Proprietary Technologies

CSOL Proprietary Technologies

A process for the preparation of (-)-Englerin A, including analogues and intermediates

A process for the total synthesis of enantiomerically pure (-)-Englerin A from readily available cheap raw materials and using a key catalytic cyclization step has been developed. This procedure allows for the preparation of analogs of (-)-Englerin A, a natural product known for its high activity against renal cancer.
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Natural products extracted from plants, water sponges and animals represent a considerable source of bioactive compounds and usually find numerous therapeutic applications. In particular, most anti-cancer drugs are inspired by natural products (e.g.: taxol). (-)-Englerin A, extracted from the east african plant Phyllanthus engleri was recently shown to have a strong activity in inhibiting the growth of renal cancer cells.

Renal cancer is still one of the major cause of disfunction in adults and current therapies are directed to patients with metastatic cancers, do not produce complete responses and present numerous secondary effects. (-)-Englerin A and its analogs might enable to tackle with these disadvantages, thanks to the high activity and selectivity of the natural product against renal cancer cells growth inhibition. Possible therapeutic applications of (-)-Englerin A and its analogs therefore benefit from an important comercial opportunity.

The total synthesis developped in our institute allows for the preparation of (-)-Englerin A from geraniol, a cheap raw material available in large amounts, in 18 synthetic steps, with an overall yield of 7%. The key step of the reaction is a gold(I) catalyzed cyclization step that allows for the establishment of the polycyclic scaffold of (-)-Englerin A stereoselectively. Another gold(I) catalyst with a commercial ligand may be used for this step.

Furthermore, an intermediate is formed along the synthesis that allow for modification of the core of (-)-Englerin A and for the synthesis of analogs of the natural product, which result in useful for drug development and hit/lead identification.

Main advantages:

  • First reported total synthesis of enantiomerically pure (-)-Englerin A
  • Efficient stereoselective key cyclization step
  • Scalable synthesis (multigram)
  • Possibility to develop library of analogs for evaluation of bioactivity and hit identification (drug discovery)
  • Natural product is highly active and selective against renal cancer

References:

Echavarren et al. Angew. Chem. Int. Ed. 2010, 49, 3517-3519