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Synthetic and pharmacophoric studies of quinocarcin




Ehrlich, Paul P., author
Williams, Robert M., advisor

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A new synthetic approach to the stereoselective total synthesis of the structurally unique antitumor antibiotic quinocarcin (1) is described. The utilization of model studies in this approach has led to novel methodologies concerning the construction of 1-(hydroxymethyl)-8-methoxy-1,2,3,4-tetrahydroisoquinolin-4-one (195) and several variably substituted pyrrolidines (180, 181, 182 and 183). These methodologies are discussed in terms of their synthetic utility as well as their mechanistic aspects. The synthetic approach to quinocarcin described herein allowed for the construction of several oxazolidine containing alkaloids which incorporate various aspects of the 8-11- iminoazepinotetrahydroiso-quinoline skeleton of quinocarcin. To this end the synthesis of a new tetracyclic oxazolidine moiety (240), which mimics quinocarcin's DNA nicking capabilities and represents the isolation of the pharmacophore of this novel antibiotic was achieved. The significance of the chemical stability and biological activity of 240 relative to quinocarcin is discussed.


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Antineoplastic antibiotics


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