Dedicated to Professor Rovfammet on the occasion of his 65th birthdayThe era of fi-lactam antibiotics, which represent the most important class of drugs against infectious diseases caused by bacteria, began more than fifty years ago with the discovery of penicillin G. Further improvements by isolation and structure elucidation of new natural compounds, and systematic chemical modification of these, is a striking example of to what extent chemistry can contribute to the progress of drug therapy. The complex relationship between structure and activity requires, even today, a largely empirical approach. The minimum structural unit for antibiotic activity had to be revised several times over decades. Both the activated b-lactam ring with an acidic group and the nature and spatial arrangement of the other substituents and rings decisively affect the potency, antibacterial spectrum, pharmacokinetics, and toxicity. Totally synthetic mono-and bicyclic compounds from the series of monobactams, penems, carbapenems, 1-oxacephems, and l-carbacephems are increasingly joining the classic groups obtained by semisynthesis from 6-aminopenicillanic acid and 7-aminocephalosporanic acid.
Tetracycline antibiotics continue to play an important role in human and veterinary medicine and in animal nutrition. The classical tetracyclines obtained by fermentation have been supplemented by products of partial synthesis which provide, in particular, the advantages of better pharmacokinetic properties and greater tolerance. Following a brief review of older work, the present article describes partial and total syntheses of tetracyclines, the influence of electronic, steric, and lipophilic factors and of complex formation on biological activity. The inhibition of biochemical systems invoked in interpretation of the mode of action of tetracyclines and problems involved in the development of resistance are discussed. OHStrong intramolecular interactions occurring between the acidic hydroxyl groups at positions 3, 10, and 12 and neighboring carbonyl groups lead to greatly diminished reactivity towards reagents typical for these groups. The 4-dimethylamino and the 12a-hydroxy groups can be removed by reduction. 722
Vol. 86 di-t-butylphenol, yield 36(%, m.p. 105' (lit." 103.5-104.5°); E.s.r. Measurements.-The spectra of the phenoxy radicals 1,2-bis(3,5-di-t-butyl-4-hydroxyphenyl)ethane, yield 6y0, m.p.were obtained in solution with a Varian V-4500 spectrometer 171-172 (lit .5 169-170').utilizing 100 kc. modulation.Oxidation of a-tocopherol with K-bromosuccinimide or with tetrachloro-o-quinone in aqueous acetonitrile leads to the formation of 9-hydroxy-a-tocopherone (111), the cyclic hemiacetal tautomer of tocopherylquinone. At p H ' 5.5, the dienone has a half-life time of 44 min ; in petroleum ether, the half-life time is extended to 3-4 hr.The compound is converted into the quinone by acid or alkali and is readily reduced to tocopherol by a variety of agents. The oxidation-reduction potential of a-tocopherol, measured for the first time under reversible conditions, was found to be +720 mv. Oxidation of a-tocopherol in the presence of acetate ion leads to an analogous, highly labile acetoxydienone. The energetics of chromanols and quinones in oxidative phosphorylation are discussed in light of the new data A preliminary account of this work has been publisbed: Biochem. Biophys.
Professor Rolf Sammet zum 65. Geburtstag gewidmetVor mehr als 50 Jahren begann mit der Entdeckung von Penicillin G die Ara der P-LactamAntibiotica, die bis heute die wichtigste Wirkstoffklasse gegen bakterielle Infektionskrankheiten bilden. Die Weiterentwicklung durch Isolierung und Strukturaufklarung naturlicher Verbindungen und durch deren systematische chemische Abwandlung ist ein eindrucksvolles Beispiel dafiir, welchen Beitrag die Chemie zum Fortschritt der medikamentosen Therapie zu leisten vermag. Der komplizierte Zusammenhang zwischen Struktur und Wirksamkeit erfordert auch heute noch ein weitgehend empirisches Vorgehen. Die minimale strukturelle Einheit fur die Wirksamkeit muI3te im Laufe der Jahrzehnte mehrfach revidiert werden. Nicht nur der aktivierte 0-Lactamring rnit einer aciden Gruppe, sondern auch Natur und raumliche Anordnung der ubrigen Substituenten und Ringe beeinflussen entscheidend die Wirkungsstarke, Wirkungsbreite, Pharmakokinetik und Vertraglichkeit. Zu den klassischen Praparategruppen, die durch Partialsynthese aus 6-Aminopenicillansaure und 7-Aminocephalosporansaure gewonnen werden, gesellen sich zunehmend totalsynthetisch hergestellte mono-und bicyclische Verbindungen aus der Reihe der Monobactame, Peneme, Carbapeneme sowie I-Oxa-und l -Carbacepheme.
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