HALICHONDRINS

Molecular Weight (Halichondrin B): 1111.31 g/mol
Molecular Formula (Halichondrin B): C₆₀H₈₆O₁₉

Source: The Japanese sponge Halichondria okadai (PORIFERA)
Activity: tubulin interactive agent
Status: Synthetic analogs are currently in clinical trials.

A compound given the name halichondrin B, belonging to a chemical family known as the macrolides, was isolated by Uemura et al (1985) from the Japanese sponge Halichondria okadai. Since this time, several similar macrolides have been found in an array of Pacific and Indian Ocean sponge genera including Axinella, Phakellia, and Lissodendroryx.

Initial investigations into the bioactivity of the compound revealed that halichondrin B apparently bound tubilin at a site close to the so-called vinca site and altered tubulin depolymerization. Early experimental work also demonstrated in vivo activity, but further work advancing the compound was hindered by lack of the natural product.

The National Cancer Institutes provided funds for a New Zealand research consortium to trawl-harvest the one metric ton of the deepwater sponge Lissodendoryx sp. that would be needed to yield sufficient halichondrins to continue evaluation and development. NCI also funded successful efforts to culture this sponge in shallow water.

At approximately the same time, a Harvard synthetic chemistry lab succeeded in the total synthesis of halchondrin B and also the related structure norhalichondrin B. This group produced supplies of the compound via synthesis for use in NCI-sponsored clinical trials. This synthetic work was expanded upon by scientists working for Japanese pharmaceutical company Eisai, who successfully produced a range of halichondrin B variants that remained bioactive but were also more structurally stable than their natural counterpart. One of the Eisai halichondrin analogs, E7389, is currently in phase I clinical studies under the auspices of NCI.

NCBI PubChem compound summary page - [ LINK ]

NCBI PubMed biomedical literature citations and abstracts - [ LINK ]

References

Newman DJ, and GM Cragg. 2004. Advanced Preclinical and Clinical trials of natural Products and Related Compounds from marine Sources. Current Medicinal Chemistry 11:1693-1713.