Novel mitosenes substituted at the 6-position were synthesized for antineoplastic screening. More than 26 new compounds were made by two synthetic routes. A Nenitzescu-type synthesis provided ethyl 1-acetoxy-2,3-dihydro-5,8-dione-7-methoxy-1H-pyrrolo{1,2-a}indole-9-carboxylate. However, selective reduction of this ester could not be achieved satisfactorily. A more practical route via annelation of a commercially available indole was successful in completing the planned scheme of 6-substituted mitosene congeners. The third ring (pyrrolidine) was added by condensation of ethyl acrylate with ethyl 5-methoxyindole-2-carboxylate. After decarboxylation at position 2, the ketone at position 1 was reduced and acetylated. Then the carbon at the 9 position was introduced by Vilsmeier-Haack formylation and the quinone moiety was synthesized via a nitration, reduction, and oxidation sequence. Subsequently, the aldehyde was most satisfactorily reduced to an alcohol with sodium borohydride and the quinone was regenerated with Fremy's salt. 1-acetoxy-6-desmethyl-7-methoxymitosene was made by forming a carbamate at position 9 by treatment of the 9-alcohol with phenyl chloroformate and displacing the phenoxy group with ammonia. Other 1,6,7-substituted mitosene congeners were made using N-methylcarbamate formation via methyl isocyanate and the 9-alcohol. The 6-chloro and 6-bromo analogs were formed by treatment of the 6-H congener, 1-acetoxy-2,3-dihydro-5,8-dioxo-9-(hydroxymethyl)-7-methoxy-1H-pyrrolo{1,2-a}indole methylcarbamate, with the desired halogen in acetic acid and sodium acetate. The 7-methoxy group could be displaced by ammonia for the 6-bromo compound and by pyrrolidine for the 6-H compound to form respectively the 7-amino-6-bromo and 7-pyrrolidino-6-H 1-acetoxy-2,3-dihydro-5,8-dioxo-9-(hydroxymethyl)-1H-pyrrolo{1,2-a}indole methylcarbamates. The 6-methyl analog (1-acetoxy-7-methoxy-N-methyl-carbamoylmitosene) was made from a previously synthesized precursor. Attempted syntheses of the 6-azido and 6-amino analogs by displacing the 6-bromo substituent with sodium azide were met by gross rearrangement of the resulting adducts. Preliminary antitumor screening against P388 leukemia in mice showed these analogs to be too inactive for use as antineoplastic agents. The 6-methyl substituent was shown to be most potent in bacteriophage induction in E. coli for this series of 6-substituted mitosene analogs.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/187786 |
| Date | January 1984 |
| Creators | CASNER, MICHAEL LAWRENCE. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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