Functionalization of artemisinin : new drugs for new purposes

Although artemisinin and its derivatives demonstrate promising screening results against malaria parasite, they still suffer from some drawbacks which render them far from ideal drugs. Cytotoxicity is one of the major problems. Furthermore, artemisinins are potential therapeutic agents against different pathogenic targets (e.g. cancer or tuberculosis). Tailored-made compounds for specific targeted pathogen are urgently needed. In this thesis, different novel derivatives are introduced. The initial idea, design and the screening are included. After the introduction in the first chapter, the second chapter starts to mention the synthesis of different glycosylated compounds which recognize the galectin receptors on cancer cells. The screening results of the N-glycosylated analogues are excellent. However, the compounds are not stable in acidic condition. Therefore, the C-glycosylated analogues were designed to overcome the problem. Two of the compounds were successfully made. The third chapter reveals the possibility of utilizing ‘Click reaction’ in artemisinin. Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry. Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) is the most popular example of click reaction which using cuprous ion to accreleration Huisgen 1,3-dipolar cycloaddition to give a single regioisomer.It was found that CuAAC was completely compatiable to artemisinin without reducing the peroxide bridge. Furthermore, both azide and alkynyl derivatives of artemisinin can be used as the scaffold. The fourth chapter discusses the use of novel co-factor model to design mechanism-based inhibitors of flavin cofactor. According to the model, artemisinin may perturb one of the important redox cycles, so as to exert oxidative stress on the parasite. Therefore, the inhibitors will bind tightly to the flavin cofactor of parasite after the artemisinin nucleus exert its function, causing malfunctioning of active site. These inhititors would be potential drugs for the pathogens which are vulnerable under oxidative condition like malaria parasites and mycobacterium. These derivatives were successfully made, and one candidate demonstrates an extraordinary activity against malaria at nanomolar scale. Chapter five involves the synthesis of artemisone homologues. Artemisone is a 10-amino-subsituted artemisinin derivative prepared by our group. Its Phase II data have already demonstrated that artemisone is curative when used in patients with non-severe malaria. The development of artemisone is continuing and the comparison between artesunate is going to be established for Phase II trials involving patients who do not respond to treatment with artesunate. But, artemisone is hydrolytic reactive under acidic condition and decompose at high temperature. These drawbacks prevent its usage in Africa where is humid and hot. Novel C-linked artemisone homologues were made. Surprisingly, the homologues was showed to have much lower activities compared to its parent compound which suggests the direct connection of C-10 and heteroatom is an important issue in potency. Last but not least, the last chapter reveals the design of new antibiotic as a mimic of platensimycin. Platensimycin is a novel class of antibiotic with unique mode of action by selectively inhibiting the β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) which are an essential component in fatty acid biosynthesis in Gram-positive bacteria. It was reported that the aromatic ring on platensimycin plays an important role in binding with protein on FabF/B so as to exert its effect. With the structural similarity between artemisinin and tetracyclic cage on platensimycin, the adduct of artemisinin and the aromatic ring which mimics the construction of platensimycin might be a useful compounds to target on FabF/B which is essential in bacterial growth. The antibiotic screening exhibited poor activities against different bacteria