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Development of a Convergent Enantioselective Synthetic Route to (-)-Myrocin G.


ABSTRACT: Myrocins are a family of antiproliferative antibiotic fungal metabolites possessing a masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity of these natural products to a DNA cross-linking mechanism, but this hypothesis was not confirmed by studies with native DNA. We recently reported a total synthesis of (-)-myrocin G (4), the putative active form of the metabolite myrocin C (1), that featured a carefully orchestrated tandem fragment coupling-annulation cascade. Herein, we describe the evolution of our synthetic strategy toward 4 and report the series of discoveries that prompted the design of this cascade coupling. Efforts to convert the diosphenol (-)-myrocin G (4) to the corresponding 5-hydroxy-?-lactone isomer myrocin C (1) are also detailed. We present a preliminary evaluation of the antiproliferative activities of (-)-myrocin G (4) and related structures, as well as DNA cross-linking studies. These studies indicate that myrocins do not cross-link DNA, suggesting an alternative mode of action potentially involving a protein target.

SUBMITTER: Tomanik M 

PROVIDER: S-EPMC7520802 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Development of a Convergent Enantioselective Synthetic Route to (-)-Myrocin G.

Tomanik Martin M   Economou Christos C   Frischling Madeline C MC   Xue Mengzhao M   Marks Victoria A VA   Mercado Brandon Q BQ   Herzon Seth B SB  

The Journal of organic chemistry 20200702 14


Myrocins are a family of antiproliferative antibiotic fungal metabolites possessing a masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity of these natural products to a DNA cross-linking mechanism, but this hypothesis was not confirmed by studies with native DNA. We recently reported a total synthesis of (-)-myrocin G (<b>4</b>), the putative active form of the metabolite myrocin C (<b>1</b>), that featured a carefully orchestrated tandem fragment c  ...[more]

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