Chemistry and Life

Medicinal chemistry. Pharmacology. Toxicology. Environmental sciences.


Why are there so few boron containing drugs?

TavaboroleThe antifungal drug tavaborole was approved by the FDA a few weeks ago. One thing that is unusual about the chemical structure of tavaborole is the boron atom that it contains. Boron is not a common element in pharmaceutical drugs. The cancer drug bortezomib (Velcade) comes to mind, but there aren’t many. The antibiotic compound boromycin contains boron too, but it’s not a marketed drug.

So what’s wrong with boron that prevents its widespread use in pharmaceuticals? As far as I know, and also according to a review in EMBO Reports, there is nothing inherently bad about boron in terms of it being used in medicines. It seems to be that medicinal chemists simply don’t try to use it often.

The company that developed tavaborole, Anacor Pharmaceuticals, is trying to take advantage of this omission. Their whole pipeline of drug candidates are relatively simple organoboron compounds. You can carve out some novel chemical space in terms of intellectual property that way.

I have encountered a similar situation in my career, except instead of an underutilized element, it involved an underutilized functional group. In developing the anticonvulsants JNJ-26990990 and JNJ-26489112, we were able to patent some very simple* compounds because they contained the relatively uncommon sulfamide functional group. We encountered no inherent problems with druggability associated with the sulfamide groups, and noticed that it showed up relatively infrequently in the patent literature, so we came to the conclusion that it was an underappreciated and underutilized functional group in medicinal chemistry.

*Readers in the drug discovery field can imagine how pleased our scale-up group was to learn that our first clinical candidate could be prepared in one step from commercially available materials.


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Mayapple and podophyllotoxin

May apple leafThe woods here in Pennsylvania at this time of year are starting to burst into their summer greenery. One of the plants that is prominent at the moment is the mayapple (Podophyllum peltatum). It is a small herbaceous perennial with an umbrella-like leaf on a single stalk. Underneath this umbrella a single flower blooms which eventually grows into a fruit, the “apple”. The fruit is edible when ripe, but the roots and leaves are quite poisonous.  Even touching the root may cause dermatitis.

The extract of the root (actually a rhizome) is known as podophyllin.  This extract is a complex mixture of chemical compounds including flavonols and lignans.  One of those lignins, podophyllotoxin, is the individual toxin primarily responsible for the poisonous nature of the plant.

Mayapple flowerAs is sometimes the case with poisonous plants, the mayapple has found use medicinally.  Native Americans and early American settlers used it for a variety of ailments.  In modern medicine, both the mixture podophyllin and the purified compound podophyllotoxin have found use in the topical treatment of warts.

Medicinal chemists have also taken note of the properties of podophyllotoxin.  Two semi-synthetic derivatives of podophyllotoxin, teniposide and etoposide, have been developed as pharmaceutical drugs for use in cancer treatment.  These two drugs act as topoisomerase inhibitors.

So it seems we’ve progressed from using the whole plant to using a crude extract, then to using a purified chemical, and finally to using semi-synthetic derivatives designed to hit a specific target enzyme.  What comes next?



Soursop and annonacin

Soursop is a tropical fruit from the plant Annona muricata.  It is also sometimes called graviola or pawpaw.  It is apparently becoming popular as a dietary supplement.  Extracts have been shown to be able to kill some types of cancer cells in vitro (in “test tube studies”).  There doesn’t appear to be any clinical study in humans, but that hasn’t stopped supplement manufacturers from claiming soursop to be an all-natural miracle cancer cure.

The bioactive constituents of soursop have been identified as members of the acetogenin class of compounds.  In particular, soursop contains a chemical called annonacin that has been found to posses in vitro anticancer activity; for example, it can cause cell growth arrest and apoptosis in the MCF-7 breast cancer cell line.

However, annonacin is also a neurotoxin.

This is a common problem encountered by medicinal chemists.  When optimizing chemical compounds for one particular desirable pharmacological effect, one can also get an unwanted “off-target” effect that is associated with it. These off-target activities can be the source of a pharmaceutical drug’s side effects. It is often hard to get rid of these off-target activities entirely, so the idea is to find compounds that maximize the ratio between desirable and undesirable effects.

For annonacin, investigators are looking into the fact that it is a mitochondrial complex I inhibitor, which can lead to destruction of neurons and gives rise to the potential to cause neurodegenerative disease. There are also a number of published studies that show an association between heavy consumption of soupsop and Parkinson’s disease, or more broadly, atypical parkinsonism.

The research that makes a connection between soursop and anticancer effects is preliminary and hasn’t been established in humans.  The research that makes a connection between soursop and neurodegeneration spans in vitro studies, animal studies, and epidemiological studies.  For a health supplement, that certainly doesn’t sound like a good bet to me.

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Chemical structure of dianhydrogalactitolDianhydrogalactitol (VAL-083) is an experimental cancer drug currently in clinical trials.  This caught my attention because of its chemical structure.  It is a simple sugar derivative with two epoxide groups.  These epoxide groups are very reactive, and so the compound falls into the class of cancer drugs known as DNA alkylating agents.  This is an old class of drugs, and the trend in oncology research has been to move away from these types because they tend to be indiscriminate in the kinds of cells they kill.  They are good at damaging DNA and this simply keeps cells from multiplying.  Since tumor cells are doing too much multiplying, the tumor is damaged somewhat more than other tissues.

This chemical certainly looks like a cancer drug from the 1970s.  And in fact, there are reports in the literature of clinical trials of dianhydrogalactitol from that time period.  So why is Del Mar Pharmaceuticals reviving this old drug now?  It must make an interesting story.  Dianhydrogalactitol seems to have had little success as a potential cancer drug 30 or 40 years ago, but it may be getting a second chance now.  According to these reports the US FDA and the European Medicines Agency have each granted it orphan drug status for the treatment of glioma, a type of brain tumor.

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Goat’s rue, galegine, and metformin

Galegine (top) and metformin (bottom)

Galegine (top) and metformin (bottom)

There’s an interesting story of how a medicinal plant inspired the discovery of the pharmaceutical drug metformin, which is currently used in the management of type 2 diabetes.

Goat’s rue (Galega officinalis) is an herb that was used in traditional medicine since the Middle Ages to treat diabetic symptoms.  The first scientific studies of the chemical constituents of goat’s rue found a variety of alkaloidal guanidine derivatives that were putatively responsible for its pharmacological effects.  However, they tended to be quite toxic.  One of them, galegine, was found to be less toxic.  It was identified as isoprenyl guanidine and it was studied clinically in the 1920s.  These trials showed blood glucose lowering effects in diabetic patients, but were ultimately unsuccessful, primarily due to a short duration of action.

This work inspired further investigation and the biguanides were identified as compounds with greater potential.  Three of them, phenformin, buformin, and metformin, made it to the market.  Phenformin and buformin have since been withdrawn, but metformin is still the drug of choice for management of type 2 diabetes.