Natural products as IL-6 inhibitors for inflammatory diseases: Synthetic and SAR perspective

Abstract

Interleukin-6 (IL-6), a pleiotropic cytokine, plays a pivotal role in the pathophysiology of various diseases including diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. The signaling pathways associated with IL-6 offer promising targets for therapeutic interventions in inflammatory diseases and IL-6-dependent tumors. Although certain anti-IL-6 monoclonal antibodies are currently employed clinically, their usage is hampered by drawbacks such as high cost and potential immunogenicity, limiting their application. Thus, the imperative arises to develop novel small non-peptide molecules acting as IL-6 inhibitors. Various natural products derived from diverse sources have been investigated for their potential to inhibit IL-6 activity. Nevertheless, these natural products remain inadequately explored in terms of their structure-activity relationships. In response, our review aims to provide syntheses and structure activity perspective of natural IL-6 inhibitors. The comprehensive amalgamation of information presented in this review holds the potential to serve as a foundation for forthcoming research endeavors by medicinal chemists, facilitating the design of innovative IL-6 inhibitors to address the complexities of inflammatory diseases. Interleukin-6 (IL-6), a pleiotropic cytokine, plays a pivotal role in various diseases such as diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. This has spurred the development of several clinical valuable drugs, while the IL-6 signaling pathway continues to attract attention in the field of drug discovery and development. Madindolines (A and B), exemplar natural inhibitors of IL-6, have demonstrated sub-micromolar IC50 values in IL-6-dependent MH60 cell lines. This review encompasses the total and formal synthesis of madindolines (A and B), explores structure-activity relationships, and delves into the biological implications of these compounds. Furthermore, the IL-6 inhibitory potential of natural products exhibiting diverse chemotypes is thoroughly examined. The insights presented herein intend to ignite novel approaches for pioneering IL-6 inhibitors by synergizing acquired knowledge and computational methodologies and serve as a driving force for expanded explorations into novel IL-6 inhibitors, propelling a wave of future investigations.