Digitalisforschung in Berlin‐Buch – Rückblick und Ausblick

Abstract

Der Arzt William Withering führte 1785 mit seinem Buch „An Account of the Foxglove and some of its Medical Uses”︁ Präparate aus Digitalisblättern in die Therapie der Wassersucht (des Herzversagens) ein und erklärte: „The following remarks consist partially of matter of fact, and partially of opinion. The former will be permanent; the latter must vary with the detection of error, or the improvement of knowledge. I hazard them with diffidence, and hope they will be examined with candour.”︁ Diese Bemerkungen sind hier vom Seniorautor angeführt, da er die Schwierigkeit sieht, einen ausgewogenen Bericht über sein lebenslanges Forschungsprojekt zur Digitalis‐Weiterentwicklung zu bieten. Seine Entscheidung, sich der Digitalisforschung zu widmen, entstand am Krankenbett, an dem er als Arzt die furchtbaren Endstadien des Herzversagens erlebte, in denen für die Kranken keine wirkliche Hilfe mehr möglich ist. Unglücklicherweise paßte dieses Vorhaben nicht in das vom Wissenschaftsministerium der DDR dekretierte Forschungsprogramm, so daß er das Digitalisprojekt zugunsten von Biomembran‐Untersuchungen einstellen sollte. Glücklicherweise entging er dem Verdikt durch Etikettierung der digitalisartig wirkenden Steroide als chemische Sonden für die Zellmembran‐lokalisierte Na+/K+ ‐transportierende ATPase, die er gerade als den Digitalisrezeptor erkannt hatte. Über die Arbeit der Autoren wird hier erstmals im Zusammenhang berichtet. Ziel des Überblicks ist, die Forschung für die Lösung einer großen Aufgabe zu fördern: die Entwicklung von Steroidwirkstoffen zur Verhinderung und Heilung der Herzinsuffizienz.

Chemical Synthesis of the Cardiotonic Steroid Glycosides and Related Natural Products

“…b) The allene oxide approach to 17b-butenolide installation. c) Wiesners partial synthesis of digitoxigenin (1) from testosterone (21). and stereoselectively epoxidized using vanadyl acetylacetonate followed by a second stereoselective epoxidation of the D [15,16] double bond with meta-chloroperbenzoic acid (mCPBA).…”

“…The preferential reactivity of C/D trans-steroid systems at C17 from the a side is exploited and inversion/oxidation of C14 is also accomplished simply and efficiently. The enone 22 (Scheme 1c), obtained from testosterone (21), is treated with b-furyl lithium yielding exclusively the b-tertiary alcohol, which is acetylated and then subjected to a stereospecific allylic rearrangement (CaCO 3 , heating) to deliver the C15-b-hydroxy intermediate 24. Hydrogenation of the D 15,16 double bond occurs with complete a-facial selectivity resulting in the D-ring cyclopentanol (25), thus setting the stage for a key furan oxidation step.…”

“…[19] In fact, patients often receive 60 % of the toxic dose [20] to obtain a therapeutic response. In the pursuit of safer cardiotonic drugs [6,21] and new chemical entities [10b, 14b] derived from related scaffolds, organic synthesis will play a leading role due to the topological complexity of the relevant targets. This Review aims to outline both partial and de novo synthetic approaches to the medicinally important and structurally captivating cardenolide and bufadienolide steroid families, with an emphasis on the stereocontrolled construction of the pharmacophoric aglycone (genin) framework.…”

Identification of cardiac glycosides in fractions from Periploca forrestii by high-performance liquid chromatography/diode-array detection/electrospray ionization multi-stage tandem mass spectrometry and liquid chromatography/nuclear magnetic resonance

“…As a result, a total of nine trace cardiac glycosides (peaks 1-9) were tentatively determined. Of these, eight (2)(3)(4)(5)(6)(7)(8)(9) are new compounds and one (1) is reported from P. forrestii for the first time.…”

“…Cardiac glycosides are a class of natural products that are used clinically to increase cardiac contractile force in patients with congestive heart failure and cardiac arrhythmias. Recently, epidemiological data [4][5] along with reports based on both the in vitro [6][7][8] and in vivo [9][10] demonstration of cardiac glycosides-mediated anti-cancer activity further emphasize the possibility of developing this class of compounds as antitumor agents. Therefore, the development of a reliable analytical method for cardiac glycosides can benefit the rapid identification and targeted isolation of new cardiac glycosides in plant extracts.…”