Jonathan Sessler talks to Michael Brown about what motivated him to discover texaphyrin and about the aims of the companies he co-founded

	Jonathan Sessler is a professor at The University of Texas, US. He is co-founder of Pharmacyclics, a company developing biomedical applications of expanded porphyrins, and Anionics, a company that targets various commercial opportunities associated with anion recognition chemistry. He is an associate editor and a member of the editorial board for Chemical Communications.

 

What inspired you to become a chemist?

My love for chemistry started in the seventh grade at school when I had the chance to do some experiments as part of the curriculum. Also, my father was a physicist and we had a small laboratory in our house. I was able do experiments in there, such as making esters. These exploits finally came to an end when I successfully synthesised nitroglycerine and blew up half the lab! When my dad came home, he said that all good chemists end up blowing themselves up. The inference about my abilities (or lack thereof) was clear!

What is the most significant aspect of your work?
Over the course of my career, it has been the use of new macrocycles for drug development. However, right now, it is the transition between supramolecular chemistry and polymer chemistry. We are particularly excited about a joint project with Chris Bielawski's group at The University of Texas. It combines the chemistry of various specific neutral anion receptors (these are more biocompatible than charged receptors) with polymeric materials. This is allowing us to couple the specificity of the receptors with the well controlled hydrophobic environment of polymers.

Our neutral anion-binding agents rely on hydrogen bonding and thus fail to capture these charged species in aqueous environments. Conversely, polymers lack specificity as receptor systems, but they have a known track record as, for example, ion exchange resins. In fact, some ion exchange resins are used for water purification and are even ingested to control levels of potassium in renal failure patients. What we are finding is that by combining supramolecular chemistry and polymer chemistry, we can generate highly ion-specific materials that act as effective ion extractants. We postulate that the interfacial environment created by the receptor-modified polymers may have a polarity that is reduced compared to water and may, in fact, be similar to that of membranes.

We can extract ions into organic media using receptors that would never work by themselves.

How did you discover texaphyrins and what was your motivation?

As mentioned above, the main focus of my effort over most of my career has been to develop anti-cancer drugs using compounds that we call 'expanded porphyrins'. In this context, we have put a particular emphasis on texaphyrins. This work was inspired, in part, by my own history. As a student, I underwent treatment for Hodgkin's lymphoma, and I went through radiation treatment as a senior at the University of California, Berkeley. I decided to do post graduate studies at Stanford University, as it was reputed for its chemistry and the particular treatment that I needed. Dr Henry Kaplan, at Stanford, had developed radiation treatment for soft tumours - radiation had been used for years for hard tumours - and he set up a school for the treatment of Hodgkin's disease. In my third year, I had a relapse and underwent chemotherapy in the care of Dr Richard Miller. He suggested that as I was a chemist, I should be able to come up with a new cancer drug. My PhD and post doctoral work were in the area of porphyrins, which are pigments found in blood.

I had my first exposure to porphyrins while preparing synthetic oxygen carriers in Professor Collman's group while a graduate student at Stanford. As a postdoctoral fellow, I then incorporated these classic pigments into Jean-Marie Lehn's cryptand structures, continuing work started by a previous postdoctoral fellow, Andy Hamilton. So, by the time I began my independent career, I was experienced at handling pyrrolic macrocycles.

Then, when I arrived in Texas, I realised that blood pigments only had four sub-units called pyrroles, and it would be interesting to investigate the chemistry of systems with five pyrroles. Texas, known as the 'Lone Star State', has a five point star as an emblem, so I was motivated to make a politically correct molecule with five nitrogens instead of four. We called the molecule 'texaphyrin'. It turned out that by expanding the core of the porphyrin, texaphryin became attractive as an anti-cancer agent.

There are several reasons why texaphyrin is attractive as a drug candidate. Firstly, it can act as a ligand for larger metals, in particular gadolinium, which is MRI active. It also displayed tumour specificity equal to or superior to that of porphyrins, a class of materials known to be retained selectively in cancerous sites. In the course of studying this molecule, we realised it was easier to reduce than a porphyrin and could capture electrons readily. This meant it could work as a radiation enhancer, thereby complementing one of the best-established treatments for some forms of cancer, in particular metastatic brain cancer. We realised that if we could capture electrons, we could increase the amount of active oxygen species that lead to an anti-cancer effect. Dr Darren Magda, a former student and employee of Pharmacyclics, carried out research to investigate the mechanism of action of the texaphyrins; he discovered that they enhance the formation of oxygen-based radicals, while activating a number of biochemical pathways that lead to an increased concentration of oxygen at tumours. It is well known that oxygen coupled with radiation is much more effective for the treatment of cancer. In fact, radiation treatment is often given in fractionated doses to allow reoxygenation of the tumour.

Could you tell us about the companies you co-founded?
When I was undergoing treatment, there were no drugs to prevent the nausea associated with the treatment so it was pretty tough. Dr Richard Miller suggested that we use our chemical talents to make better drugs; that motivated us to develop texaphyrin and set up Pharmacyclics.

I am a co-founder of Pharmacyclics. However, Dr Richard Miller got the company up and running. He recently stepped down and Bob Duggan now runs the company and is working to set up a new Phase III clinical trial focused on the use of a gadolinium complex of texaphyrin, called motexafin gadolinium (MGd), in conjunction with radiation therapy. It is expected that this trial will start in 2009. MGd has been administered to about 1000 patients to date and the trials have been promising but not quite good enough for regulatory approval; we hope that the planned trial will allow this situation to be rectified.

It took a combination of dedication, science and money to bring this drug to the point where it is. Everyone involved, from Dr Darren Magda, who figured out how it works, to Dr Greg Hemmi, who was instrumental in producing the compounds on an industrial scale, as well as Dr Miller and Mr Duggan, to name but a few of many, has been instrumental in getting these compounds from discovery to advanced clinical trials.

The second company I co-founded is Anionics. We are working towards developing the polymeric materials that I mentioned earlier; we aim to use them to remove anions from renal patients and for water purification. This research is waiting for a real technological breakthrough to occur - we have the infrastructure in place.

The company is run by Dr Martin Johnson, one of my first graduate students, and an entrepreneur in his own right. As an academic professor there is a lot of red tape involved if I want to be directly involved in the running of the companies mentioned, so I act as an advisor to Dr Johnson.

Collaborations are very important in modern research. Why are they beneficial?
Science, in particular chemistry, is an international enterprise and the efficiency that comes from taking advantage of the expertise of others is great. The days when one person can do it all are limited. I benefit tremendously from having friends and collaborators all over the world. Collaboration is essential in my work and I am very lucky to have many expert colleagues who collaborate with me.

What do you enjoy most about working on Chemical Communications?
The opportunity to interact with people has increased as a result of working for Chemical Communications. It is a joy to have friends all over the world and to be able to meet other researchers at meetings and conferences. Making personal connections with other academics and monitoring the work of researchers that contribute to the journal is gratifying. The opportunity to interact with other board members and the RSC office staff, making new friends and acquaintances, and expanding the circle of colleagues all over the planet is also good.

Could you tell us a bit about the Chemistry Circuses that are hosted at The University of Texas?
My post graduate students host Chemistry Circuses and I act as the master of ceremonies. We carry out demonstrations such as igniting hydrogen and helium balloons to show the different effects. We do this for various university visitors, about half a dozen times a year. When we have visiting high school students, we show them some exciting aspects of chemistry. I also show the chemistry behind the breathalyser test where chromium(VI) is able to oxidise whisky. Needless to say, I always have to test the 'reagent'!

What do you do in your spare time?
My main hobby is jogging; I go once or twice a week for an hour or two. I also love windsurfing and skiing. I lived in Geneva for a year, where I learnt French and learnt to ski. I have a love of languages and that is partly why I like to travel. French was the first language I learnt, but I am continuing to add to that collection as best I can.