Simplified silvestrol analogues with potent cytotoxic activity

BC Hawkins; LM Lindqvist; D Nhu; PP Sharp; D Segal; AK Powell; M Campbell; E Ryan; JM Chambers; JM White; MA Rizzacasa; G Lessene; DCS Huang; CJ Burns

Journal article

Simplified silvestrol analogues with potent cytotoxic activity

BC Hawkins, LM Lindqvist, D Nhu, PP Sharp, D Segal, AK Powell, M Campbell, E Ryan, JM Chambers, JM White, MA Rizzacasa, G Lessene, DCS Huang, CJ Burns

Chemmedchem | WILEY-V C H VERLAG GMBH | Published : 2014

DOI: 10.1002/cmdc.201400024

Abstract

The complex natural products silvestrol (1) and episilvestrol (2) are inhibitors of translation initiation through binding to the DEAD-box helicase eukaryotic initiation factor 4A (eIF4A). Both compounds are potently cytotoxic to cancer cells in vitro, and 1 has demonstrated efficacy in vivo in several xenograft cancer models. Here we show that 2 has limited plasma membrane permeability and is metabolized in liver microsomes in a manner consistent with that reported for 1. In addition, we have prepared a series of analogues of these compounds where the complex pseudo-sugar at C6 has been replaced with chemically simpler moieties to improve drug-likeness. Selected compounds from this work pos..

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University of Melbourne Researchers

Jonathan White Author

Mark Rizzacasa Author

Guillaume Lessene Author

David Huang Author

Related Projects (1)

Small Molecule X-ray Molecular Structure Elucidation Facility

X-ray diffraction plays a key role in identification and molecular characterisation. X-ray techniques are the single most widely used analyt..

Grants

Awarded by Australian National Health and Medical Research Council

Funding Acknowledgements

Prof. Jonathan Baell is thanked for useful discussions, Dana Buczek is acknowledged for analytical support and H. Ierino for technical assistance. Dr. David Owen is thanked for assistance in establishing the photochemical reactor and Dr. John Flygare for samples of key intermediates and silvestrol. This work is supported by scholarships, fellowships and grants from the Australian National Health and Medical Research Council (Early Career Fellowship to L. M. L.; Research Fellowship to D. C. S. H.; program grants: 461221 and 1016701; Independent Research Institutes Infrastructure Support Scheme, grant 361646); the Victorian State Government Operational Infrastructure Support (OIS) Grant; the Australian Cancer Research Foundation; the Canadian Institutes of Health Research (Postdoctoral Fellowship to L. M. L., who is also a Bisby Fellow); Cancer Therapeutics CRC (D.N., J.M.C., M. A. R.); and Dyson Bequest funding (Dunn Fellowship to C.J.B.).