Hydroxamic acids are an important class of organic compounds owing to their presence in numerous biologically active molecules. Several hydroxamic acids are regarded as potential drugs, mainly for treatment of cancer but also a number of other diseases. The project suggests chemical strategies for high-throughput generation of structurally diverse hydroxamic acids.
A hydroxamic acid bears the functional group RC(O)N(OH)R’, with R and R’ as organic residues and CO as a carbonyl group. Some hydroxamic acids (e.g. vorinostat, belinostat, and trichostatin A) are histone deacetylase inhibitors (HDIs) meaning they inhibit the enzyme histone deacetylase (HDAC). HDIs have long been used in psychiatry as mood stabilizers. More recently, several HDIs have entered clinical trials for treatment of various types of cancer. Furthermore, individual HDAC enzymes have been linked to a variety of other diseases, including chronic pain and cystic fibrosis. The project presents mild and reliable chemical strategies for synthesis of a range of structurally diverse hydroxamic acids.
In order to synthesize molecules with various functional groups, the ability to block and unblock reactivity in a controlled way is essential. Therefore, the use of so-called protecting groups is a vital tool in organic chemistry. However, some disadvantages are inevitable when using protecting groups. Firstly, two steps are added to the total step count, protection and deprotection. Secondly, the protecting groups limit the types of chemistry that can be performed as too harsh treatment, such as acidic- and basiclabile or metal-catalyzed hydrogenation, may damage the target molecule.
In contrast, removing protecting groups by UV-light is a mild method. Thus, photocleavable protecting groups are highly applicable for the synthesis of structural complex and sensitive compounds, including biologically important molecules. The project presents the development of a novel O-hydroxylamine photo-cleavable protecting group, based on the methyl-6-nitroveratryl moiety. Application of the protected hydroxylamine derivative for the synthesis of a broad range of N-alkylated hydroxamic acids was demonstrated.
Importantly, the construct is shown stable towards a diverse set of reaction conditions, as well as orthogonal with conventional protecting groups. The O-protected hydroxylamine derivative was applied to synthesize a small collection of N-alkylated suberanilohydroxamic acid as subtype selective HDAC inhibitors.
During an external stay at Nanyang Technological University, Singapore, compounds targeting the quorum sensing network in Pseudomonas aeruginosa, important for the treatment of bacterial infections, was also synthesized.
llustration:
Synthesis of O-hydroxylamine protecting group