Epub 2013 Jun 27.

New York University School of Medicine, New York, New York.

Research on stability and change in delinquent behavior over time has important implications for both the individual and the criminal justice system. The present research looks at this issue by examining the associations between the trajectories of delinquent behavior in adolescence and adult functioning. Data for the present study are from a four-wave longitudinal study of African American and Hispanic participants. Participants provided information at mean ages 14, 19, 24, and 29. We used growth mixture modeling to extract trajectory groups of delinquent behavior in adolescence and young adulthood. Regression analyses were conducted to examine whether memberships in the trajectory groups of delinquent behavior from mean age 14 to mean age 24 were associated with violence, substance abuse and dependence, partner discord, peer substance use, and residence in a high-crime neighborhood at mean age 29 when compared with the reference trajectory group of participants with low or no delinquent behavior. Four trajectory groups of delinquent behavior were identified: the no/low, the decreasing, the moderate, and the high persistent trajectory groups. Memberships in the trajectory groups were significantly correlated with variations in adult functioning. Memberships in some trajectory groups of delinquent behavior are significant predictors of later violent behavior, substance abuse and dependence, partner discord, peer substance use, and residence in a high-crime neighborhood. The findings reinforce the importance of investing in interventions to address different patterns of delinquent behavior. Findings are discussed in relation to previous investigations with non-Hispanic White samples.
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http://dx.doi.org/10.1002/ab.21493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795961PMC
May 2014

The Association of Externalizing Behavior and Parent-Child Relationships: An Intergenerational Study.

J Child Fam Stud 2012 Jun;21(3):418-427

Department of Psychiatry, New York University School of Medicine, New York, NY 10016.

We investigated the influence of the child's behavior on the quality of the mutual parent-child attachment relationships across three generations. We did so using a prospective longitudinal study which spanned 20 years from adolescence through adulthood. Study participants completed in-class questionnaires as students in the East Harlem area of New York City at the first wave and provided follow-up data at 4 additional points in time. 390 participants were included in these analyses; 59% female, 45% African American, and 55% Puerto Rican. Using structural equation modeling, we determined that externalizing behavior in the child was negatively related to the mutual parent-child attachment relationship for two generations of children. We also found continuity in externalizing behavior for the participant over time and from the participant to his/her child. Additionally, we found continuity in the quality of the mutual attachment relationship from the participant's relationship with his/her parents to the participant's relationship with his/her child. Finally, the mutual attachment relationship of the participant with his/her parents had a negative association with the participant's externalizing behavior in adulthood. Based on these results, we propose that family interventions should focus on the role of the child's externalizing behavior in the context of the parent-child attachment relationship. Furthermore, we suggest that prevention programs should address externalizing behavior as early as possible, as the effects of externalizing behavior in adolescence can persist into adulthood and extend to the next generation.
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http://dx.doi.org/10.1007/s10826-011-9493-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650851PMC
June 2012

Individuality and contextual influences on drug dependence: a 15-year Prospective longitudinal study of adolescents from Harlem.

J Genet Psychol 2012 Oct-Dec;173(4):355-73

New York University School of Medicine, Department of Psychiatry, 215 Lexington Ave., 15th Fl., New York, NY 10016, USA.

In this 15-year longitudinal study the authors investigated individual and contextual factors that predispose adolescents from a disadvantaged urban area to drug dependence in adulthood. Adolescents were recruited from schools serving East Harlem in New York City. Of the 838 participants followed to adulthood, 59% were women, 55% were African American, and 45% were Puerto Rican. Self-report data were obtained on externalizing and internalizing problems, substance use, and contextual influences across adolescence and young adulthood. Drug dependence was assessed in adulthood. Multivariate logistic regressions of drug dependence were performed on the whole sample and separately by gender. Each of the domains was associated with adult drug dependence. Although mean gender differences were found, most associations of risk factors with drug dependence did not vary significantly by gender. Treating externalizing and internalizing problems, reducing substance use, and providing coping skills for adverse contextual influences in adolescence and young adulthood may reduce the likelihood of becoming drug dependent in adulthood.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530137PMC
http://dx.doi.org/10.1080/00221325.2011.620998DOI Listing
February 2013

Comorbid trajectories of tobacco and marijuana use as related to psychological outcomes.

Subst Abus 2012 ;33(2):156-67

Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.

Heterogeneous classes of comorbid trajectories of tobacco and marijuana use were examined in order to determine how they are related to subsequent antisocial behavior, poor self-control, and internalizing behavior. Data are from a 4-wave longitudinal study of African American (n = 243) and Puerto Rican (n = 232) adolescents and adults in the community. Logistic regression analyses were employed to measure the association between the comorbid trajectories of tobacco and marijuana use and the psychological difficulty variables. The authors found 6 joint trajectory groups. The authors compared the non-or-experimental tobacco/marijuana use group with the other user groups in each of the psychological difficulty domains. The infrequent tobacco/late-onset marijuana use and chronic tobacco/marijuana use groups differed most strongly from the non-or-experimental tobacco/marijuana use group across the antisocial behavior, poor self-control, and internalizing problems domains. The chronic tobacco/maturing out marijuana use group also had significant associations in each of these domains. The infrequent tobacco/marijuana use and late-onset tobacco/infrequent marijuana use groups had no or weak associations with the psychological outcomes. Tobacco and marijuana cessation programs should identify and address comorbid use of tobacco and marijuana, and antisocial behavior, poor self-control, and internalizing problems, which are associated with histories of comorbid use of the 2 substances.
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http://dx.doi.org/10.1080/08897077.2011.640202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325512PMC
August 2012

Psychometric study of the Aberrant Behavior Checklist in Fragile X Syndrome and implications for targeted treatment.

J Autism Dev Disord 2012 Jul;42(7):1377-92

Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Medical Center, 2825 50th Street, Sacramento, CA 95817, USA.

Animal studies elucidating the neurobiology of fragile X syndrome (FXS) have led to multiple controlled trials in humans, with the Aberrant Behavior Checklist-Community (ABC-C) commonly adopted as a primary outcome measure. A multi-site collaboration examined the psychometric properties of the ABC-C in 630 individuals (ages 3-25) with FXS using exploratory and confirmatory factor analysis. Results support a six-factor structure, with one factor unchanged (Inappropriate Speech), four modified (Irritability, Hyperactivity, Lethargy/Withdrawal, and Stereotypy), and a new Social Avoidance factor. A comparison with ABC-C data from individuals with general intellectual disability and a list of commonly endorsed items are also reported. Reformulated ABC-C scores based on this FXS-specific factor structure may provide added outcome measure specificity and sensitivity in FXS clinical trials.
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http://dx.doi.org/10.1007/s10803-011-1370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290710PMC
July 2012

Developmental trajectories of marijuana use from adolescence to adulthood: personality and social role outcomes.

Psychol Rep 2011 Apr;108(2):339-57

Department of Psychiatry, New York University School of Medicine, 215 Lexington Ave., 15th Fl., New York, NY 10016, USA.

Longitudinal trajectories of marijuana use from adolescence into adulthood were examined for adverse life-course outcomes among African-Americans and Puerto Ricans. Data for marijuana use were analyzed at four points in time and on participants' personality attributes, work functioning, and partner relations in adulthood using growth mixture modeling. Each of the three marijuana-use trajectory groups (maturing-out, late-onset, and chronic marijuana-users) had greater adverse life-course outcomes than a nonuse or low-use trajectory group. The chronic marijuana-use trajectory group was highly associated with criminal behavior and partners' marijuana use in adulthood. Treatment programs for marijuana use should also directly address common adverse life-course outcomes users may already be experiencing.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117277PMC
http://dx.doi.org/10.2466/10.18.PR0.108.2.339-357DOI Listing
April 2011

High throughput screens yield small molecule inhibitors of Leishmania CRK3:CYC6 cyclin-dependent kinase.

PLoS Negl Trop Dis 2011 Apr 5;5(4):e1033. Epub 2011 Apr 5.

Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

Background: Leishmania species are parasitic protozoa that have a tightly controlled cell cycle, regulated by cyclin-dependent kinases (CDKs). Cdc2-related kinase 3 (CRK3), an essential CDK in Leishmania and functional orthologue of human CDK1, can form an active protein kinase complex with Leishmania cyclins CYCA and CYC6. Here we describe the identification and synthesis of specific small molecule inhibitors of bacterially expressed Leishmania CRK3:CYC6 using a high throughput screening assay and iterative chemistry. We also describe the biological activity of the molecules against Leishmania parasites.

Methodology/principal Findings: In order to obtain an active Leishmania CRK3:CYC6 protein kinase complex, we developed a co-expression and co-purification system for Leishmania CRK3 and CYC6 proteins. This active enzyme was used in a high throughput screening (HTS) platform, utilising an IMAP fluorescence polarisation assay. We carried out two chemical library screens and identified specific inhibitors of CRK3:CYC6 that were inactive against the human cyclin-dependent kinase CDK2:CycA. Subsequently, the best inhibitors were tested against 11 other mammalian protein kinases. Twelve of the most potent hits had an azapurine core with structure activity relationship (SAR) analysis identifying the functional groups on the 2 and 9 positions as essential for CRK3:CYC6 inhibition and specificity against CDK2:CycA. Iterative chemistry allowed synthesis of a number of azapurine derivatives with one, compound 17, demonstrating anti-parasitic activity against both promastigote and amastigote forms of L. major. Following the second HTS, 11 compounds with a thiazole core (active towards CRK3:CYC6 and inactive against CDK2:CycA) were tested. Ten of these hits demonstrated anti-parasitic activity against promastigote L. major.

Conclusions/significance: The pharmacophores identified from the high throughput screens, and the derivatives synthesised, selectively target the parasite enzyme and represent compounds for future hit-to-lead synthesis programs to develop therapeutics against Leishmania species. Challenges remain in identifying specific CDK inhibitors with both target selectivity and potency against the parasite.
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http://dx.doi.org/10.1371/journal.pntd.0001033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071374PMC
April 2011

Oligopeptidase B deficient mutants of Leishmania major.

Mol Biochem Parasitol 2011 Jan 29;175(1):49-57. Epub 2010 Sep 29.

Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, Scotland, UK.

Oligopeptidase B is a clan SC, family S9 serine peptidase found in gram positive bacteria, plants and trypanosomatids. Evidence suggests it is a virulence factor and thus therapeutic target in both Trypanosoma cruzi and T. brucei, but little is known about its function in Leishmania. In this study L. major OPB-deficient mutants (Δopb) were created. These grew normally as promastigotes, had a small deficiency in their ability to undergo differentiation to metacyclic promastigotes, were significantly less able to infect and survive within macrophages in vitro, but were virulent to mice. These data suggest that L. major OPB itself is not an important virulence factor, indicating functional differences between trypanosomes and Leishmania in their interaction with the mammalian host. The possibility that an OPB-like enzyme (designated OPB2) in L. major might compensate for the loss of OPB in Δopb was investigated via by mapping its sequence onto the 1.6Å structure of L. major OPB. This suggested that the residues involved in the S1 and S2 subsites of OPB2 are identical to OPB and hence the substrate specificity would be similar. Consequently there may be redundancy between the two enzymes.
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http://dx.doi.org/10.1016/j.molbiopara.2010.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130898PMC
January 2011

Recombinant Leishmania mexicana CRK3:CYCA has protein kinase activity in the absence of phosphorylation on the T-loop residue Thr178.

Mol Biochem Parasitol 2010 Jun 23;171(2):89-96. Epub 2010 Mar 23.

Wellcome Trust Centre for Molecular Parasitology and Division of Infection & Immunity, Faculty of Biomedical and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.

The activity of cyclin-dependent kinases (CDKs), which are key regulators of the eukaryotic cell cycle, is regulated through post-translational mechanisms, including binding of a cyclin and phosphorylation. Previously studies have shown that Leishmania mexicana CRK3 is an essential CDK that is a functional homologue of human CDK1. In this study, recombinant histidine tagged L. mexicana CRK3 and the cyclin CYCA were combined in vitro to produce an active histone H1 kinase that was inhibited by the CDK inhibitors, flavopiridol and indirubin-3'-monoxime. Protein kinase activity was observed in the absence of phosphorylation of the T-loop residue Thr178, but increased 5-fold upon phosphorylation by the CDK activating kinase Civ1 of Saccharomyces cerevisiae. Seven recombinant L. major CRKs (1, 2, 3, 4, 6, 7 and 8) were also expressed and purified, none of which were active as monomers. Moreover, only CRK3 was phosphorylated by Civ1. HA-tagged CYCA expressed in L. major procyclic promastigotes was co-precipitated with CRK3 and exhibited histone H1 kinase activity. These data indicate that in Leishmania CYCA interacts with CRK3 to form an active protein kinase, confirm the conservation of the regulatory mechanisms that control CDK activity in other eukaryotes, but identifies biochemical differences to human CDK1.
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http://dx.doi.org/10.1016/j.molbiopara.2010.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857504PMC
June 2010

Course of comorbidity of tobacco and marijuana use: psychosocial risk factors.

Nicotine Tob Res 2010 May 15;12(5):474-82. Epub 2010 Mar 15.

Department of Psychiatry, New York University School of Medicine, 215 Lexington Avenue, New York, NY 10016, USA.

Introduction: This longitudinal study examined the psychosocial factors associated with the comorbidity of pairs of tobacco and marijuana use trajectories from adolescence extending into adulthood in two ethnic groups, Blacks and Puerto Ricans.

Methods: Data on psychosocial functioning and tobacco and marijuana use at four points in time were obtained.

Results: The association between the trajectories of tobacco and marijuana use was quite high. Pairs of comorbid trajectories of tobacco and marijuana use may share at least three kinds of influence: (a) a constellation of externalizing personality risk factors, (b) Depressive Mood and low Ego Integration, and (c) identification with certain group values.

Discussion: Knowledge of the risk and protective factors for pairs of comorbid trajectories of use may strengthen the foundation for individual and group targets for prevention and treatment programs.
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http://dx.doi.org/10.1093/ntr/ntq027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861886PMC
May 2010

Searching for novel cell cycle regulators in Trypanosoma brucei with an RNA interference screen.

BMC Res Notes 2009 Mar 23;2:46. Epub 2009 Mar 23.

Division of Infection & Immunity, Faculty of Biomedical and Life Sciences and Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow, UK.

Background: The protozoan parasite, Trypanosoma brucei, is spread by the tsetse fly and causes Human African Trypanosomiasis. Its cell cycle is complex and not fully understood at the molecular level. The T. brucei genome contains over 6000 protein coding genes with >50% having no predicted function. A small scale RNA interference (RNAi) screen was carried out in Trypanosoma brucei to evaluate the prospects for identifying novel cycle regulators.

Results: Procyclic form T. brucei were transfected with a genomic RNAi library and 204 clones isolated. However, only 76 RNAi clones were found to target a protein coding gene of potential interest. These clones were screened for defects in proliferation and cell cycle progression following RNAi induction. Sixteen clones exhibited proliferation defects upon RNAi induction, with eight clones displaying potential cell cycle defects. To confirm the phenotypes, new RNAi cell lines were generated and characterised for five genes targeted in these clones. While we confirmed that the targeted genes are essential for proliferation, we were unable to unambiguously classify them as cell cycle regulators.

Conclusion: Our study identified genes essential for proliferation, but did not, as hoped, identify novel cell cycle regulators. Screening of the RNAi library for essential genes was extremely labour-intensive, which was compounded by the suboptimal quality of the library. For such a screening method to be viable for a large scale or genome wide screen, a new, significantly improved RNAi library will be required, and automated phenotyping approaches will need to be incorporated.
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http://dx.doi.org/10.1186/1756-0500-2-46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674452PMC
March 2009

"The red zone": temporal risk for unwanted sex among college students.

J Interpers Violence 2008 Sep 4;23(9):1177-96. Epub 2008 Mar 4.

Department of Psychology, Bucknell University, Lewisburg, PA 17837, USA.

The "red zone" usually refers to the first few weeks of the first semester at college, when female students are believed to be at greatest risk for experiencing unwanted sex. We tested this notion using data from a survey study of 207 first-and second-year students (121 women, 84 men) at a small, liberal arts university. Results demonstrated only one significant elevation in incidence rates of first- and second-year women's unwanted sexual experiences (sexual touching, attempted and completed anal, oral, and vaginal sex), between the end of the first month and fall break (mid-October) during the second year at school. Previous research and local information about the relevant behaviors of sorority and fraternity members is discussed in light of these findings to provide heuristic material for further empirical testing. Because risk may involve both temporal and situational factors, systematic collection and dissemination of local data are recommended.
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http://dx.doi.org/10.1177/0886260508314308DOI Listing
September 2008

AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis.

Clin Cancer Res 2007 Jun;13(12):3682-8

AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.

Purpose: In the current study, we examined the in vivo effects of AZD1152, a novel and specific inhibitor of Aurora kinase activity (with selectivity for Aurora B).

Experimental Design: The pharmacodynamic effects and efficacy of AZD1152 were determined in a panel of human tumor xenograft models. AZD1152 was dosed via several parenteral (s.c. osmotic mini-pump, i.p., and i.v.) routes.

Results: AZD1152 potently inhibited the growth of human colon, lung, and hematologic tumor xenografts (mean tumor growth inhibition range, 55% to > or =100%; P < 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumor-bearing athymic rats treated i.v. with AZD1152 revealed a temporal sequence of phenotypic events in tumors: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (>4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumors. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of AZD1152 treatment.

Conclusions: These data suggest that selective targeting of Aurora B kinase may be a promising therapeutic approach for the treatment of a range of malignancies. In addition to the suppression of histone H3 phosphorylation, determination of tumor cell polyploidy and apoptosis may be useful biomarkers for this class of therapeutic agent. AZD1152 is currently in phase I trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-2979DOI Listing
June 2007

Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase.

J Med Chem 2007 May 21;50(9):2213-24. Epub 2007 Mar 21.

AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.
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http://dx.doi.org/10.1021/jm061335fDOI Listing
May 2007

Bioindicators and reproductive effects of prolonged 17beta-oestradiol exposure in a marine fish, the sand goby (Pomatoschistus minutus).

Aquat Toxicol 2007 Mar 14;81(4):397-408. Epub 2007 Jan 14.

Fisheries Research Services, Marine Laboratory, PO Box 101, 375 Victoria Road, Aberdeen AB11 9DB, UK.

The effects of 17beta-oestradiol (E2) on mortality, growth rates, sexual maturation, hepatic vitellogenin (VTG) mRNA expression and reproductive success were investigated during an 8-month, water-borne exposure of a marine fish, the sand goby (Pomatoschistus minutus). Indicators of oestrogenic exposure were investigated as predictors of population-level reproductive success. E2 exposure concentrations were <5 (below limit of detection), 16+/-3, 97+/-20 and 669+/-151 ng l(-1) (bootstrap means and standard errors). The carrier solvent (<20 microl l(-1) propan-2-ol) significantly reduced the rate of egg production compared to untreated fish, but did not significantly affect male VTG mRNA expression, brood size, or the other studied parameters. Fish exposed to 16 ng l(-1) E2 showed few adverse effects compared with solvent only-exposed fish. Exposure to 97 ng l(-1) E2 significantly inhibited male sexual maturation, induced male VTG mRNA expression and delayed spawning. The 97 ng l(-1) E2 exposed population also produced fertile eggs at a significantly slower rate than solvent controls; however, brood size, fertility and overall reproductive success were not significantly affected. Exposure to 669 ng l(-1) E2 significantly increased mortality, adversely affected haematological parameters and caused an almost total lack of reproductive activity, with both sexes failing to mature. Reproductive failure following exposure to 669 ng l(-1) E2 was evident in both sexes when crossed with untreated animals. This work indicates that marine fish are similarly as sensitive to oestrogenic exposure as freshwater fish, that exposure biomarkers such as VTG are more sensitive to exposure than are reproductive effects, and that the use of carrier solvents in long-term reproductive studies should be avoided.
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http://dx.doi.org/10.1016/j.aquatox.2006.12.020DOI Listing
March 2007

Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors.

J Med Chem 2006 Feb;49(3):955-70

AstraZeneca, Centre de Recherches, Parc Industriel Pompelle, BP1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.

The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.
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http://dx.doi.org/10.1021/jm050786hDOI Listing
February 2006