Synthesis-driven mapping of the dictyodendrin alkaloids

The dictyodendrin alkaloids have been described as the first telomerase inhibitors of marine origin. As such they represent interesting lead compounds in the quest for small molecule inhibitors of this tumor-marker enzyme. Described herein is the preparation of a collection of dictyodendrin-like com...

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Bibliographic Details
Published inTetrahedron Vol. 65; no. 33; pp. 6519 - 6534
Main Authors Buchgraber, Philipp, Domostoj, Mathias M., Scheiper, Bodo, Wirtz, Conny, Mynott, Richard, Rust, Jörg, Fürstner, Alois
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 15.08.2009
Elsevier
Subjects
Alkaloids
Chemistry
Chemistry, Organic
DNA
Gold
Indoles
Physical Sciences
Science & Technology
Telomerase
Titanium
Titanium
Alkaloids
Gold
Indoles
Telomerase
DNA
PERMETHYL STORNIAMIDE
LOW-VALENT TITANIUM
NATURAL-PRODUCTS
FACILE TOTAL SYNTHESIS
DNA-CLEAVING PROPERTIES
CROSS-COUPLING REACTIONS
KETO ESTER CYCLIZATION
BIOLOGICAL EVALUATION
MULTIDRUG-RESISTANCE
CYCLOISOMERIZATION REACTION
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Summary:The dictyodendrin alkaloids have been described as the first telomerase inhibitors of marine origin. As such they represent interesting lead compounds in the quest for small molecule inhibitors of this tumor-marker enzyme. Described herein is the preparation of a collection of dictyodendrin-like compounds that hinges on the formation of their indole subunit by reductive cyclization of appropriate keto-amide precursors mediated by low valent titanium. It is shown that the underlying concept can be extended from the synthesis of heterocycles to the preparation of phenol and aniline derivatives using oxo-acid, oxo-nitrile or oxo-lactam derivatives as the substrates; such arene formations can even be carried out in cascade. Exploratory studies into the closure of the B-ring of the dictyodendrins with the aid of electrophilic reagents such as Ph 3PAuCl/AgSbF 6 or I + revealed the bias of these polycyclic heteroarenes to undergo unusual skeletal rearrangements. It is demonstrated that the individual dictyodendrins and analogues are capable of cleaving double stranded DNA under oxidative conditions, provided that they exhibit at least one unprotected phenol group in their periphery. [Display omitted]
ISSN:0040-4020
1464-5416
DOI:10.1016/j.tet.2009.06.058