Combinatorial synthesis through disulfide exchange: discovery of potent psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA).

Psammaplin A is a symmetrical bromotyrosine-derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Among the most active leads derived from these studies are compounds 104, 105, 113, 115, 123, and 128. The present, catalytically-induced, disulfide exchange strategy may be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.

Optimization and mechanistic studies of psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA).

As described in the preceding article, utilizing a novel combinatorial disulfide exchange strategy, a library of psammaplin A (1) analogues was constructed and screened for antibacterial activity leading to the identification of a collection of diverse lead compounds. These combinatorial leads were subsequently refined, through parallel synthesis, to afford a series of highly potent antibacterial agents (e.g. 17, 57, 58, 69, and 70), some possessing greater than 50-fold higher activities than the natural product. Evaluation of the selectivity and serum binding properties of some of the most promising compounds and preliminary studies directed at deciphering the mechanism of action of this novel class of antibacterial agents are also included.

Solid phase synthesis of complex natural products and libraries thereof.

Natural products have served as an important source of medicinal compounds and pharmaceutical leads over the last century. Within the last 10 years, significant interest has developed in applying combinatorial chemistry techniques to the study of natural products and their biological activities. In this review, we examine several representative efforts wherein natural product skeletons have been constructed or immobilized on solid support and subsequently derivatized, giving rise to analog libraries useful in understanding the structure-activity relationships of the parent natural product. Issues such as target selection, library design, linker development, automation, and library characterization are addressed.

Combinatorial synthesis of novel and potent inhibitors of NADH:ubiquinone oxidoreductase.

BACKGROUND: NADH:ubiquinone oxidoreductase (complex I) is the first of three large enzyme complexes located in the cell's inner mitochondrial membrane which form the electron transport chain that carries electrons from NADH to molecular oxygen during oxidative phosphorylation. There is significant interest in developing small molecule inhibitors of this enzyme for use as biological probes, insecticides and potential chemopreventive/chemotherapeutic agents. Herein we describe the application of novel natural product-like libraries to the discovery of a family of potent benzopyran-based inhibitors. RESULTS: Initially a combinatorial library of benzopyrans, modeled after natural products, was synthesized using a solid phase cycloloading strategy. Screening of this diversity oriented library for inhibitory potency against NADH:ubiquinone oxidoreductase activity in vitro using bovine heart electron transport particles provided several lead compounds which were further refined through a series of focused libraries. CONCLUSIONS: Using this combinatorial library approach, a family of potent 2,2-dimethylbenzopyran-based inhibitors was developed with IC(50) values in the range of 18-55 nM. Cell-based assays revealed that these inhibitors were rather non-cytotoxic in the MCF-7 cell line; however, they were quite cytostatic in a panel of cancer cell lines suggesting their potential as chemotherapeutic/chemopreventive candidates.

Total synthesis and chemical biology of the sarcodictyins.

The sarcodictyins A-F and eleutherobin comprise a family of marine-derived diterpenoids with potent cytotoxicities against various tumor cell lines. Investigations have revealed that several of these compounds exert their cytotoxic effects through tubulin binding in a mechanism analogous to that of the clinical anticancer drug Taxol. The biological importance, challenging molecular architecture, and relative scarcity of these natural products have prompted several groups to undertake their total chemical synthesis. In this review, we summarize the current synthetic efforts and examine the preliminary structure-activity relationships which have emerged from early combinatorial libraries.

A facile method for the solution and solid-phase synthesis of substituted [3.3.1] bicycles.

[reaction: see text] Interest in bicyclic natural products from the Guttiferae classification has led to the development of an improved method for the selenium-mediated cyclization of alkenyl-substituted beta-dicarbonyls (I) to form a variety of bicyclo[3.3.1]nonan-9-ones (II) both in solution and on solid support.

[Alcohol in pregnancy and fetal heart damage]. / Alkohol in der Schwangerschaft und kindliche Herzschäden.

Alcohol abuse and addiction during pregnancy can induce damage of the heart muscle and heart defects in the offspring. Between 1973 and 1991 216 children with fetal alcohol syndrome were diagnosed and examined for congenital heart defects. In 63 children (= 29,1%) heart defects were present, established mainly by heart catheterization and/or echocardiography. Most frequently ventricular septal defects (24/63) and atrial septal defects (23/63) occurred, less frequent were AV-defects (3), PDA (3), Fallots teralogy (5), and other malformations (5). Biopsy during heart surgery in 3 children revealed histological and electron microscopic changes of alcohol-cardiomyopathy. Heart defects are predominantly found in children with higher degree of severity concerning the clinical syndrome, less frequently in alcohol effects (4/38 = 11%). Alcohol in pregnancy, even in the course of so called social drinking, usual drinking and binge drinking has to be considered as an essential and preventable co-factor within the multifactorial etiology of congenital heart defects.

[Difficulties in interpreting the cardiotocogram in atrioventricular arrhythmia of the fetal heart]. / Interpretationsschwierigkeiten des Kardiotokogramms bei atrio-ventrikulärer Erregungsleitungsstörung des fetalen Herzens.

During a routine screening examination of a pregnancy during the 28th gestational week, a pericardial effusion and ascites were recognized in the fetus. Ultrasound B- and M-mode evaluation (echocardiography) revealed an atrio-ventricular block grade III with commencing cardiac insufficiency. Cardiac monitoring (CTG) by ultrasound (HP 8040A Fetal Monitor) documented primarily the fetal atrial activity when the logic switch was turned off, but after it was turned on there was no continuous recording. When fetal heart action was recorded by abdominal electrocardiogram (AFEKG) the cardiotocography showed simultaneously a ventricular frequency of 50/min. and a maternal frequency of 70-80/min. This case confirms that the registration of fetal heart action without real-time imaging is only of limited value in cases of cardiac-conduction anomalies. It is important that during ultrasound screening examination, the cardiac heart action is carefully evaluated.

[Rupture of a coronary artery aneurysm in mucocutaneous lymph node syndrome (Kawasaki syndrome). Demonstration of the coronary aneurysms by 2-dimensional echocardiography]. / Ruptur eines Coronararterien-Aneurysmas bei mukokutanem Lymphknotensyndrom (Kawasaki-Syndrom). Darstellung der Koronaraneurysmen durch 2-dimensionale Echokardiographie.

A further case of mucocutaneous lymphnode syndrome (MCLS) in infancy with multiple aneurysms both of the coronary arteries and systemic arteries is presented. Aged four months the male infant died of rupture of an aneurysm of the right coronary artery causing a hemopercardium. The aneurysms both of the coronary and systemic arteries were diagnosed intra vitam by 2-dimensional echocardiography.

[Prenatal diagnosis and therapy of hydro-/chylothorax with fetal hydrops]. / Pränatale Diagnostik und Therapie des Hydro-/Chylothorax mit Hydrops fetalis.

The prenatal diagnosis of a massive bilateral hydro-/chylothorax at 34 weeks of gestation is presented. It was associated with a marked hydrops which probably had resulted from protein depletion into the pleural cavity and/or elevation of intrathoracic pressure with subsequent obstruction of venous return. So the hydro-/chylothorax is to be considered a further cause of the congenital hydrops universalis. After induction of lung maturation with dexamethasone the infant was delivered by a primary cesarean section at 36 weeks of pregnancy. The immediately following intensive care guaranteed the circulatory function and ventilation. The pleural effusions were managed successfully by careful continuous intrapleural drainage and intravenous protein substitution. Last not least, the survival of the infant despite the massive findings is to be owed to the close cooperation of pediatricians and obstetricians.

[Liver cirrhosis due in alpha-1-antitrypsinin deficiency and development of an arteriovenous shunts of the lungs]. / Leberzirrhose bei Alpha-1-Antitrypsin-Mangel und Entwicklung arteriovenöser shunts der Lungen.

A 10.5 year old girl with liver cirrhosis due to AAT-deficiency (Pi type ZZ) developed cyanosis and clubbing of finger and toes. Clinical aspect of a cyanotic heart disease appeared with 10 years, 7 years after diagnosis of cirrhosis. By contrast echocardiography existence of intrapulmonary arterio-venous shunts was demonstrated. When determined during the first year of life, serum-alpha-1-globulin-fraction of the patient was found to be normal. The result indicates, that even in severe AAT-deficiency of Pi type ZZ direct determination of AAT is necessary for diagnosis of the disease.

[Diverticulum of the brachiocephalic trunk--angiographic image and embryologic significance]. / Das Divertikel des Truncus brachiocephalicus--Angiographische Darstellung und embryologische Deutung.

A diverticulum of the brachiocephalic trunk is described in 5 children with unilateral absence of the pulmonary artery, in a child with tetralogy of Fallot, and in an other child with Bland-White-Garland syndrome. The diverticulum is a remnant of a contralateral ductus arteriosus, which cLosed after birth and represents the origin of the distal part of the sixth aortic arch.

Absent pulmonary artery. A hint to its embryogenesis.

Cardiac catheterization was performed in nine patients with unilateral absence of a pulmonary artery. Aortography revealed a diverticulum of the innominate artery in five of six patients in whom the aortic arch and absent pulmonary artery were on opposite sides. It is suggested that the diverticulum indicates fetal systemic blood supply to the affected lung through the distal part of the sixth aortic arch, which--consisting of ductal tissue--obliterated after birth, leaving the diverticulum where the ductus joins the innominate artery.

[Cardiotoxic effect of the tocolytic agent fenoterol (partusisten) in the neonate (author's transl)]. / Kardiotoxische Wirkung des Tokolytikums Fenoterol (Partusisten).

Forty-two children of mothers treated with beta-adrenergic drugs were investigated cardiologically during a period of 3 1/2 years. Eleven neonates were seen to suffer from severe toxic myocardiopathy associated with heart failure. The mothers had in part been given excessive fenoterol doses for 13 weeks on the average. One child died of regressive myocardial alterations as confirmed by autopsy. Suspicion of toxic myocardiopathy was suggested in another 16 children. Related to the very large number of mothers treated with tocolytic agents, fenoterol-induced myocardiopathy so far appears to be rare. In agreement with other reports, however, our observations suggest the possibility of severe, even perilous myocardial damage. Therefore, the indication and dosage of fenoterol should be subjected to more rigid criteria than so far applied.