Life Sciences Commons^™

Reactions Of Iminoglycines With C60 Fullerene And Their Unambiguous Characterisation Using Nmr Spectroscopy, Paul A. Keller, Stephen G. Pyne, Bill C. Hawkins

Paul Keller

This review examines the addition of iminoglycine derivatives to C60, yielding protected fullerenyl pyrroline derivatives. Subsequent reduction with sodium cyanoborohydride produces ring-opening adducts which are protected fullerenyl α-amino acids. Pyrroline bisadducts can be produced using tethers to link two iminoglycine units together, and variations include combining with malonate reactive groups this giving rise to interesting observations as to the regioselectivity of such reactions. All derivatives are fully characterised by NMR spectroscopy, and in the case of bis-adducts, the regioselectivity is determined from 1H/13C and 13C/13C connectivity patterns using HMBC and INADEQUATE experiments, respectively, thus eliminating the need for comparative techniques …

New Cyclic Peptides Via Ring-Closing Metathesis Reactions And Their Anti-Bacterial Activities, Timothy P. Boyle, John B. Bremner, Jonathan Coates, John Deadman, Paul A. Keller, Stephen G. Pyne, David I. Rhodes

Paul Keller

As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold as potential novel anti-bacterial agents, we explored the synthesis of simple tyrosine-based systems. These were prepared via key intermediates containing internal allylglycine and allyltyrosine residues for subsequent ring closing metathesis reactions. Although the resulting anti-bacterial activity against Staphylococcus aureus was modest, this represents a novel and simple route to this class of compounds. One intermediate acyclic dipeptide precursor showed good activity against S. aureus with an MIC of 7.8 µg/mL.

Regioselective Synthesis Of Novel E-Edge-[60]Fullerenylmethanodihydropyrroles And 1,2-Dihydromethano[60]Fullerenes, Leila Chaker, Graham E. Ball, James R. Williams, Glenn A. Burley, Bill C. Hawkins, Paul A. Keller, Stephen G. Pyne

Paul Keller

Treatment of a tethered N-(diphenylmethylene)glycinate-malonate derivative with [60]fullerene under Bingel conditions yielded an e-edge-[60]fullerenylmethanodihydropyrrole adduct in a regioselective manner. The regiochemical outcome was independent of the order of addition of either the N-(diphenylmethylene)glycinate or the malonate moieties. This new bis-adduct was also prepared in 13C enriched form allowing for its unequivocal structural characterization by 2D INADEQUATE NMR experiments. Ring-opening of the dihydropyrrole functionality of the bisadducts under reductive conditions gave exclusively novel dihydromethano[60]fullerene derivatives.

The Role Of The Hpa Axis In Psychiatric Disorders And Crf Antagonists As Potential Treatments, Paul A. Keller, A. Mccluskey, J. Morgan, S. M. O'Connor

Paul Keller

An overview of the links between the Hypothalamic-Pituitary-Adrenal (HPA) axis and psychiatric disorders is presented. The current treatments are outlined, indicating that they are insufficient to meet the needs of those that suffer from these affective disorders. Therefore, there is an urgent need for the generation of new therapeutics, in particular, against new targets. The association of the corticotrophin releasing factor (CRF) and the HPA axis indicates that CRF antagonists should be beneficial as potential therapeutics.

A Convenient And Efficient Synthesis Of (S)-Lysine And (S)-Arginine Homologues Via Olefin Cross-Metathesis, Timothy P. Boyle, John B. Bremner, Jonathan A. Coates, Paul A. Keller, Stephen G. Pyne

Paul Keller

A convenient five step synthesis of (S)-homolysine, incorporating a key olefin cross-metathesis step in the chain extension methodology, has been developed, together with a six step related synthesis of a new homologue of arginine, (S)-bishomoarginine.

Antimalarial Activity Of 2,4-Diaminopyrimidines, J. Morgan, R. Haritakul, Paul A. Keller

Paul Keller

A series of 2,4- and 4,6-diaminopyrimidines were prepared and evaluated for their in vitro antimalarial activity. Of the 12 compounds tested 7 showed reasonable activity with 1 having a sub-micromolar IC50.

Aryl Nitro Reduction With Iron Powder Or Stannous Chloride Under Ultrasonic Irradiation, A. B. Gamble, James A. Garner, Christopher Gordon, S. M. J. O'Conner, Paul A. Keller

Paul Keller

The selective reduction of aryl nitro compounds in the presence of sensitive functionalities, including halide, carbonyl, nitrile and ester substituents under ultrasonic irradiation at 35 kHz is reported in yields of 39-98%. Iron powder proved superior to stannous chloride with high tolerance of sensitive functional groups and high yields of the desired aryl amines in relatively short reaction times. Simple experimental procedure and purification also make the iron reduction of aryl nitro compounds advantageous over other methods of reduction.

Control Of Hiv Through The Inhibition Of Hiv-1 Integrase: A Medicinal Chemistry Perspective, Christopher Gordon, R. Griffith, Paul A. Keller

Paul Keller

This article reviews the current status of classes of HIV-1 integrase enzyme inhibitors. These classes include peptide-based inhibitors, natural products, polyhydroxylated aromatics, diketo acids, naphthyridines, and sulfonated compounds including sulfonic acids. Discussions of structure activity relationships are presented and include the current overview of the structure-based model, suitable for the further design and development. To date, the advances in the medicinal chemistry of HIV-1 integrase inhibitors have relied mostly on ligand-based designs leading to most displaying similar binding interactions within the active site or at the dimer interface. This paves the way for single enzyme mutations rendering entire compound classes …

The Prevention Of Preterm Labour – Corticotropin Releasing Hormone Type 1 Receptors As A Target For Drug Design And Development, Paul A. Keller, K. Kirkwood, J. Morgan, S. Westcott, A. Mccluskey

Paul Keller

The role of the corticotropin releasing hormone in the onset of labour and the subsequent medicinal chemistry implications of CRH antagonists for the prevention of premature birth, and identification of the CRH type 1 receptor as the target for this drug design, are reviewed here.

A New Methodology For The Simulation Of Flexible Protein – Ligand Interactions, James A. Garner, John Deadman, David I. Rhodes, Renate Griffith, Paul A. Keller

Paul Keller

A methodology has been developed for the simulation of induced fit between a ligand and its target protein. It utilizes constrained molecular dynamics where atoms determined to be immobile from difference distance matrix studies are fixed. Application of this methodology to HIV-1 reverse transcriptase (RT) as the example target protein has demonstrated its robustness. Short simulation times are sufficient to achieve good refinement of docking poses resulting from exchange of structurally dissimilar inhibitors between crystal structures.

Corticotropin Releasing Hormone - A Gpcr Drug Target, C. Hemley, A. Mccluskey, Paul A. Keller

Paul Keller

Corticotrophin Releasing Hormone (CRH) is a primary hormone in the fight or flight response targeting a membrane bound G-protein coupled receptor (GPCR). Many people worldwide stand to benefit by the development of CRH agonists and antagonists for the treatment of anxiety and depression, with additional therapeutic targets including Alzheimer’s, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR …

Combining Structure-Based Drug Design And Pharmacophores, Renate Griffith, T. T. T. Luu, James A. Garner, Paul A. Keller

Paul Keller

Development towards integrated computer-aided drug design methodologies is presented by utilising crystal structure complexes to produce structure-based pharmacophores. These novel pharmacophores represent the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The protein-ligand complexes can also yield information about all interactions that ligands could potentially form with the binding site, as well as about the size of the binding cavity. Together, these describe a 'superligand', which can also be viewed as a pharmacophore. Various types of novel pharmacophores are discussed and compared, using HIV-1 Reverse …

Body Mass Index, Treatment Practices, And Mortality In Patients With Acute Heart Failure, Timothy Fitzgibbons, Olga Hardy, Darleen Lessard, Joel Gore, Jorge Yarzebski, Robert Goldberg

Jorge L. Yarzebski

OBJECTIVES: Obesity is associated with an increased risk of heart failure (HF). Among patients presenting with acute HF, however, differences in clinical characteristics, treatment regimens, and short-term prognosis of varying weights are largely unknown, particularly from a broader population-based perspective. METHODS: A total of 3722 patients admitted with acute HF to 11 greater Worcester (Massachusetts, USA) hospitals during 1995 and 2000 were categorized as being lean (n = 216), normal weight (n = 1465), overweight (n = 1007), or obese (n = 1034) at the time of hospitalization. RESULTS: Obese patients with decompensated HF were significantly younger (mean age = …

Prognosis Of Acute Myocardial Infarction Complicated By Complete Heart Block (The Worcester Heart Attack Study), Robert Goldberg, Juan Zevallos, Jorge Yarzebski, Joseph Alpert, Joel Gore, Z. Chen, James Dalen

Jorge L. Yarzebski

As part of a community-based study of patients hospitalized with acute myocardial infarction (AMI) in the Worcester, Massachusetts, metropolitan area, changes over time in the incidence rates of complete heart block (CHB) complicating AMI, and the prognostic impact of CHB on the in-hospital and long-term survival of these patients were examined. In all, 4,762 patients with validated AMI hospitalized at 16 hospitals in the Worcester metropolitan area during 1975, 1978, 1981, 1984, 1986 and 1988 constituted the study sample. The incidence rates of CHB complicating AMI remained relatively stable at 5.8% over the 13-year (1975 to 1988) period studied. The …

Changes Over Time In The Use Of Aspirin In Patients Hospitalized With Acute Myocardial Infarction (1975 To 1997): A Population-Based Perspective, Elizabeth Jackson, Ramya Sivasubramian, Frederick Spencer, Jorge Yarzebski, Darleen Lessard, Joel Gore, Robert Goldberg

Jorge L. Yarzebski

OBJECTIVE: The purpose of this study was to examine 2 decade-long trends in the use of aspirin and associated outcomes in patients hospitalized with acute myocardial infarction. BACKGROUND: Aspirin has been shown to be beneficial in the secondary prevention of AMI. However, little is known about changes over time in the use of aspirin in patients hospitalized with AMI and associated outcomes, particularly from a more generalizable population-based perspective. METHODS: We examined trends in aspirin use and hospital and long-term outcomes in 9336 metropolitan Worcester, Mass, residents hospitalized with validated AMI in all area hospitals between 1975 and 1997. RESULTS: …

Thirty-Year Trends (1975-2005) In The Magnitude, Patient Characteristics, And Hospital Outcomes Of Patients With Acute Myocardial Infarction Complicated By Ventricular Fibrillation, Robert Goldberg, Jorge Yarzebski, Frederick Spencer, Juan Zevallos, Darleen Lessard, Joel Gore

Jorge L. Yarzebski

Limited contemporary data are available describing the incidence rates, hospital prognosis, and factors associated with the occurrence of ventricular fibrillation (VF) in patients hospitalized with acute myocardial infarction (AMI). The objectives of our study were to examine 3-decade-long trends (1975 to 2005) in the magnitude, predictors, and hospital case-fatality rates associated with VF in residents of a large New England metropolitan area hospitalized at all area medical centers with an uncomplicated AMI. The study population consisted of 7,472 residents of the Worcester (Massachusetts) metropolitan area hospitalized with an uncomplicated AMI in 15 annual periods from 1975 to 2005. The overall …

Temporal Trends (1975 Through 1990) In The Incidence And Case-Fatality Rates Of Primary Ventricular Fibrillation Complicating Acute Myocardial Infarction. A Communitywide Perspective, David Chiriboga, Jorge Yarzebski, Robert Goldberg, Joel Gore, Joseph Alpert

Jorge L. Yarzebski

BACKGROUND: As part of a population-based study of acute myocardial infarction, we examined changes over time in the incidence and in-hospital case-fatality rates of primary ventricular fibrillation complicating acute myocardial infarction. METHODS AND RESULTS: Patients with validated acute myocardial infarction hospitalized at 16 hospitals in the Worcester, Mass, metropolitan area between 1975 and 1990 comprised the study sample. During the 15-year study period, 5.1% of patients developed primary ventricular fibrillation in the setting of uncomplicated acute myocardial infarction, with this rate remaining relatively constant over time. Both age- and multivariable-adjusted analyses showed no significant trend in the incidence rates of …

Long-Term Trends (1986-2003) In The Use Of Coronary Reperfusion Strategies In Patients Hospitalized With Acute Myocardial Infarction In Central Massachusetts, Robert J. Goldberg, Frederick A. Spencer, Joseph Okolo, Darleen M. Lessard, Jorge L. Yarzebski, Joel M. Gore

Jorge L. Yarzebski

BACKGROUND: The objectives of our study were to examine long-term (1986-2003) trends in the use of percutaneous coronary interventions (PCI) and thrombolytic therapy in the management of patients hospitalized at all Central Massachusetts medical centers with acute myocardial infarction (AMI). Our secondary study goal was to examine factors associated with use of these coronary reperfusion strategies. Limited contemporary data are available about changing trends in the use of coronary reperfusion strategies, particularly from a population-based perspective. METHODS: The sample consisted of 9422 greater Worcester (MA) residents hospitalized with AMI at all metropolitan Worcester medical centers in 10 annual periods between …

A Community-Wide Perspective Of Gender Differences And Temporal Trends In The Use Of Diagnostic And Revascularization Procedures For Acute Myocardial Infarction, David Chiriboga, Jorge Yarzebski, Robert Goldberg, Z. Chen, Jerry Gurwitz, Joel Gore, Joseph Alpert, James Dalen

Jorge L. Yarzebski

This study compares the overall use, as well as temporal trends, of various diagnostic and revascularization procedures for acute myocardial infarction (AMI) in men and women. The study sample comprised a total of 2,924 men and 1,838 women with validated AMI admitted to any of the 16 teaching and community hospitals in the Worcester, Massachusetts, metropolitan area during 1975, 1978, 1981, 1984, 1986 and 1988. During the period under study there was a significant increase in use of each of the examined procedures during hospitalization for AMI in both men and women. Increasing use of multiple procedures was also seen …

Temporal Trends And Associated Factors Of Inpatient Cardiac Rehabilitation In Patients With Acute Myocardial Infarction: A Community-Wide Perspective, Frederick Spencer, Bobak Salami, Jorge Yarzebski, Darleen Lessard, Joel Gore, Robert Goldberg

Jorge L. Yarzebski

PURPOSE: Cardiac rehabilitation (CR) has been shown to be an important therapeutic intervention after the development of acute myocardial infarction (AMI), but historically has been underused. Inpatient CR often represents cardiac patients' first exposure to risk factor modification education and acts as a gateway to outpatient programs. METHODS: The authors performed a longitudinal study of the use of inpatient CR in 5204 Worcester residents hospitalized with validated AMI in seven 1-year periods between 1986 and 1997. RESULTS: The overall rate of referral to inpatient CR was 68%, with a slight decline in use to less than 60% in the authors' …

Communitywide Trends In The Use And Outcomes Associated With Beta-Blockers In Patients With Acute Myocardial Infarction: The Worcester Heart Attack Study, Helme Silvet, Frederick Spencer, Jorge Yarzebski, Darleen Lessard, Joel Gore, Robert Goldberg

Jorge L. Yarzebski

BACKGROUND: Despite the benefits associated with beta-blocker therapy in patients with acute myocardial infarction (AMI), limited recent data are available describing the extent of use of this therapy and the associated hospital and long-term outcomes, particularly from the perspective of a population-based study. Data are also limited about the characteristics of patients with AMI who do not receive beta-blockers. This study examines more than 2 decades of trends in the use of beta-blockers in hospitalized patients with AMI. METHODS: Communitywide study of 10,374 patients hospitalized with confirmed AMI in all metropolitan Worcester hospitals during 12 annual periods between 1975 and …

The Impact Of The Stent Era On The Management Strategy For Acute Myocardial Infarction: A Population-Based Perspective, Harold Dauerman, Robert Goldberg, Jorge Yarzebski, Darleen Lessard, Joel Gore

Jorge L. Yarzebski

We determined trends in the use of invasive diagnostic and revascularization strategies from a multihospital community-wide perspective for patients suffering acute myocardial infarction (AMI). Comparing 3,824 patients treated in the prestent era (1986-1993) to 1,915 patients hospitalized during the stent era (1995-1997), there was a significant increase in the use of invasive procedures and revascularization techniques across a broad spectrum of AMI patients during their index hospitalization. This resulted in a higher-risk profile of patients referred for invasive management of AMI in the stent era. Cathet. Cardiovasc. Intervent. 51:255-258, 2000.

Multidecade-Long Trends (1986-2005) In The Utilization Of Coronary Reperfusion And Revascularization Treatment Strategies In Patients Hospitalized With Acute Myocardial Infarction: A Community-Wide Perspective, Jared Wasser, Robert Goldberg, Frederick Spencer, Jorge Yarzebski, Joel Gore

Jorge L. Yarzebski

OBJECTIVES: The objectives of our community-wide investigation were to describe multidecade-long trends (1986-2005) in the utilization of thrombolytic therapy, percutaneous coronary interventions, and coronary artery bypass graft surgery in patients hospitalized with acute myocardial infarction (AMI). METHODS: The study sample consisted of 9422 greater Worcester (MA) residents hospitalized with confirmed AMI at all metropolitan Worcester medical centers in 11 annual periods between 1986 and 2005. RESULTS: Increases in the utilization of percutaneous coronary interventions were observed between 1986 (2.0%) and 2005 (50.7%) with the most rapid increases beginning in the late 1990s. Utilization of coronary artery bypass graft surgery during …

Two-Decade-Long Trends (1975-1997) In The Incidence, Hospitalization, And Long-Term Death Rates Associated With Complete Heart Block Complicating Acute Myocardial Infarction: A Community-Wide Perspective, Frederick Spencer, Samer Jabbour, Darleen Lessard, Jorge Yarzebski, Shmuel Ravid, Virginia Zaleskas, Michael Hyder, Joel Gore, Robert Goldberg

Jorge L. Yarzebski

BACKGROUND: The purpose of this community-wide study was to describe a >2-decade-long experience (1975-97) in the incidence and death rates associated with complete heart block (CHB) in patients with acute myocardial infarction (AMI). Limited population-based data exist describing recent, and changes with time therein, incidence and case-fatality rates associated with CHB complicating AMI.

METHODS: We conducted an observational study of 9082 metropolitan Worcester, Mass, residents (1990 census = 437,000) hospitalized with validated AMI in all greater Worcester hospitals during 11 1-year periods between 1975 and 1997.

RESULTS: Overall, CHB developed in 5.0% of patients with AMI. The incidence rates of …

Use Of The Invasive Management Strategy For Patients With Non-Q-Wave Myocardial Infarction: An Observational Database Report From The Worcester Heart Attack Study, Harold Dauerman, Jorge Yarzebski, Joel Gore, Darleen Lessard, Robert Goldberg

Jorge L. Yarzebski

BACKGROUND: Recent randomized clinical trials have suggested a benefit of an invasive management strategy in patients with acute coronary syndromes. However, the broader use and impact of the invasive management approach has not been established for patients with acute coronary syndromes beyond the relatively narrow patient populations studied in randomized, clinical trials. METHODS: Residents of the Worcester, Mass, area who were hospitalized with non-Q-wave acute myocardial infarction (AMI) at all area hospitals in 5 annual periods between 1990 and 1997 comprised the sample of interest (n = 2436). We examined the extent of use of an invasive versus a conservative …

Trends In Atrial Fibrillation Complicating Acute Myocardial Infarction, Jane Saczynski, David Mcmanus, Zheng Zhou, Frederick Spencer, Jorge Yarzebski, Darleen Lessard, Joel Gore, Robert Goldberg

Jorge L. Yarzebski

Atrial fibrillation (AF) is a common complication of acute myocardial infarction (AMI) and this arrhythmia is associated with increased morbidity and mortality in patients with AMI. Limited information is available, however, about changing, and contemporary, trends in the incidence and death rates associated with AF complicating AMI. We examined the magnitude and impact of AF and the risk of stroke and hospital and long-term death rates in a population-based study of patients hospitalized with AMI. The study population consisted of 7,513 residents of the Worcester, Massachusetts, metropolitan area hospitalized with AMI at all greater Worcester medical centers during 9 biennial …

Contemporary Trends In Evidence-Based Treatment For Acute Myocardial Infarction, Marco Fornasini, Jorge Yarzebski, David Chiriboga, Darleen Lessard, Frederick Spencer, Philip Aurigemma, Joel Gore, Robert Goldberg

Jorge L. Yarzebski

BACKGROUND: Guidelines for the management of patients with acute myocardial infarction recommend the routine use of 4 effective cardiac medications: angiotensin-converting enzyme inhibitors, aspirin, beta-blockers, and lipid-lowering agents. Limited data are available, however, about the contemporary and changing use of these therapies, particularly from a population-based perspective. The study describes differences in the use of these medications during hospitalization for acute myocardial infarction according to age, gender, and period of hospitalization.

METHODS: The study population consisted of 6334 women and men treated at 11 hospitals in the Worcester, Mass, metropolitan area for acute myocardial infarction in 6 annual periods between …

Temporal Trends And Factors Associated With Extent Of Delay To Hospital Arrival In Patients With Acute Myocardial Infarction: The Worcester Heart Attack Study, Jorge Yarzebski, Robert Goldberg, Joel Gore, Joseph Alpert

Jorge L. Yarzebski

Factors associated with delay to hospital arrival after the onset of symptoms suggestive of acute myocardial infarction (AMI) were examined in the late 1960s and 1970s, but recent data concerning these characteristics are limited. The purpose of the present study was to examine overall and temporal distributions of the extent of patients' delay from the time of onset of AMI symptoms to hospital arrival and factors associated with delay in seeking medical care from a multihospital, population-based perspective. Review of medical records was undertaken of patients hospitalized with a discharge diagnosis of AMI in 16 teaching and community hospitals in …

Twenty Year Trends (1975-1995) In The Incidence, In-Hospital And Long-Term Death Rates Associated With Heart Failure Complicating Acute Myocardial Infarction: A Community-Wide Perspective, Frederick Spencer, Theo Meyer, Robert Goldberg, Jorge Yarzebski, Mark Hatton, Darleen Lessard, Joel Gore

Jorge L. Yarzebski

OBJECTIVES: To describe from a population-based perspective, recent and temporal (1975-1995) trends in the incidence, in-hospital and postdischarge case-fatality rates of heart failure (HF) complicating acute myocardial infarction (AMI). BACKGROUND: Extremely limited data are available describing the incidence and case-fatality rates associated with HF complicating AMI from a community-wide perspective. METHODS: The medical records of 6,798 residents of the Worcester, Massachusetts metropolitan area with validated MI and without previous HF hospitalized in 10 annual periods between 1975 and 1995 were reviewed. RESULTS: The proportion of AMI patients developing HF during hospitalization declined between 1975-1978 (38%) and 1993-1995 (33%) (p < 0.001). …

Patient Delay And Receipt Of Thrombolytic Therapy Among Patients With Acute Myocardial Infarction From A Community-Wide Perspective, Robert Goldberg, Jerry Gurwitz, Jorge Yarzebski, J. Landon, Joel Gore, Joseph Alpert, P. Dalen, James Dalen

Jorge L. Yarzebski

The duration of patient delay from the time of onset of symptoms of acute myocardial infarction (AMI) to hospital presentation, and the relation of delay time and various patient characteristics to receipt of thrombolytic therapy were examined as part of a community-based study of patients hospitalized with AMI in the Worcester, Massachusetts, metropolitan area. In all, 800 patients with validated AMI hospitalized at 16 hospitals in the Worcester metropolitan area in 1986 and 1988 constituted the study sample. Patients delayed on average 4 hours between noting symptoms suggestive of AMI and presenting to area-wide emergency departments with no significant change …