Misale, Antonio; (2012) Synthesis of Angucycline-based Small Molecules as Potential STAT3:STAT3 Protein-Protein Interaction Inhibitors for Cancer Therapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Inhibition of the STAT3:STAT3 protein-protein interaction is an attractive approach for cancer therapy as it can lead to suppression of tumour cell growth and induce apoptosis. The racemic ochromycinone (STA21) is one of the few known small-molecule STAT3:STAT3 inhibitors. Our synthetic efforts focused on synthesis of the natural product YM-181741, which possesses at least three points for chemical variation to prepare compound libraries as potential STAT3:STAT3 inhibitors. Synthesis of the angucycline molecule was achieved employing an approach based on a Gold (III)-catalysed intramolecular [4+2] benzannulation reaction. A facile and highly efficient route for the preparation of racemic form of the natural product was developed that offers a high degree of flexibility for modification of the scaffold at different stages of its synthesis. The enantioselective synthesis of (S)-YM181741 was successfully carried out through the (R)-diyne building block via an enantioselective copper-catalysed 1,4-conjugate addition reaction on a system bearing a γ-coordinating group, in order to install the chirality on the diyne moiety. The optimised reaction conditions afforded the Michael adduct in good yield and high enantiomeric excess (up to 96% ee). Further chemical elaboration of the (±)-YM-181741 natural product was investigated in order to explore the necessary chemical diversity to assess a preliminary model of interaction between the SH2 domain of STAT3 and the angucycline scaffold. The biological evaluation of the focused library allowed the identification of angucycline derivatives possessing high binding affinity for the SH2 region and the ability to inhibit STAT3 transcriptional activity.

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