Friday, March 11, 2016

Anesthesia, cancer, and the wrong pipe: A quick tour of cycloalkanes

The simplest organic molecules out there are alkanes, which consist of one or more carbon atoms coated with hydrogen atoms. If you loop an alkane chain you get a cycloalkane. For today's post I'll be looking at a couple of cycloalkanes and their relevance to human health and biology at large.

Cyclopropane is an unstable carbon atom triangle. It's a gas at room temperature, and its lack of stability makes it explosive when mixed with oxygen. Back in the day, medical folks became interested in using a similar gas known as propylene or propene (a chain of three carbon atoms, not joined as a ring, two of them double bonded) to knock people out before surgery (in other words, as a general anesthetic). After some investigation, they realized it was way too toxic to the heart to justify its use. A couple of researchers (Lucas and Henderson, working at U of Toronto) wondered if the toxicity was due to impurities in the propylene, one of which they figured was cyclopropane. In a fun twist, the gaseous triangle was found to be an effective general anesthetic in its own right (rapid onset, not irritating, potent), and a less toxic one to boot (although it did occasionally cause abnormal heart rhythms). In fact, all of the smaller cycloalkanes will put you to sleep if you inhale them. After enjoying some success in the operating room, cyclopropane use declined as newer anesthetics not prone to causing explosions or heart problems were introduced.

Gauges for anesthetic gases, cyclopropane being the orange one on the left (Source)

Cyclobutane is another unstable gas, this time a square of carbon atoms instead of a triangle. Although the molecule on its own isn't particularly noteworthy with respect to biology, cyclobutane groups are present within a diverse group of larger biomolecules. Squares can arise in our DNA when our skin cells are exposed to sunlight. The energy from UV radiation is sufficient to cause adjacent pyrimidines within DNA to become linked together by two carbon-carbon bonds, forming a square. If the pyrimidine dimer isn't repaired, it can disrupt DNA replication and lead to mutations, which in turn can lead to skin cancer. Although it participates in the development of skin cancer, cyclobutane is also found in the anticancer drug carboplatin, a platinum-containing derivative of cisplatin. It works by binding to DNA within cancer cells, disrupting their ability to divide. Looking beyond humans for a bit, cyclobutane-containing compounds have been found in bacteria and beetles. Certain bacterial residents of oxygen-depleted, ammonium-rich waters (e.g. a big tank of sewage) have in their cell walls weirdo lipids called ladderanes. These contain three or five fused cyclobutane rings at one end, and may be involved in protecting the bacteria against toxic substances. Tripartilactam is the product of a Streptomyces bacterium found in balls of dung prepared by dung beetles as a home for their offspring. It's made up of three fused rings, the middle of which is cyclobutane, and can inhibit the enzyme Na+/K+ ATPase (the target of the heart drug/poison digoxin).

Cyclopentane is a a five-carbon ring taking the form of a flammable liquid at room temperature. A comprehensive toxicological assessment I just intensely skimmed concluded it was practically nontoxic. The biggest concern with it from a poisoning standpoint is it's fairly easy to accidentally inhale it into your lungs (pulmonary aspiration) if you decide to swallow it, owing to its low surface tension and low viscosity. Among other things, cyclopentane is a solvent (it dissolves stuff), a propellant in aerosol spray cans, and is used by drug manufacturers to make their various products.

Our little tour ends with cyclohexane, an alkane ring of six carbon atoms. Its main claim to fame is being a solvent used in laboratories all over the world. As such, I'm sure it's made a very minor contribution to research relevant to human health. Cyclohexane, a component of crude oil, has also been used to model the breakdown of oil by microorganisms, such as bacteria in Gulf Coast waters impacted by the Deepwater Horizon spill.


Boros G et al. 2015. Identification of cyclobutane pyrimidine dimer-responsive genes using UVB-irradiated human keratinocytes transfected with in vitro-synthesized photolyase mRNA. PLoS One 10(6):e0131141. [Full text]

Chaban VV, Nielsen MB, Kopec W, Khandelia H. 2014. Insights into the role of cyclic ladderane lipids in bacteria from computer simulations. Chemistry and Physics of Lipids 181:76-82.

Galvin JB, Marashi F. 1999. Cyclopentane. Journal of Toxicology and Environmental Health, Part A 58(1-2):57-74.

Jaekel U, Zedelius J, Wilkes H, Musat F. 2015. Anaerobic degradation of cyclohexane by sulfate-reducing bacteria from hydrocarbon-contaminated marine sediments. Frontiers in Microbiology 6:116. [Full text]

Johnstone M. 1950. Cyclopropane anesthesia and ventricular arrhythmias. British Heart Journal 12(3):239-244. [Full text]

Lucas GHW and Henderson VE. 1929. A new anesthetic: Cyclopropane. Canadian Medical Association Journal 21(2):173-175. [Full text]

Park SH et al. 2012. Tripartilactam, a cyclobutane-bearing tricyclic lactam from a Streptomyces sp. in a dung beetle's brood ball. Organic Letters 14(5):1258-1261.

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