Monday, February 15, 2010

Enantioselective synthesis of Kinamycin F - a new hope for anticancer drug development ?

The kinamycins are a series of naturally occurring compounds endowed with intriguing molecular architectures and potent biological properties such as  antibiotic and antitumor activities. These novel diazofluorene-containing compounds defied chemical synthesis since their initial disclosure by Omura et al. in 1970 until the first total synthesis of kinamycin C by Porco et al. in late 2006.

Now, researchers from Yale University,  have  developed a new method to recreate this structure that allows them to synthesize the kinamycins with much greater efficiency than previously possible.
As per the claim by the researchers,  key to the success of the route was  the development of a three-step sequence for construction of the diazonapthoquinone (diazofluorene, blue in structure source : JACS) function of the natural product.

While scientists have produced kinamycins in the laboratory in the past, the Yale team was able to halve the number of steps required to go from simple, easily obtainable precursors to the complete molecule from 24 down to 12. 

This sequence comprises fluoride-mediated coupling of a β-(trimethylsilylmethyl)-cyclohexenone and halonapthoquinone, palladium-mediated cyclization to construct the tetracyclic scaffold of the natural product, and mild diazo-transfer to a complex cyclopentadiene to introduce the diazo function. Ortho-quinone methide intermediates, formed by reduction and loss of dinitrogen from (structure), have been postulated to form in vivo, and this approach provides a straightforward synthetic pathway to such compounds.

This research is of great importance because by shortening the synthesis one can now prepare these molecules in the quantities required for further studies, including animal studies and even clinical trials.

Working with researchers at the Yale School of Medicine and the Yale Chemical Genomics Screening Facility, the team has begun testing several of the compounds against cancer cells, with promising preliminary results. Next, they will work to understand the exact mechanism that makes the compounds,  which are benign on their own  highly toxic once they penetrate cells. Lead researcher Dr. Seth Herzon, says "the key to success will be whether they can develop selectivity - whether they can kill cancer cells in the presence of non-cancerous tissue". Dr.Herzon  is also optimistic about lomaiviticin A (which also has the reactive core kinamycin,  and is even more toxic and could prove even more effective in destroying cancer cells)...let us hope positive results from this study....

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