Conjuring a Supernatural Product – DelMarine

Abstract

The asmarine alkaloids constitute a small family of terpene-nucleobase marine metabolites defined by a unique N-hydroxy-diazepine pharmacophore that effects moderate to potent cytotoxicity against several cancer cell lines. Isolation of the metabolites from an unidentified producer organism provided enough material for initial assay, but this material was soon exhausted, impeding further study. Procurement of material through synthesis is the obvious solution. Here we chronicle our discovery of simple but potent asmarine analogues that solve the material supply problem.

1 Introduction

2 Project Selection

3 Project Design

3.1 The Big Picture

3.2 Synthetic Strategy

3.3 Challenges in the Design

4 The Quest to Find Bioactive Asmarines

4.1 Model Systems as Proof of Concepts

4.2 Stereoselectivity Investigation with Clerodane-Appended Cyclization Precursors

4.2.1 Obtaining the Cyclization Precursor

4.2.2 Results from Cyclization Screening

4.3 Toward the Synthesis of Asmarine A

4.4 A Turning Point: Screening Forward

5 Biological Investigation of the Asmarine Scaffold

5.1 Cytotoxicity Assays of our Synthetic Intermediates and their Enantiomers

5.2 Synthesis of Analogues for a More In-Depth Biological Investigation

6 Synthesis of Simple Asmarine Analogues and their Cytotoxicity

7 Conclusion

Key words

antitumor agents - cyclization - ene reaction - natural products - regioselectivity

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