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Moving beyond the genome to fight cancer

The first total synthesis of the complex natural product chaetocin expands the tools to reverse lethal gene expressions

Unlocking our genetic blueprint is well underway with the sequencing of the human genome, but a secondary layer of structure on the genome that affects gene expression, the ‘epigenome,’ remains largely unmapped.

The packing structure of the epigenome can be altered by chemically modifying histones, spool-like proteins around which DNA strands are wrapped within our cells. Histones physically control access to genes, and adding small functional groups such as acetyl or methyl units to them can selectively switch certain genes on and off.

Recent developments in methods that can controllably influence these DNA architectures have focused on the methylation of histone proteins. Now, a research team led by Mikiko Sodeoka from the RIKEN Advanced Science Institute in Wako, Japan, has produced the first total synthesis of chaetocin1, a natural product that inhibits the activity of histone methyltransferases—enzymes that play critical roles in gene expression. The results of this work could enable new therapeutics for destructive diseases such as cancer.

A ‘tail’ of influence

Histones contain floppy ‘tail’ regions, terminated by an amino acid with a free amine group, that extend from the body of the protein. These tails can influence the epigenome structure and serve as extremely active sites for chemical modification. Histone methyltransferase enzymes catalyze the addition of methyl units to lysine and arginine amino acid side chains in this tail, forming strong bonds in the process. This reaction does not change the genetic code of the protein, but radically influences transcription processes—giving histone methylation an influential role in inherited gene expression patterns.

Normally, the levels of histone methylation are delicately balanced within our cells. However, dysfunction of histone methyltransferases can alter the epigenome and lead to abnormalities—notably, the loss of expression of tumor-suppressing genes. Therapies that can selectively control the activity of these enzymes hold great potential for new cancer therapeutics without the dangerous side effects of chemotherapy.

Natural guides

The number of chemicals that can modulate histone methyltransferase enzymes is limited. According to team-member Yoshitaka Hamashima, also from RIKEN, only a few compounds that can selectively inhibit these enzymes have been reported to date. He says, “it is only chaetocin that comes from natural sources.”

Chaetocin is a natural alkaloid produced by Chaetomium minutum, a form of wood mold. The complex and elegantly symmetric structure of this molecule features eight rings and several functional groups, most notably a pair of disulfide bridges attached to two terminal rings. Chaetocin has been extensively investigated for its antibacterial behavior and ability to suppress cell growth, and has the potential to play an important role in modifying the epigenome.

Several research groups have produced related analogues of chaetocin, but the total synthesis of this molecule has eluded organic chemists since its discovery forty years ago—setting up a significant test to the synthetic skills of Sodeoka and her team. “The fact that no one had succeeded in the total synthesis after its isolation in 1970 drove us to embark on this formidable challenge,” says Hamashima.

Risk and reward

The final part of the reaction—construction of the disulfide bridges—involved some risky chemistry, Hamashima notes. “In our initial plan, we expected that the double-decker structure of chaetocin might control the approach of hydrogen sulfide from the outer side. But nobody was convinced that it would work well.” The team was extremely gratified when the final step in the reaction, which involved ten bond-forming and -cleaving events, generated chaetocin with the correct geometrical structure.

Overall, the team’s method demonstrates a highly efficient way to produce chaetocin, because the total synthesis required only nine chemical transformations.

Bridging differences

With the chemical synthesis of chaetocin complete, Sodeoka and colleagues prepared various analogues of the molecule—two optical isomers of chaetocin, and a version missing the disulfide bridges. The latter allowed them to examine the structure–activity relationship between this natural product and a particular histone methyltransferase enzyme called G9a, in collaboration with Minoru Yoshida’s group also from RIKEN Advanced Science Institute. Although both chaetocin isomers showed strong inhibitory activity, the molecule without the sulfur bridges was inactive—demonstrating the critical role of this functionality.

Hamashima says that the target enzyme has a domain, close to chaetocin’s binding site, which is full of amino acids called cysteines. Cysteines have a thiol (-SH) side chain that may be able to form transitory bonds with the critical disulfide bridges of chaetocin. “While the exact mechanism is still unclear,” he says, “we speculate that such chemical bond formations are responsible for the inhibition of G9a.”

The researchers believe that further studies into the molecular mechanisms of chaetocin should deliver a new generation of enzyme-specific pharmaceuticals that can control gene expression patterns—an important step in the treatment of cancerous diseases. “Contributing to human health by creating new drugs is our goal,” says Hamashima. “In the future, the day will come when we can wake up silent genes in cells at will by simply adding chemical modulators.”

About the Researcher

Mikiko Sodeoka, Yoshitaka Hamashima and Eriko Iwasa

Mikiko Sodeoka received her BS and MS degrees from Chiba University and was awarded a PhD in pharmaceutical sciences from the same institution in 1989. She worked at the Sagami Chemical Research Center from 1983 to 1986, after which she joined the Faculty of Pharmaceutical Sciences at Hokkaido University as a research associate. She spent time as a postdoctoral fellow at Harvard University, USA, and then joined The University of Tokyo in 1992. In 1996, she became a group leader at the Sagami Chemical Research Center, and later became an associate professor at The University of Tokyo in 1999. In 2000, she joined Tohoku University as a full professor, and since 2004, she has been chief scientist of the Synthetic Organic Chemistry Laboratory at RIKEN. In 2008, she was also appointed as research director of the Sodeoka Live Cell Chemistry ERATO project.

Yoshitaka Hamashima received his BS and MS degrees from The University of Tokyo and was awarded his PhD in 2003 from the same institution. In 2001, he joined Tohoku University as an assistant professor, and was promoted to lecturer in 2005. He is now a senior researcher at RIKEN. He received the Meiji Seika Award in Synthetic Organic Chemistry in 2003, the Thieme Journal Award in 2006, and the Pharmaceutical Society of Japan Award for Young Scientists in 2006. His current research interests include catalytic reactions, organometallic chemistry and bioactive compound synthesis.

Eriko Iwasa graduated from the Faculty of Engineering, Seikei University, and obtained her master degree at Tokyo Gakugei University. In 2007, she entered a doctoral course at Saitama University and joined RIKEN's Junior Research Associate Program. In 2010, she became a research assistant of the Sodeoka Live Cell Chemistry ERATO project.

Journal information

1. Iwasa, E., Hamashima, Y., Fujishiro, S., Higuchi, E., Ito, A., Yoshida, M. & Sodeoka, M. Total synthesis of (+)-chaetocin and its analogues: Their histone methyltransferase G9a inhibitory activity. Journal of the American Chemical Society 132, 4078–4079 (2010)

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