News

CeMM Adjunct PI Nuno Maulide’s group at the University of Vienna has developed an efficient reaction sequence to increase the oxidation state in oleanolic acid in the lab. In collaboration with the Georg Winter group at CeMM, the researchers also evaluated the antileukemic activity of the prepared compounds, revealing pronounced antiproliferative activity of a synthetic intermediate. The study, published in the renowned journal Chem, illustrates the value of interdisciplinary collaboration in basic research, when synthetic organic chemistry and cancer biology are harnessed to deliver a synergistic outcome.

Terpenes are a large class of natural products made mostly of carbon atoms and show a broad spectrum of biological activity. They can be divided in numerous subclasses, simply based on the shape of their carbon atom skeleton. However, the biological or physicochemical properties of these molecules are strongly influenced by the decoration of each carbon atom. In nature, enzymes play an essential role in the diversification of these carbon skeletons: they achieve so-called oxidations, which add “OH” (hydroxyl) groups to the carbon skeleton of terpenes and thus improve solubility and bioavailability. 

An example for the different biological availability due to the degree of oxidation are so-called oleanane terpenoids. The parent compound, oleanolic acid, is very abundant. Kilos can be extracted from various plants, such as olive trees. Oleanolic acid has a panoply of interesting biological effects in vitro. However, due to its low oxidation state – its skeleton has only one OH group – it is not readily bioavailable and poorly soluble, limiting further pharmacology. 

In contrast, other compounds isolated from similar sources such as uncargenin C or protobassic acid have a much higher oxidation state. They are significantly more soluble and thus have high potential as drugs. However, only very small amounts can be gained from nature. 

The number of OH groups determines the water solubility of a molecule: the more OH groups, the more soluble a molecule will be. Like oil itself, oleanolic acid is very greasy and does not dissolve well in biological systems. Therefore, further applications of the cheap and abundant compound in pharmacology are very difficult.

This limitation makes the laboratory synthesis of such molecules highly important. Besides enabling access to the natural products, chemical synthesis also allows to generate non-naturally occurring analogues, with great potential value and sometimes even exceeding the biological activity of the natural products themselves. Nuno Maulide’s approach was a synthesis based on natural processes: “Research development around natural products is, forgive the pun, only natural: why would we not look at what chemical tools Mother Nature has developed and try to modify them in order to help society, be it with a new drug, a new material or a new cosmetic.”

The Maulide Group has now developed an efficient reaction sequence to increase the oxidation state in oleanolic acid, in the lab. With the aid of a technique called “C−H oxidation”, the group invented a relay strategy where each newly added OH group was responsible for guiding the addition of the next one. Nuno Maulide: “It is just like in 4 × 100 m relay races that we watch during the Olympic Games: each racer does its job and then hands over the baton to the next one!”

In collaboration with the Winter Group, they also evaluated the antileukemic activity of the prepared compounds, revealing pronounced antiproliferative activity of a synthetic intermediate. The researchers are excited about possible new opportunities: “The ability of synthesis to make molecules of nature by different routes means that, in the course of synthesis, new compounds will be prepared that do not exist in nature and which never before have been made. Each and every one of these compounds presents an opportunity for discovery in biology, because they have never been tested before”.

The study “Application of Relay C−H Oxidation Logic to Polyhydroxylated Oleanane Triterpenoids” was published in Chem on 5 May 2020. DOI: 10.1016/j.chempr.2020.04.007

Authors: Martin Berger, Christian Knittl-Frank, Sophie Bauer, Georg Winter, and Nuno Maulide

Funding: Generous support by the University of Vienna is acknowledged. M. B. and C. K.-F. are fellows of the FWF-funded doctoral program MolTag (W1232). CeMM and the Winter Lab are supported by the Austrian Academy of Sciences.