The chemistry of thespesin

Zusammenfassung Thespesin, der optisch aktive gelbe Farbstoff aus den Früchten derThespesia populens Soland hat eine dimere sesquiterpene-naphthalene Struktur, die mit dem optischen inaktiven Baumwollsamen-Farbstoff Gossypol identisch ist. Die optische Aktivität des Thespesin ist bedingt durch Atropisomerie.

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Communication No. 1225 from the Central Drug Research Institute.     

The Hill equation and the origin of quantitative pharmacology

This review addresses the 100-year-old Hill equation (published in January 22, 1910), the first formula relating the result of a reversible association (e.g., concentration of a complex, magnitude of an effect) to the variable concentration of one of the associating substances (the other being present in a constant and relatively low concentration). In addition, the Hill equation was the first (and is the simplest) quantitative receptor model in pharmacology. Although the Hill equation is an empirical receptor model (its parameters have only physico-chemical meaning for a simple ligand binding reaction), it requires only minor a priori knowledge about the mechanism of action for the investigated agonist to reliably fit concentration-response curve data and to yield useful results (in contrast to most of the advanced receptor models). Thus, the Hill equation has remained an important tool for physiological and pharmacological investigations including drug discovery, moreover it serves as a theoretical basis for the development of new pharmacological models.     

The notion of nature in chemistry

If nature is by definition the object of the natural sciences, then the dichotomy ‘natural’ versus ‘chemical’, held by both chemists and nonchemists, suggests an idiosyncrasy of chemistry. The first part of the paper presents a selective historical analysis of the main notions of nature in chemistry, as developed in early Christian views of chemical crafts, alchemy, iatrochemistry, mechanical philosophy, organic chemistry, and contemporary drug research. I argue that the dichotomy as well as quasi-moral judgments of chemistry have been based on static and teleological notions of nature throughout history and that chemists, unlike physicists, have neglected the dynamic notion of nature. The second part provides a philosophical criticism of the former notions and argues for the latter as well as for an explicit discourse about values in chemistry.     

The chemistry of the polymyxin antibiotics

Zusammenfassung Die Chemie der Polymyxine, einer Klasse von basischen Polypeptid-Antibiotika, begann 1954, als durch Gegenstromverteilung erstmals ein definierter Vertreter, das Polymyxin B₁ in reiner Form isoliert werden konnte (L. C.Craig). Partialhydrolyse mit Mineralsäuren führte zum Schluss, dass es sich um Cyclohepta- oder Cyclooctapeptide mit Seitenketten handelt, die, -Diaminobuttersäure (Dab) enthalten (W.Hausmann).Amidartige Verknüpfung der Seitenkette mit einer Fettsäure [(+)-6-Methyloctansäure (MOA) oder 6-Methylheptansäure (IOA)] (S.Wilkinson) verleiht diesen Antibiotika den Charakter von Invertseifen. Sie sind besonders gegen gramnegative Erreger wirksam. Schwierigkeiten bereiteten die Aufklärung der Verknüpfungsweise der Seitenkette (- oder-) und die Beantwortung der Frage, ob das Molekül nebend-Phenylalanin in der Ringsequenz noch einend-, -Diaminobuttersäurerest in Nachbarschaft zur Fettsäure in der Seitenkette enthält. Synthetische Versuche mitd-, -Diaminobuttersäure an dieser Stelle führten zu hochaktiven Produkten, die aber mit natürlichem Polymyxin B₁ nicht identisch waren. Entscheidende Fortschritte wurden mit dem bakteriellen Enzym Nagarse (T.Suzuki) erzielt, das schrittweise die Seitenkette bis zum Ringpeptid abbaut. Dabei ergab sich, dass den Polymyxinen die allgemeine Struktur eines Cycloheptapeptides mit-verknüpfter Seitenkette zukommt (Figur 4).Die Polymyxine B₁ E₁ (Colistin A) sowie Circulin A unterscheiden sich voneinander nur durch eine Variation in der gleichen Dipeptidsequenz des 7-gliedrigen Ringes. Die im Polymyxin B₁ vorhandene Dipeptidsequenzd-Phe-l-Leu ist in Polymyxin E₁ (Colistin A) durchd-Leu-l-Leu und in Circulin A durchd-Leu-Ll-Ile ersetzt. Im Polymyxin D₁ ist neben dem Ersatz der entsprechenden Sequenz durchl-Leu-l-Thr noch ein, -Diaminobuttersäurerest der Seitenkette durch eind-Serin ausgetauscht. Die entsprechenden Verbindungen mit dem Index 2 unterscheiden sich von denjenigen mit dem Index 1 durch einen Austausch der (+)-6-Methyloctansäure durch 6-Methylheptansäure.Die Struktur von Polymyxin B₁ E₁ und Circulin A konnte durch Totalsynthese gesichert werden (K.Vogler). Weitere Fortschritte in der Erforschung der Natur der noch unbekannten Vertreter sind in Kürze zu erwarten.     

The pharmacology of Parkinson's disease: Basic aspects and recent advances

Summary Basic aspects and recent advances in the understanding of the pharmacological mechanism of action of the clinically most used antiparkinson drugs are reviewed. Recent human and animal biochemical investigations clearly confirm and extend previous findings indicating that benserazide is much more potent than carbidopa as peripheral decarboxylase inhibitor. L-DOPA in combination with benserazide or carbidopa constitutes the best available therapy for Parkinson's disease (PD). To reduce peaks and rapid fluctuations of L-DOPA plasma levels (possibly responsible for peak-dose dyskinesias and end-of-dose deterioration) a slow-release formulation of L-DOPA in combination with benserazide or with benserazide plus catechol-O-methyltransferase inhibitors should be developed. In parkinsonian patients under long-term L-DOPA therapy monoamine oxidase inhibitors type B (MAO-B) e.g. (–)-deprenyl and firect dopamine receptor agonists (bromocriptine, lisuride, pergolide etc.), due to their L-DOPA-sparing effects, alleviate in some cases L-DOPA-induced side-effects e.g. dyskinesias and on-off phenomena. However, since (–)-deprenylm, due to its metabolism to (–)methamphetamine and (–)amphetamine, seem to have indirect sympathomimetic activity, new selective MAO-B inhibitors devoid of indirect sympathomimetic effects should be tested clinically to assess the functional role of pure MAO-B inhibition in the therapy of PD. The auxiliary therapy with direct dopmaine receptor agonists of the D-2 subtype represents another valid approach which should be further investigated in order to find novel dopamine agonists, less expensive than bromocriptine and strictly selective for D-2 receptor sites.     

CFTR pharmacology

CFTR protein is an ion channel regulated by cAMP-dependent phosphorylation and expressed in many types of epithelial cells. CFTR-mediated chloride and bicarbonate secretion play an important role in the respiratory and gastrointestinal systems. Pharmacological modulators of CFTR represent promising drugs for a variety of diseases. In particular, correctors and potentiators may restore the activity of CFTR in cystic fibrosis patients. Potentiators are also potentially useful to improve mucociliary clearance in patients with chronic obstructive pulmonary disease. On the other hand, CFTR inhibitors may be useful to block fluid and electrolyte loss in secretory diarrhea and slow down the progression of polycystic kidney disease.     

Kainate receptor pharmacology and physiology

Glutamate is the primary neurotransmitter in the central nervous system. One of the classes of ionotropic glutamate receptors is kainate receptors. Recent developments in the pharmacology of kainate receptors have resulted in the emergence of several selective agonists and antagonists. These compounds have allowed scientists to begin to probe the functional properties of these receptors in neurons and gain a better understanding of the role of these receptors in the nervous system.     

The specification of asymmetric configuration in organic chemistry

Zusammenfassung Ein früherer Vorschlag⁴ für die Spezifizierung der asymmetrischen Konfiguration organischer Verbindungen wurde modifiziert und erweitert. In der vorliegenden Abhandlung wird mehr Nachdruck auf Beispiele gelegt, welche das Verfahren erläutern, als auf eine formelle Darlegung der Prinzipien in allgemeiner Form. Die prinzipiellen und praktischen Gründe, welche für ein allgemeines Verfahren zur Spezifizierung der absoluten asymmetrischen Konfigurationen sprechen, werden diskutiert. Da ein solches Verfahren nur auf wenigen eindeutigen Regeln beruhen soll, muss es folgende Bedingungen erfüllen: 1. die Reste, welche die Asymmetric bedingen, müssen auf Grund einer permanenten, internen Eigenschaft geordnet werden; 2. das dreidimensionale Muster, welches so erhalten wird, muss direkt als Klassifikationsgrundlage dienen.Ebenso wie in der früheren Mitteilung wird auch in der vorliegenden Abhandlung als ordnende Eigenschaft von Gruppen, welche sich in ihrer chemischen Konstitution unterscheiden, die Atomnummer verwendet. Darüber hinaus wird gezeigt, wie die feineren Unterschiede, welche Asymmetrie verursachen, wie die Atommasse sowie Konfiguration und Position der Gruppen, berücksichtigt werden können.Das Verfahren wurde soweit ausgebaut, dass man es auf alle bekannten Typen der optischen Isomerie organischer Verbindungen anwenden kann. Zur Spezifizierung der Konfiguration werden neue Symbole vorgeschlagen, welche ausschliesslich die absolute Konfiguration darstellen sollen.     

The chemistry and biology of inhibitors and pro-drugs targeted to glutathione S-transferases

The cytosolic glutathione S-transferases are a family of structurally homologous enzymes with multiple functions, including xenobiotic detoxification, clearance of oxidative stress products, and modulation of cell proliferation and apoptosis signaling pathways. This wideranging functional repertoire leads to several possible therapeutic uses for isoform-specific GST inhibitors. These inhibitors may be used, in principle, to modulate tumor cell drug resistance, as sensitizers to therapeutically directed oxidative stress, to enhance cell proliferation and to augment anti-malarial drugs. With increasing knowledge of GST structural and function, rational design strategies and mechanism-based inhibitors have been exploited successfully. However, design of isoform specificity remains a significant challenge in GST inhibitor development. Strategies for further inhibitor design and their possible limitations, along with potential therapeutic uses, are summarized.Received 24 November 2004; received after revision 12 January 2005; accepted 11 February 2005     

Analytical chemistry

Cellular and Molecular Life Sciences -     

The chemistry of certain imines related to the diterpene alkaloids

Zusammenfassung Aconitum- und Delphinium-Alkaloide gehen teilweise ungewöhnliche chemische Reaktionen ein, deren Ursache in der polycyclischen Struktur, im besonderen in deren hohem Grad von Brückenbildungen zu suchen ist.Einige dieser Reaktionen, speziell solche der Imine und Imminiumsalze der Diterpenalkaloide Atisin und Veatchin werden diskutiert.

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Parts of this paper were presented before the Symposium on Enamine Chemistry at the American Chemical Society meeting in Chicago, September 6 (1961), and at the International Phytochemistry Symposium held during the Golden Jubilee Congress of the University of Hong Kong on September 12 (1961).     

Bromelain: biochemistry, pharmacology and medical use

Bromelain is a crude extract from the pineapple that contains, among other components, various closely related proteinases, demonstrating, in vitro and in vivo, antiedematous, antiinflammatory, antithrombotic and fibrinolytic activities. The active factors involved are biochemically characterized only in part. Due to its efficacy after oral administration, its safety and lack of undesired side effects, bromelain has earned growing acceptance and compliance among patients as a phytotherapeutical drug. A wide range of therapeutic benefits has been claimed for bromelain, such as reversible inhibition of platelet aggregation, angina pectoris, bronchitis, sinusitis, surgical traumas, thrombophlebitis, pyelonephritis and enhanced absorption of drugs, particularly of antibiotics. Biochemical experiments indicate that these pharmacological properties depend on the proteolytic activity only partly, suggesting the presence of nonprotein factors in bromelain. Recent results from preclinical and pharmacological studies recommend bromelain as an orally given drug for complementary tumor therapy: bromelain acts as an immunomodulator by raising the impaired immunocytotoxicity of monocytes against tumor cells from patients and by inducing the production of distinct cytokines such as tumor necrosis factor-α, interleukin (Il)-1β, Il-6, and Il-8. In a recent clinical study with mammary tumor patients, these findings could be partially confirmed. Especially promising are reports on animal experiments claiming an antimetastatic efficacy and inhibition of metastasis-associated platelet aggregation as well as inhibition of growth and invasiveness of tumor cells. Apparently, the antiinvasive activity does not depend on the proteolytic activity. This is also true for bromelain effects on the modulation of immune functions, its potential to eliminate burn debris and to accelerate wound healing. Whether bromelain will gain wide acceptance as a drug that inhibits platelet aggregation, is antimetastatic and facilitates skin debridement, among other indications, will be determined by further clinical trials. The claim that bromelain cannot be effective after oral administration is definitely refuted at this time. Received 25 August 2000; received after revision 29 March 2001; accepted 30 March 2001