| RESEARCH HIGHLIGHTS |
to block these pathways synergistically,” says Choong. The study has important treatment
implications. “The JAK2 inhibitor, ruxolitinib, is the drug of choice for treatment of MPNs,” explains Choong. “But since JAK2 is a common signaling molecule involved in diverse functional pathways, blocking its activity would produce many side-effects. We found
that MEK/ERK inhibitors could work syner- gistically with the JAK2 inhibitor (ruxolitinib), which would allow us to achieve the same therapeutic goal using lower quantities of the inhibitors, thus reducing side-effects.” The researchers intend to search for ways
to prevent the abnormal interaction between CALR mutants and the thrombopoietin receptor. “Now we know how CALR mutants
affect thrombopoietin receptor signaling, we can look for ways to block the interactions between CALR and the thrombopoietin receptor,” notes Choong.
1. Chachoua, I., Pecquet, C., El-Khoury, M., Nivarthi, H., Albu, R.-I. et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood 127, 1325−1335 (2016).
Catalysis:
THE POWER OF THREE
INSIGHT INTO THE ROLE OF A THREE-RING LIGAND MAY IMPROVE PALLADIUM- CATALYZED REACTIONS USED FOR SYNTHESIZING ORGANIC PRODUCTS
Palladium-catalyzed organic reactions, such as Sonogashira cross-coupling, may be made more efficient and substrate-tolerant as a result of new findings at A*STAR. Having previously developed a catalyst that
outperforms existing state-of-the art analogs, the researchers now show how a catalyst structure sparks unprecedented activity1. Sonogashira cross-coupling — which
assembles molecules by joining terminal alkynes to chlorinated aromatic compounds, while keeping the triple bond intact — is used for synthesizing organic products destined to become pharmaceuticals and molecular electronics. Typically, the assem- bling relies on a copper salt that increases the catalytic productivity by assisting the alkyne addition to the catalyst. However, this salt also promotes the formation of
6 A*STAR RESEARCH
by-products that require complex and time-consuming purification. Yee Hwee Lim and co-workers from the
A*STAR Institute of Chemical and Engi- neering Sciences and Singapore Bioimaging Consortium have solved this issue by creating a palladium complex, without copper, that can still catalyze Sonogashira cross-coupling. Lim explains that the less metal used, the better it is for downstream purification stages. “To use this catalyst in an industrial process, we want to decrease the metal content,” she adds. As well as being more efficient, the
copper-free system can be applied to a broader
Cy*Phine-based palladium catalyst for copper-free Sonogashira cross-cou- pling reactions. The benzene rings (highlighted in red) block potential side reactions involving the ligand.
range of substrates than its commercially available analogs. This performance enhancement hinges on the Cy*Phine ligand, which consists of a phosphine-type molecule bearing three interconnected benzene rings. However, its underlying mechanism remained unclear. With Adrian Matthew Mak from the
A*STAR Institute of High Performance Computing, Lim’s team has computationally identified the main steps of the catalytic cycle. They discovered that the rate limiting step is where the alkyne binds to the catalyst–aro- matic substrate complex.
ISSUE 5 | OCTOBER – DECEMBER 2016
© 2016 A*STAR Institute of Chemical and Engineering Sciences, A*STAR Institute of High Performance Computing, and A*STAR Singapore Bioimaging Consortium
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