Indena process opens up taxane chemistry

Related tags Active pharmaceutical ingredient Paclitaxel

The taxane class of cancer drugs has established itself as a
mainstay in the treatment of a range of solid tumours, but to date
there are still only two of these compounds on the market.

One of the reasons for this is that the precursors of these drugs are derived from natural sources, and the chemical routes required to arrive at a final active pharmaceutical ingredient (API) tend to be complex and cumbersome.

Now, Italian company Indena has developed a new semisynthetic pathway for a new taxane, called ortataxel (14 beta-hydroxydeacetylbaccatin), which could become the third drug in this class to reach the market after Bristol-Myers Squibb's Taxol (paclitaxel) and Sanofi-Aventis' Taxotere (docetaxel).

Moreover, the new agent could have improved properties over its predecessor, and the synthetic route has raised the possibility of developing a library of easily-produced, related taxanes that could form the basis of additional new drug candidates.

Indena came up with the new synthetic process for ortataxel in collaboration with the Institute of Organic Chemistry and Fotoreactivity (ISOF, Istituto per la Sintesi Organica e Fotoreattività) in Bologna and the Alessandro Marchesini Institute of Organic Chemistry of the University of Milan.

This new protocol uses 10-deacetylbaccatin (10-DAB), a molecule naturally abundant in European yew tree (Taxus baccata​) leaves as a precursor. Paclitaxel was originally derived from the rarer Pacific yew tree, but the development of a semisynthetic process from T baccata​ had a significant effect in broadening the supply and use of the drug.

Indena and its collaborators successfully carried out the enolisation of intermediate 13-oxo-7-protected baccatin, obtained via this semisynthetic protocol, and achieved the production of ortataxel from 10-DAB. But they also discovered that it was possible to make a wide range of derivatives of ortataxel by adding different chemical groups at position 14 of the molecule.

On the back of this research, Indena has now started two projects - buildings libraries of either 14 beta-amino or 1,14-carbonate derivatives - in the hope of identifying novel taxane drug candidates. Some of these derivatives have already undergone in vitro and in vivo testing at the Grace Cancer Drug Centre at Roswell Park Memorial Institute in the US.

Ortataxel - or BAY 59-8862 - is currently in Phase II trials funded by German pharmaceutical company Bayer, and is much more potent than paclitaxel and docetaxel, and seems to be active in cancers that have developed resistance to the older taxanes.

Taxotere sales were €1.4 billion last year, while B-MS' sales of former blockbuster Taxol continued to show the effects of generic competition but still reached $934 million (€770m).

Indena presented the research at the 228th American Chemical Society's annual national meeting and exposition in Philadelphia.

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