Simplified medicine of complex natural products: the crystallization of nature and human wisdom April 10, 2019 Source: CPhI Pharmaceutical Online Drug development based on natural products has always been a top priority for drug development. Statistics show that more than half of the new clinical drugs approved by the FDA over the years come from natural products or their derivatives. From the natural product drugs, it also breeds many drug development fields such as natural product extraction and separation, total synthesis, structural modification, activity evaluation, and clinical research. If the natural products themselves are regarded as the ingenuity of nature, then the final products of these natural products combine the wisdom of human intelligence, which is the crystallization of nature and human wisdom. Figure 1 Natural product development strategy As shown in Figure 1, according to the drug development strategy, the drug development of natural products can be divided into two main lines: First, the isolated active natural product directly becomes a lead drug molecule, and then enters the clinic through optimized evaluation; One is the structure-activity relationship evaluation, modification, simplification, or the construction of chemical molecules inspired by natural products, and the lead drug molecules are obtained through biological activity evaluation, and then enter the clinic through optimization evaluation. Figure 2: Natural product simplification strategy Of course, in the development of natural product drugs, due to its own problems, it limits its drug development. These problems include: 1. Low natural content, difficult to protect market demand; 2. Complex structure, full synthesis, semi-synthesis is very difficult ; 3. Although it has therapeutic activity, it has great toxic and side effects, which limits its use; 4. Transmembrane infiltration, in vivo efficacy, poor pharmacokinetic data, etc. These problems are also the bottleneck of many natural product drug development. Thus, structural simplification based on structure-activity relationship analysis is particularly important in the development of natural product drugs. The simplified structure is often easily obtained by techniques such as total synthesis and semi-synthesis, which ensures the demand of the subsequent market. As shown in Figure 2, the simplification of the natural product can be divided into two types according to the know and the unknow of the target of the natural product: one is that in the case where the target of the natural product is known, it is often According to the characteristics of the target, the structure of the natural product is adjusted, the part of the natural product and the target is retained, and the unnecessary fragment structure is removed; secondly, in the case where the target of the natural product is unknown, it is often required to pass through the system. Analysis of structure-activity relationship, and then retain and eliminate the fragment structure. In this way, under the premise of ensuring the activity of the drug molecule and reducing the side effects of the drug, the structure of the drug molecule is simplified, and it is easy to obtain a large amount by synthesis or the like. Figure 3. Morphine morphing process simplification process Among the simplified products based on natural products, morphine derivatives are a typical example of the development of analgesic drugs. As shown in Figure 3, morphine itself is a complex five fused ring structural molecule and is a μ-opioid receptor agonist (Ki = 1.8 nM). In the simplified study, the researchers obtained the new drug molecule levorphanol and Butorphanol by removing the E-ring. The new drug molecules phenazocine, pentazocine and fluopentazocine were obtained by removing the C-ring and E-ring. The new B-ring, C-ring and E-ring were obtained. The drug molecules pethidine, α-prodine and fentanyl; Methadone was obtained by removing the B ring, the C ring, the D ring and the E ring. It can be seen from the above that the structurally complex morphine finally obtains the drug molecule Methadone which retains only one ring (A ring), which is the well-known analgesic drug methadone. The drug molecule has a longer action time than morphine. It is not easy to produce tolerance, low drug dependence, not only to ensure the analgesic effect, but also greatly reduce the role of the original drug addiction. Thus, the role of complex natural products in simplifying the development of drugs in drug development can be seen. Of course, there are many examples of medicinal drugs like morphine through simplified strategies, and as our understanding of the simplification of complex natural products continues to deepen, there will be more and more success stories in the future, let us wait and see. references: Structural Simplification of Natural Products, Chem. Rev., 2019. Laboratory Diagnostic,Reagent Strips For Urinalysis,Assay Kits,LETIA Assay Kit,Urinalysis Assay Kits Jilin Sinoscience Technology Co. LTD , https://www.contoryinstruments.com
