Synthesis of Drug Discovery Molecules

Solid-phase organic synthesis offers several advantages over conventional solution phase chemistry, primarily easier purification and experimental simplicity. In the project, solid-phase synthesis of a range of biologically interesting molecules was performed. Several of these are relevant to drug discovery, one example being Trioxacarin DC-45-A2, a naturally occurring anti-tumor antibiotic.

Half a century ago chemist Robert Bruce Merrifield revolutionized peptide synthesis by introducing solid-phase organic synthesis. He was later awarded the Nobel Prize. Merrifield’s method relies upon a linker, which anchors the substrate to the solid support. Through iterative circles of amino acid coupling and de-protection the desired peptide is built and ultimately released from the solid support by cleavage of the linker. The method has greatly expanded the number of chemical transformations which can be applied for the routine synthesis of organic molecules on solid support. This has triggered the generation of combinatorial libraries both in academia and industry, ultimately leading to the identification of new drugs and catalysts.

Firstly, derivatives of the well-known drug doxorubicin, used in treatment of a wide range of cancers including leukemia, were synthesized. The doxorubicin derivatives were synthesized on photo-labile solid support, compatible with bead-based screening. Two different strategies were developed leading to the synthesis of doxorubicin derivatives with both amino acids and peptide fragments attached in good to excellent crude purities.

Secondly, total synthesis of Trioxacarcin DC-45-A2 was performed during an external stay with the Nicolaou group at the Rice University, USA. Trioxacarcin DC-45-A2 is a naturally occurring anti-tumor antibiotic and a biosynthetic precursor to a variety of other biologically active molecules. A new synthetic route was developed. The new route featured distinct and high yielding steps and thus provided superior access to one of the key building blocks in terms of overall yield, step count and scalability. Furthermore, a route to another major building block was developed featuring a Stille cross-coupling as the key step.

Thirdly, synthesis of poly-fused heterocycles was investigated. Poly-fused heterocycles are a class of compounds relevant to drug discovery – specifically the search for new biologically active compounds. The efforts led to the development and optimization of a key aldol condensation/conjugate addition sequence for the synthesis of poly-fused heterocycles.

Finally, the project involved a literature survey on solid-phase organic synthesis and photolabile linkers.


Illustration:
Bead-based platform integrating solid-phase synthesis and cell-based screening.