Anticipating, deciphering, imicking molecular complexity of natural substances – ANTIDEPRIM

The consortium is an international leader in the development and use of the most modern tools for so-called «dereplicative« analysis. Particular emphasis is placed on the «anticipation« aspect. The extension of the concepts to synthetic chemistry also allows important advances in the field

The cornerstone of anticipation in our project is the design of the continuously updated MetWork in silico metabolization tool. The first results of the application of the «three-layer« strategy have yielded important results. The spirit of the project can be found in two publications on the biosynthesis and synthesis of camellimidazoles and nesteretal A.

The strategy continues with the aim of exploring chemodiversity in an original way. Molecules of marine origin and of complex to very complex structures are currently being studied in the consortium as well as the constant improvement of anticipation tools.

“Bio-inspired metabolomes” illuminates diacetyl assembly pathways toward nesteretal A-like cage molecule. A. Leblond, I. Houari, Y. Beauxis, K. Leblanc, E. Poupon, M. Beniddir, Org. Lett. 2022, in press [10.1021/acs.orglett.2c00108].
In silico anticipation of metabolic pathways extended to organic chemistry reactions: a case study with caffein alkaline hydrolysis and the origin of camellimidazoles. V. Turpin, M. A. Beniddir, G. Genta-Jouve, A. Skiredj, J.-F. Gallard, K. Leblanc, P. Le Pogam, E. Poupon, Chem. Eur. J. 2020, 26, 12936–12940 [10.1002/chem.202002196]

Natural products (NPs) sometimes display an incredible molecular complexity which origin remains unclear. Biochemical pathways enabling, from simple precursors originating from primary metabolism, such level of levels of complexity are also often unknown. Their understanding constitutes a major challenge and implications beyond biochemistry are numerous e.g. in organic synthesis. We will confront: i- the elucidation of molecular complexity in nature (biosynthesis), ii- the anticipation of molecular complexity with bio-informatics relying on artificial intelligence (retrobiosynthesis), iii- reality of chemical reactivity in the lab. A virtuous cycle will consequently be unleashed for the discovery of new cascade reactions leading to complex molecular architectures (e.g. for total synthesis) and also new NPs. The project will clearly anchor molecular chemistry and NPs chemistry in the era of big data and machine learning.
In more details, the project will hinge on the chemistry of complex alkaloids of marine origin. A classical reaction of organic synthesis – the Chichibabin pyridine synthesis – will be selected as a model as it is postulated to occur in the course of the biosynthesis of complex alkaloids such as the haouamines and araiosamines. Four workpackages will be studied to harness the global philosophy of the project.