Natural Product Synthesis in the 21st Century: Beyond the Mountain Top

Abstract

Research into natural products emerged from humanity's curiosity about the nature of matter and its role in the materia medica of diverse civilizations. Plants and fungi, in particular, supplied materials that altered behavior, perception, and well-being profoundly. Many active principles remain well-known today: strychnine, morphine, psilocybin, ephedrine. The potential to circumvent the constraints of natural supply and explore the properties of these materials led to the field of natural product synthesis. This research delivered new molecules with new properties, but also led to fundamental insights into the chemistry of the nonmetal elements H, C, N, O, P, S, Se, and their combinations, i.e., organic chemistry. It also led to a potent culture focused on bigger molecules and races to the finish line, perhaps at the expense of actionable next steps. About 20 years ago, the field began to contract in the United States. Research that focused solely on chemical reaction development, especially catalysis, filled the void. After all, new reactions and mechanistic insight could be immediately implemented by the chemistry community, so it became hard to justify the lengthy procurement of a complex molecule that sat in the freezer unused. This shift coincided with a divestment of natural product portfolios by pharmaceutical companies and an emphasis in academic organic chemistry on applications-driven research, perhaps at the expense of more fundamental science. However, as bioassays and the tools of chemical biology become widespread, synthesis finds a new and powerful ally that allows us to better deliver on the premise of the field. And the hard-won insights of complex synthesis can be better encoded digitally, mined by data science, and applied to new challenges, as chemists perturb and even surpass the properties of complex natural products. The 21st century promises powerful developments, both in fundamental organic chemistry and at the interface of synthesis and biology, if the community of scientists fosters its growth. This essay tries to contextualize natural product synthesis for a broad audience, looks ahead to its transformation in the coming years, and expects the future to be bright.

Occurrence of ‘Natural Selection’ in Successful Small Molecule Drug Discovery

“…We concur with the sentiment that "the local chemical space of a natural product can prove superior to the natural product itself." 57 Adding NP fragment-based parameterisation to enhance machine learning models and influence generative chemistry is recommended.…”

Occurrence of “Natural Selection” in Successful Small Molecule Drug Discovery

“…Sir James Black, discoverer of propranolol and cimetidine, famously stated that “the most fruitful basis for the discovery of a new drug is to start with an old drug.” 56 In the genomic era, the Black principle holds ever true, as medicinal chemists, knowingly or unknowingly, are repeatedly using a small group of established NP fragments to discover clinical candidates. We concur with the sentiment that “the local chemical space of a natural product can prove superior to the natural product itself.” 57 Adding NP fragment-based parametrization to enhance machine learning models and influence generative chemistry is recommended.…”

Natural Product-Inspired Dopamine Receptor Ligands

“…The significance of natural products in pharmaceuticals cannot be overstated as over 30% of all FDA-approved new molecular entities (NMEs) are derived directly or inspired from microbial and plant species . Optimized by natural selection pressures, natural products are refined to have optimal interactions with biological macromolecules, membrane permeability, biomolecular compatibility, and stability, thus sharing key properties of drug likeness. , A recent analysis revealed that over 80% of CNS agents are derived directly or inspired from natural products, and the scaffolds of just 20 natural products yielded more than 400 clinically approved CNS drugs …”