Synthesis of novel C-9 carbon substituted derivatives of artemisinin

Meyer, Daniel; Smeilus, Toni; Pliatsika, Dimanthi; Mousavizadeh, Farnoush; Giannis, Athanassios

doi:10.1016/j.bmc.2017.03.021

Cited by 4 publications

(2 citation statements)

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“…In other work, P450 BM3 , a widely used self-sufficient fatty acid CYP from Bacillus megaterium, was elegantly employed by Fasan and co-workers in the late-stage hydroxylation of the antimalarial drug artemisinin . Transformations at the chemically easily accessible positions such as C9 and C10 had been performed earlier using synthetic reagents and catalysts . In contrast, it was known that P450-mediated metabolism occurs, inter alia, at the chemically difficult to access C6 and C7 positions .…”

Section: Introductionmentioning

confidence: 99%

“…Transformations at the chemically easily accessible positions such as C9 and C10 had been performed earlier using synthetic reagents and catalysts . In contrast, it was known that P450-mediated metabolism occurs, inter alia, at the chemically difficult to access C6 and C7 positions . In order to reach this difficult goal by P450 BM3 catalysis, a mutant FL#62 with 16 point mutations was first tested which had been identified earlier in a fingerprint process based on saturation mutagenesis (SM) and color-based screening of 12 500 mutants using bulky surrogate substrates .…”

Section: Introductionmentioning

confidence: 99%

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P450-Catalyzed Regio- and Diastereoselective Steroid Hydroxylation: Efficient Directed Evolution Enabled by Mutability Landscaping

et al. 2018

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Cytochrome P450 monooxygenases play a crucial role in the biosynthesis of many natural products and in the human metabolism of numerous pharmaceuticals. This has inspired synthetic organic and medicinal chemists to exploit them as catalysts in regio-and stereoselective CH-activating oxidation of structurally simple and complex organic compounds such as steroids. However, levels of regio-and stereoselectivity as well as activity are not routinely high enough for real applications. Protein engineering using rational design or directed evolution has helped in many respects, but simultaneous engineering of multiple catalytic traits such as activity, regioselectivity, and stereoselectivity, while overcoming tradeoffs and diminishing returns, remains a challenge. Here we show that the exploitation of information derived from mutability landscapes and molecular dynamics simulations for rationally designing iterative saturation mutagenesis constitutes a viable directed evolution strategy. This combined approach is illustrated by the evolution of P450 BM3 mutants which enable nearly perfect regio-and diastereoselective hydroxylation of five different steroids specifically at the C16-position with unusually high activity, while avoiding activity−selectivity trade-offs as well as keeping the screening effort relatively low. The C16 alcohols are of practical interest as components of biologically active glucocorticoids.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%