Graduate student researchers can positively affect the world with their work.  My graduate training in medicinal chemistry allowed me to develop new routes to two anticancer drugs—and these may yet be used to make the drugs.

As a PhD student, I established new synthetic routes to indotecan and indimitecan (below).  These drugs are under investigation now in Phase I clinical trials for patients with solid tumors.  In doing this, I filled notebooks with repeated and failed reactions and new ways of running them—I believe it was three 80-page notebooks over two years.  I got to the second-to-last step and I needed months just to find a purification method; it turned out to be bathing the oily, impure solid in chloroform with ether or hexanes, and draining away the solvent to collect a purple powder.  My labmate and I later tried to cut two steps from the total sequence by making a key intermediate in a then-recently discovered way.  But, the method (reported in 2009) was low-yielding in our application:  only ca. 10% yields were achieved on the 1-2 gram scale.  Making the new routes remains my proudest career accomplishment, regardless of whether or not the innovation gets used.  I cannot discuss here the details about the new routes’ commercial viability.  But at a minimum, the new routes are higher-yielding overall than the ones already in use.

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In the first place, I set out to make new molecules that are structurally similar to the Phase I drugs.  Many of these 20 molecules (examples below) performed well in test-tube tests for potential anticancer activities.  Either the molecule slowed the division of cultured cancer cells, or poisoned the Topoisomerase I enzyme, or both.

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All of this work was published in the premier journal for my former specialty, the Journal of Medicinal Chemistry.  Working with me and guiding my work were my mentor, Professor Mark Cushman, and a therapeutics development laboratory at the U.S. National Cancer Institute headed by Dr. Yves Pommier.  Without them, and my fellow labmates, none of this could have been done.

It can be emotionally rewarding to do medicinal chemistry research, especially when your work can make a difference for patients.  In future posts I will write about my other experiences as a student in my graduate program.  It could be helpful or at least interesting to you, if you are curious about how new drugs are made.

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Link to article:  http://pubs.acs.org/doi/abs/10.1021/jm401814y

Top image:  Model of indimitecan in the target binding site.  Generated by the author.

Disclaimer:  This is not medical advice.

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