The structural modification of natural products for novel drug discovery

ABSTRACT

Introduction: Throughout history, natural products (NPs) have provided a rich source of compounds that have wide applications in the fields of medicine, health sciences, pharmacy and biology. Although naturally active substances are good lead compounds for the discovery of new drugs, most of them suffer from various deficiencies or shortcomings, such as complex structures, poor stability and solubility. Therefore, structural modification of NPs is needed to develop novel compounds with specific properties.

Areas covered: This article presents an overview on the structural modifications of NPs in drug development. The application of multiple classes of NPs to the treatment of conditions such as cancers, infection, Alzheimer’s and diabetes are discussed. This article also reveals that modification of NPs is a versatile approach to explore their mode of actions, which may lead to the discovery of novel drugs.

Expert opinion: NPs are usually described by structural diversity and complexity. The use of isolated NPs as scaffolds for modification is a good approach to drug discovery and development. Despite many limitations associated with NPs, the total synthesis, semisynthetic modification, SAR-based modification, sometimes even a single atom alteration, may lead to the discovery of a novel drug.

KEYWORDS:

• Natural products
• structural modification
• drug design
• drug development

Article highlights

• NPs are vital sources of drug discovery; however, their various deficiencies or shortcomings limit their wide applications in drug development, and thus, structural modification of NPs is in urgent need to develop novel entities with specific properties.

• Major changes may be needed for the structural modification of NPs, but most often they only need fine tuning, as sometimes even a single alteration can make a great difference.

• NPs embody inherent structural complexity and biological activity, and modification of NPs is a versatile approach to explore their mode of actions.

• Making logical and systematic changes to NPs is an effective way to increase their potency and activity spectrum and therefore counter resistance mechanisms.

• Biologically active NPs often have privileged scaffolds and diverse biological activities; sometimes, with proper modifications, they could be used for new treatments.

• Complex NPs often suffer from high molecular weights and poor oral bioavailability. Structural modification may provide structurally simpler compounds that retain bioactivities.

• Structural modifications that reduce compound binding affinity or reactivity at the labile site may increase metabolic stability.

• Low aqueous solubility is a common problem in developing NPs into drugs, but chemical modification is a powerful strategy that could be applied to enhance the water solubility of NPs.

• Because of their unique chemical properties and potential interactions with disease-associated proteins, natural products will remain a reliable source of lead compounds in drug discovery.

This box summarizes key points contained in the article.

Acknowledgements

This manuscript was language edited by Taylor & Francis Editing Services.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This study was financially supported by grants from the National Natural Science Foundation of China (No. 81373280; 81302635; 81273377; 81673306) and the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZCX201404), and China Postdoctoral Science Foundation (no. 2015M581903).