Design And Synthesis Of Inhibitors Of Complement And Structure-activity Relationship Studies Synthesis And Revision Of Stereochemistry To Rubescensin S

Part I:Design and synthesis of inhibitors of complement and structure-activity relationship studiesThe complement system plays an important role in protecting the body against the intrusion of cellular and viral pathogens, as well as inflammation. Complement is activated by three pathways:the classical pathway, the alternative pathway and the lectin pathway. Under physiological conditions, complement activation is regulated by a series of membrane-bound and soluble complement inhibitors, involved in protecting the body against excessive complement activation. Accumulating data suggest that inappropriate activation of complement is involved in the pathogenesis of many inflammatory, autoimmune, neurodegenerative and infectious diseases. Moreover, with the development of improved animal models and genome-wide association studies, it has become apparent that some common and often untreatable diseases such as age-related macular degeneration are largely due to mutations in the complement system. The successful use of Soliris, a monoclonal antibody specific for C5, and other complement inhibitors indicates that targeting complement is a promising strategy in many clinical situations.Through high-throughput screening (HTS) in the fetal complement hemolytic assay,1-(3,4-dimethoxyphenyl)-3-(1-S-phenylethyl)urea (B1) was discovered as a hit compound that showed a moderate complement inhibition activity, with a half-maximal inhibitory concentration (IC50) value of166μM for the hemolytic assay. This prompted us to start a chemistry program to further explore this class of compounds. Extensive SAR studies were carried out on both the left-hand dimethoxyphenyl moiety and the right-hand phenylethylamine moiety of the initial HTS lead compound B1. Various analogues were synthesized and identified as complement inhibitors, in the right-hand phenylethylamine moiety that the S-configuration of the chiral center in this position is very critical. In the left-hand side benzene ring with the introduction of a five-or six-carbon chain was greatly improving their activity. Optimized compound B34has an excellent inhibition activity with IC50values as low as13nM. To improve the solubility, we tried to introduce of hydrophilic groups and compound B97was synthesized. Though the activity of compound B97was20-fold decrease, the solubility obtained some improvement. This job built important foundation for further found potential and of water-soluble complement inhibitor.We also demonstrated that the compound B34inhibited C9deposition but had no influence on the preceding C3and C4deposition by the classical, the lectin and the alternative pathway. These compounds could serve as leads for the development of small molecule agents targeting the complement system. Part II:Synthesis and revision of stereochemistry to Rubescensin SNatural products have been a rich source of medicines. The great structural diversity of natural compounds at various levels has always served medicinal chemists as a source of inspiration in their search for new molecular entities with pharmacological activity. Oridonin is an active ent-kaurane diterpenoid compound extracted from the medicinal herb Rabdosia rubescens and display diverse biological activities, including anti-inflammation, antibacterial, antifeeding, antivirus and particularly antitumor activity.But that the activity of oridonin is generally weak and poor drug-like limits its clinical application.We selected oridonin, a naturally rich and readily available ent-kauranoid diterpenoid to construct a natural product-like compound library through feasible chemical space exploration. Reserving the basic structure of oridonin, we do chemical modification in some unit of oridonin molecular and obtain some structures as the basis of a template to construct a natural product-like compound library. We hope to find some novel structure and druglike natural product-like lead compounds through a wide range of biological activity screening.Ozonolysis of oridonin gave diketone D1, compound D1was oxidized to afford the key compound D2. Compound D2provided the possibility for further construction of a natural product-like compound library. More than10compounds has synthesized and built important foundation for the further synthesis of the structural diversity of compound library.Inspired by the similar skeleton between D2and Rubescensin S, we converted D2to Rubescensin S (D17) and its isomer D16through an effective two-step transformation from D2. Using this method we confirmed that the structure of Rubescensin S has a13S configuration although13R is reported in the literature.