Unlocking the Antitubercular Mode of Action of Asperterpenoid through Total Synthesis

The rise of multi-drug resistant strains of Mycobacterium tuberculosis, the pathogen responsible for the infectious disease tuberculosis, calls for research into novel antitubercular scaffolds and targets.

Asperterpenoid is a rare sesterterpenoid with a unique and highly complex 5/7(3)/6/5 ring-fused carbon skeleton that strongly inhibits tyrosine phosphatase B, a virulence factor protein secreted by M. tuberculosis that aids human host infection. To date, total synthesis of asperterpenoid has not been accomplished.

We propose a modular synthesis of asperterpenoid from biorenewable sitolactone using a key intermolecular reductive titanium mediated Giese addition reaction.

The scope of this privileged reaction will be expanded by investigating selected epoxide substrates and Michael acceptors.

We anticipate that the synthetic strategy to asperterpenoid can be extrapolated to prepare variecolin, a structurally related sesterterpenoid that has been subject of several studies but never reached by chemical synthesis.

Based on its structural similarity to asperterpenoid, we expect that variecolin will also exhibit antitubercular activity.

We plan to study the known antitubercular activity of asperterpenoid by structural diversification and its mechanism of action by a chemical biology tools such as molecular imaging. We also plan to test variecolin for antitubercular activity.

The action is expected to contribute to new synthetic tools and strategies to prepare rare sesterterpenoid natural products, a better understanding of the promising antitubercular properties of asperterpenoid, and to demonstrate that variecolin exhibits similar bioactive behaviour.