Discovery And Optimaztion Of Novel Non-sulfonamide NAE Inhibitors And Nicotinic Acid BoNT Inhibitors

Recent years the incidence of cancer and the number of patients is increasing.Most of the available antitumor drugs generally existthe lower efficacy, toxic or side effects, drug resistance and other issues.So we need to discover and develop new antitumor drugs.In the thesis novel small molecule NAE inhibitors were designed by virtual screening and the targeted compounds were assasyed for antitumor activities.Botulinium toxin can be divided into A, B, C, D, E, F and G types. Among them type A is the most toxic and type B has been found in human food. Injecting of tetanus vaccine is the mainly method of treating tetanus at present, however, allergic reactions is popular in vaccine treatment. Based on these reasons, it is valuable to develop new small molecule drugs1 Discovery, optimization and antitumor activities of novel NAE inhibitorsNeddylation is important to maintain the balance of intracellular proteins, regulate the cell cycle and the survival of cells. The ubiquitin activating enzyme(E1, NAE), ubiquitin conjugating enzyme(E2)and ubiquitin ligase(E3) are key enzymes in the pathway. Theubiquitin and ubiquitin-like protein(Nedd8) was marked to target proteins, which led to the degradation and modification of proteins. As one of themain components of the ubiquitin ligases, Cullin-RING ligases(CRLs) play a key role inubiquitination pathway and regulate proteindegradation. The excessive expression of NEDD8 pathway in many cancer cells led to the CRLs dysfunction.NAE inhibitors can inhibit the pathway through the upstream of the Neddylation pathway. Then the protein degradation was disrupted and led to protein accumulation. In addition, the cell cycle dependent DNA replication was arrested and induced apoptosis.It is reported that MLN4924 is the first selective NAE inhibitor, which has entered the phase of clinical I phase. According to a proposed screening strategy, a novel skeleton with nonsulfonamide was discovered as NAE inhibitors. Thirty-nine compounds were synthesized and the structures of targeted compounds were confirmatory by NMR and MS analysis.Firstly, ten sulfonamides and eight non-sulfonamides had been synthesized and assayed by MTT. The result in vitro showed that sulfonamide is not the essential to antitumor activities. Based on this finding, new twenty-one compounds without sulfonamide had been designed and prepared. The followed antitumor activity assay in vitro indicated that 22 gwas the best compound of those new compounds with the IC50 value of 100 n M against HCT116.2 Optimization and activities of nicotinic acid derivativesIn our previous work, nicotinic acid derivatives indicated potent activities both in vitro and in vivo. Furthermore, a few compounds showed a broad spectrum against botulinum toxins and tetanus. However, these compounds were unstable in animals. Compounds with ether, sulfoxide and sulfone were designed by a bioisostere strategy. Among these five compounds, compound 2bindicated potent activities against botulinum toxin type A with the survival rate of 100% in vivo.