Synthese von natürlichen Haloindolen via Hetero-Cope-Umlagerung von Vinyl-N-phenylhydroxamaten

Synthesis of Natural, Halogenated Indoles via Hetero-Cope Rearrangement of Vinyl N-Phenylhydroxamates An efficient method for the synthesis of natural 4-chloro-6-methoxyindole (the promutagen from fava beans) and of the two 4,6- dibromo- and 3,4,6-tribromoindoles (produced by acorn worms, Enteropneusta) is presented. The key step is a hetero-Cope rearrangement of the intermediate N-phenyl-O-vinylhydroxylamine derivatives.     

Synthesis of new gramine-type analogs of CC-1065

Preparation of two new analogs 5 and 6 of the antitumor antibiotic CC-1065 1 are described. These compounds represent structural modifications of the active analogs 3 and 2 respectively, in which the dienone A-unit has been replaced by the tricyclic achiral gramine unit 4 . Modest cytotoxicity was exhibited by compounds 5 and 6 .     

Synthesis and cytotoxicity of a biotinylated CC-1065 analogue

Background  

The use of pretargeting technology for cancer imaging and treatment has made significant progress in the last few years. This approach takes advantage of the fact that biotin binds strongly to proteins avidin and streptavidin. Thus, a non-toxic tumor cell specific antibody is conjugated with avidin/streptavidin, and is administered to patients. After the antibody binds to tumor cells (usually 24–48 h); a clearing agent is given to remove the residual circulating antibodies in blood. Lastly, a toxic biotin-radioisotope conjugate is administered. Due to the small size of the biotin-radioisotope molecule and tight binding between biotin and avidin/streptavidin, the biotin-radioisotope rapidly binds to tumor cells with high specificity. CC-1065 (1) is one of a few classes of extremely potent antitumor agents, and a biotinalyted CBI-bearing CC-1065 analogue is a promising candidate to be used in the pretargeting technology to treat cancer.     

Ein alternativer Zugang zum PQQ-Triester

An Alternative Approach to the PQQ-Triester A novel approach to triethyl 5-methoxy-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylate ( 6 ), a close precursor of the redox cofactor PQQ of bacterial dehydrogenases, is described. Diethyl 2-oxopent-3-ynedioate ( 5 ) was used as building block for the annelation of the quinoline unit. The annelation proceeds in two steps via the diastereoselective formation of diethyl (Z)-4-{[2-(ethoxycarbonyl)-5-methoxyindol-6-yl]amiono}-2-oxopent-3-enedioate ((Z)- 7 ) followed by acid-catalyzed cyclocondensation.     

Studies on the Synthesis of the Antitumor Agent CC-1065

The title indolecarboxylate (1) is synthesized as a potential intermediate for the preparation of the central and right parts of CC-1065 (2).     

Untersuchungen zum Alkalischen Abbau von kieselgelen mittels Leitfähigkeitsmessungen

Investigations of the Alkaline Degradation of Amorphous Silica by Means of Conductivity Measurements Two silicas produced in different ways are characterized by conductometric pursuit of their reaction in alkaline medium. It is tried to interpret the parameters obtained by formal kinetic analysis of the measured results according the Avrami-Erofeev-equation and to receive references to the mechanism of the reaction.     

A unique class of duocarmycin and CC-1065 analogues subject to reductive activation

N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release) and pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.