Pharmacophore - Directed Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies

Baylor University, Waco TX

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Abstract

Project Summary/Abstract Our proposed studies of the chemistry and biology of natural products (NPs) that possess anticancer, immunosuppressive, anti-ischemic, and antibacterial effects are guided by the following inquiry: Can natural product total synthesis be more closely aligned with simultaneous biological studies by targeting designed, simplified derivatives, that each possess a proposed pharmacophore, during the retrosynthetic planning stages? This tactic, which begins with a hypothesis for a natural product’s ‘pharmacophore,’ enables collection of structure-activity relationship (SAR) data throughout a total synthesis effort enabling early discovery of simplified bioactive derivatives. Building on Wender’s call for function-oriented synthesis, this variation of retrosynthetic analysis, seeks to more closely align total synthesis efforts with concurrent biological studies and opens the potential to identify simplified versions of the natural product with similar potency or even new functions in the course of a total synthesis effort. We call this strategy ‘pharmacophore-directed retrosynthesis’ (PDR) to emphasize the importance of incorporating hypothesized pharmacophores into the retrosynthetic planning stages of a total synthesis effort. This approach has the potential to greatly accelerate harvesting the rich information content of NPs which historically has had immense impact on basic cell biology and medicine. Our strategy begins with a hypothesized pharmacophore, based on available SAR data, and this directs the retrosynthetic analysis. Stepwise, methodical introduction of structural complexity to this pharmacophore en route to the natural product enables concurrent collection of SAR data which informs probe synthesis useful for cellular target identification by our diverse group of ongoing collaborators employing biochemical, proteomic, and genetic approaches. We anticipate that our proposed research will continue to contribute to basic cell biology while also identifying new chemotypes for next generation small molecule therapeutics. Several NPs to be studied are proposed to engage protein targets covalently, thus this research will contribute to the re-emerging topic of covalent drugs. In the last grant period, a total synthesis of rameswaralide revealed the anticancer effects of a simple bicyclic b-ketoester. In addition, a synthetic intermediate, that was found to exhibit greater activity than the natural product, is showing potential as a new inhibitor chemotype for a poorly understood kinase. Several additional simplified derivatives of NPs, bearing a proposed pharmacophore, were synthesized and exhibited bioactivity. In the next grant period, we will fully develop a variant of PDR that targets alkynes as both synthetic intermediates and proteomic probes that may be more generally applicable. Inspired in some cases by our PDR approach, we are developing novel synthetic strategies including late-stage functionalizations of macrocycles reminiscent of biosynthetic tailoring enzymes, intramolecular directed CH oxidations and Diels- Alder reactions, tandem [2+2]/Grob-fragmentation reactions, and novel couplings with diborylated alkenes.