The cephalostatins. 22. synthesis of bis-steroidal pyrazine pyrones (1).

Abstract

Cephalostatin 1 (1), a remarkably strong cancer cell growth inhibitory trisdecacyclic, bis-steroidal pyrazine isolated from the marine tube worm Cephalodiscus gilchristi, continues to be an important target for practical total syntheses and a model for the discovery of less complex structural modifications with promising antineoplastic activity. In the present study, the cephalostatin E and F rings were greatly simplified by replacement at C-17 with an α-pyrone (in 12), typical of the steroidal bufodienolides, and by a dihydro-γ-pyrone (in 16). The synthesis of pyrazine 12 from 5α-dihydrotestosterone (nine steps, 8% overall yield) provided the first route to a bis-bufadienolide pyrazine. Dihydro-γ-pyrone 16 was synthesized in eight steps from ketone 13. While only insignificant cancer cell growth inhibitory activity was found for pyrones 12 and 16, the results provided further support for the necessity of more closely approximating the natural D-F ring system of cephalostatin 1 in order to obtain potent antineoplastic activity.

• Authors: George R Pettit, Bryan R Moser, Ricardo F Mendonça, John C Knight, Fiona Hogan
• Journal: Journal of natural products (J Nat Prod) Vol. 75 Issue 6 Pg. 1063-9 (Jun 22 2012) ISSN: 1520-6025 [Electronic] United States
• PMID: 22607450 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Phenazines
• Pyrazines
• Pyrones
• Spiro Compounds
• Steroids
• cephalostatin I

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Chordata, Nonvertebrate
• Humans
• Marine Biology
• Models, Molecular
• Molecular Structure
• Phenazines (chemical synthesis, chemistry, pharmacology)
• Pyrazines (chemical synthesis, chemistry, pharmacology)
• Pyrones (chemical synthesis, chemistry, pharmacology)
• Spiro Compounds (chemical synthesis, chemistry, pharmacology)
• Steroids (chemical synthesis, chemistry, pharmacology)