Small molecule drug development based on derivatization of natural products

Abstract

Natural products in a general term refer to endogenous chemical substances or secondary metabolites produced by living organisms such as animals, plants or microorganisms. Historically, natural products have been indispensable resources as medication throughout human civilization worldwide. Crude or semi-purified extracts of these living organisms, especially terrestrial plants, have been described in a variety of ancient Chinese books and utilized to treat various human diseases. With the establishment of modern scientific system, research on individual active principles or secondary metabolites from these living organisms was expanded, initially focusing on the chemistry and pharmacological effects. The isolation, purification, pharmacological validation, and market of a naturally occurring natural product morphine as a painkiller directly led to the foundation of a modern pharmaceutical company Merck in 1893. Since then a number of natural products, such as quinine and penicillin, have been introduced as important medicines for the wellbeing of mankind. Novel natural products have been the gold mine as drug leads in the field of small molecule drug discovery and development to all pharmaceutical companies for over a century. With the great advancement in synthetic organic chemistry and medicinal chemistry large volume of structurally diversified small molecules can now be rapidly produced and screened in a high throughput manner, the role of natural products in modern drug discovery and development have been largely diminished. Very often intrinsic side effects with natural products such as toxicity, limited availability, and unfavorable potency and selectivity render it more and more difficult to utilize them directly as drug candidates. Practically, synthetic transformation or total synthesis of natural products is required due to above-mentioned suboptimal physicochemical and pharmacological properties or limited availability. 2015 Nobel Prize in Physiology or Medicine was awarded to the discoveries of two natural products based novel therapies: i.e. avermectin-based therapy against infections caused by roundworm parasites and artemisinin (Qinghaosu)-based therapy against Malaria. These two natural products technically possessed certain unfavorable properties and the clinically utilized medicines were indeed their synthetic derivatives. This review is intended to illustrate the importance and significance of structural determination and synthetic transformations on natural products in modern drug discovery and development.