Biomedical subjects
Publications and source records attributed to R W Sullivan.
Glutamic acid derived hydroxamates were identified as potent and selective inhibitors of procollagen C-proteinase, an essential enzyme for the processing of procollagens to fibrillar collagens. Such compounds have potential therapeutic application in the treatment of fibrosis.
The parallel synthesis of novel inhibitors of procollagen C-terminal proteinase is described. The synthetic strategy allowed for the facile synthesis of a large number of side-chain diversified diamino acid hydroxamates, of which the D-diaminopropionic acid derivatives were shown to be single digit nanomolar PCP inhibitors.
We investigated the structure-activity relationship studies of N-[3, 5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5 -yl]carboxamide (1), an inhibitor of transcription mediated by both NF-kappaB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.
Described is the identification of a novel series of compounds that blocks the activation of two key transcription factors, AP-1 and NF-kappa B. These transcription factors regulate the expression of several critical proinflammatory proteins and cytokines and represent attractive targets for drug discovery. Through the use of high throughput screening and solution-phase parallel synthesis, inhibitors of both NF-kappa B and AP-1 were identified. In subsequent testing, these compounds were also shown to block both IL-2 and IL-8 levels in the same cells. One of the most potent compounds in this series, 28, was active in several animal models of inflammation and immunosuppression, thus validating the importance of AP-1 and NF-kappa B as potential therapeutic targets. The synthesis and preliminary structure-activity relationships of these compounds is addressed.
In previous studies, the ability of the hydrodioxyl (perhydroxyl) radical [HOO., the conjugate acid of superoxide (O2.-] to "nick" DNA under biomimetic conditions was demonstrated, and a sequence selectivity was observed. A background level of nonspecific nicking also was noted. This paper provides support for 5'-hydrogen atom abstraction from the deoxyribose ring as the initial event in the sequence-selective nicking by 02.-/HOO.. Two experiments support the proposed mechanism. First, using a defined sequence 5'-32P-labeled restriction fragment as the DNA substrate, only free (unalkylated) 3'-phosphate is produced at the site of nicking. Second, using poly (dA).poly (T) as the substrate, furfural is formed in the reaction from deoxyribose ring breakdown. Both results are consistent with 5'-hydrogen atom abstraction for initiation of the site-selective nicking. Hydrogen atom abstraction at other sites of the deoxyribose ring and/or base oxidation and loss followed by strand scission likely are responsible for the nonspecific nicking. The 5'-abstraction mechanism contrasts to those elicited by other 02-derived and metal-associated oxidants, which may provide a biomarker for the reactivity of HOO. in vivo.
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BACKGROUND: Streptococcus pneumoniae is an uncommon cause of infective endocarditis (IE). We studied the presentation, microbiologic characteristics, and outcome of nine cases of S pneumoniae IE during a 12 1/2-year period in a population of 75,000 indigenous Alaska Natives (ANs), who have documented high rates of invasive pneumococcal disease. METHODS: Fifty-six cases of IE occurred in ANs statewide during 1978 through 1990. Medical records of all nine confirmed cases of S pneumoniae IE were reviewed. Incidence rates for S pneumoniae IE and all IE were calculated. RESULTS: Alaska Natives experience S pneumoniae IE as a fulminant illness, with acute aortic valve insufficiency (100%) frequently requiring emergent valve replacement, S pneumoniae meningitis (56%), and death (33%). No patient with S pneumoniae IE had known preexisting heart disease, and the most common underlying disease was alcoholism (56%). Pneumonia was diagnosed and embolic complications were suspected in 33%. All five S pneumoniae isolates examined were penicillin sensitive and were of serotypes included in the pneumococcal vaccine. Pneumococcal IE accounted for 15.8% of all IE diagnosed in ANs. Age- and sex-adjusted incidence rates for IE of all causes and S pneumoniae IE were 8.5 and 1.5 per 10(5) persons per year, respectively. During 1986 through 1988, 4.3% of AN adults diagnosed with S pneumoniae bacteremia developed S pneumoniae IE. CONCLUSIONS: Pneumococcal endocarditis in all but one AN case required emergent valve replacement and had a 33% mortality. The annual incidence rate of S pneumoniae IE in this population was five to 37 times higher than contemporary rates elsewhere. Increased efforts to prevent pneumococcal disease in ANs appear warranted. Clinicians everywhere should anticipate the possible development of S pneumoniae IE in adult patients with pneumococcal sepsis, especially with meningitis, even with previous vaccination and prompt adequate antimicrobial therapy.
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Two cases of pulmonary arteriovenous fistulas associated with pulmonary hypertension occurring in young multiparous women are described. Both cases suggest the development of pulmonary arteriovenous fistulas subsequent to and as a consequence of the onset of pulmonary hypertension. Etiologic factors resulting in the development of the pulmonary hypertension in these patients, including the possible role of estrogens, are considered. The possible causal relationship of the pulmonary hypertension to the development of the pulmonary arteriovenous fistulas is discussed, and the importance of detecting the presence of pulmonary hypertension is stressed, since resection of the arteriovenous fistulas would be contraindicated in this situation.
Two hundred consecutive patients undergoing coronary artery bypass for stable and unstable angina pectoris were followed clinically 3 to 53 months (mean 27) and with serial electrocardiograms (ECG's) 3 to 43 months (mean 18.5) postoperatively. Complete (twelve lead) resting ECG data including preoperative, early postoperative (in hospital), and late (post hospital) studies were available in 98 per cent (196/199) of hospital survivors. A total of 2,304 ECG's were examined by two cardiologists for a total follow-up of 3,629 patient months. Myocardial infarction was defined as the appearance of a new, significant (Minnesota Code) Q wave. Fifty-four per cent (108/200) had triple vessel disease and 24 per cent (47/200) preinfarction angina pectoris by strict criteria. There was one hospital death for an operative mortality of 0.5 per cent (1/200). There was one late fatal and three late nonfatal myocardial infarctions. Seventeen patients developed new Q waves in the early postoperative period, a perioperative infarction rate of 8.5 per cent (17/200). The 43 month cumulative myocardial infarction rate, including all early and late postoperative new Q waves and three late deaths from cardiac disease, was 14 per cent. Twenty-two per cent (20/91) showed disappearance of Q waves present at the time of hospital discharge. These data suggest that the late myocardial infarction rate is low in surgically managed patients.
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Survival in patients with ischemic heart disease is closely related to the extent of coronary artery obstruction as determined angiographically. One hundred forty-nine consecutive patients underwent coronary artery bypass surgery from November, 1971, to October, 1974. There were 2 late cardiac deaths, 1 late noncardiac death, and 1 hospital death, an operative mortality rate of 0.7 per cent and a total mortality rate of 2.7 per cent. Coronary angiograms were scored according to the method of Friesinger, Page, and Ross. Fifty-four per cent (80/149) had scores of 10 or greater. Cumulative survival was analyzed according to life-table techniques; in the 80 surgically managed patients with scores of 10 or greater, survival at 3 years was 98 per cent. Friesinger's 47 nonoperated patients with similar angiographic scores had a 3 year cumulative survival of 68 per cent. Although this study compares different groups, the surgical series was composed of older patients (mean age 52 as compared to 44 years), includes 22 patients operated on urgently for preinfarction angina pectoris, and includes 18 patients with abnormal ventricular function. These data suggest that coronary artery bypass surgery can favorably influence prognosis in patients with severe coronary artery disease.
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