Dissertation
Dissertation > Medicine, health > Pharmacy > Drug basic science > Medicinal Chemistry

Structure-based Drug Design and Two Kinds of Small Organic Molecules Catalyzed Ractions

Author DengZuo
Tutor JiangHuaLiang;LiJian
School East China University of Science and Technology
Course Medicinal Chemistry
Keywords Structure-based drug design RhoA protease DENV NS2B-NS3 protease Small molecular inhibitor Small organo-molecular catalysis Synthetic methodology Friedel-Crafts reaction Michal adducts
CLC R914
Type PhD thesis
Year 2012
Downloads 46
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There are two parts in my dissertation for Ph. D. degree. Part 1 presents structure-based drug design. This part focuses on the design, synthesis and biological evaluation of novel active compounds against two important drug targets, RhoA and DENV NS2B-NS3.RhoA, a subgroup of the Ras superfamily, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. However, to date, RhoA inhibitors are macro molecules, and to our knowledge, small molecular-based inhibitors have not been reported. Therefore, we discuss the design, synthesis and discovery of first-in-class small molecular RhoA inhibitors.By using a docking-based virtual screening approach in conjunction with surface plasmon resonance (SPR) determination, three novel small molecule RhoA binders (compounds 8-10) have been discovered. According to the binding potency and synthetic complexity, compound 8 was selected as the starting point for further structural optimization. Chemical modifications were performed in three cycles. Totally,41 new compounds (8, A1~22, B1~8 and C1~10) were designed and synthesized accordingly. It was found that eight compounds showed high RhoA inhibition activities. A pharmacological assay indicated that two compounds showed significant inhibitory effects against phenylephrine (PE)-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents. To our knowledge, the two compounds are the first-in-class small molecular RhoA inhibitors.Dengue viruses (DENV), belonging to the Flaviviridae family, affect millions of people worldwide. Because drugs or vaccines against DENV are currently unavailable, effective therapeutic agent is urgently required. The dengue viral two-component nonstructural NS2B-NS3 protease is essential for viral life cycle and, consequently, is a promising drug target. However, only a few peptide or small molecule inhibitors of the DENV NS2B-NS3 protease with moderate activity have so far been reported. Therefore, we regard the design, synthesis and discovery of small molecule DENV NS2B-NS3 inhibitors.Firstly, a docking-based virtual screening approach in conjunction with protease inhibition activity assay resulted in the discovery of three inhibitors (compounds 26-28) with different scaffolds. Compound 26 was selected for further structure modifications in considering inhibitory activity, structural variability and synthetic accessibility. From virtual screening to scaffold hopping, thirty-six new compounds (26, D1~14, E1~13, F1~8) were designed and synthesized accordingly. It was found that seventeen compounds showed good NS2B-NS3 protease inhibition activities with IC50 values at micromole level. DENV-2 luciferase reporter replicon-based assays indicated that four compounds demonstrated a promising selectivity index (SI) and activity against DENV. Notably, we found the most effective small molecular dengue viral NS2B-NS3 Protease inhibitors, which may be a good lead for discovering new therapeutic agents for dengue viruses. Moreover, the second cycle modification after scaffold hopping remarkably improved the inhibitory activity of derivatives, demonstrating that the chemical modification strategy employed in this study is efficient and valuable for discovering new DENV NS2B-NS3 protease inhibitors.Part 2 concerns the development of synthetic research catalyzed by small organic molecules. We use efficient way to construct remarkable significant chemical or medical intermediates and highly synthetic useful building blocks in organic synthesis.We have developed the first direct enantioselective Friedel-Crafts reaction of indoles with isatins. The process is catalyzed by simple cupreine under mild reaction conditions and affords synthetically and biologically interesting, chiral 3-indolyl-3-hydroxy-2-oxindoles in good to excellent yields (68-97%) and with high to excellent enantioselectivities (76-91%).We have also developed a highly enantioselective organocatalytic protocol for conjugate addition of new nucleophilic carbonylmethyl 2-pyridinylsulfone to enals in good to excellent yields (51-95%) and with high to excellent enantioselectivities (89-100%). The resulting Michal adducts are versatile building blocks for a varity of organic transformations.In summary, employing structure-based virtual screening approach in conjunction with chemical synthesis and bioassay, we have designed and synthesized 77 compounds (8,26, Al-22, B1~8, C1~10, D1~14, E1~3 and F1~8) targeting two important target proteins. Two kinds of small organic molecules catalyzed reactions were probed, constructing remarkable significant chemical or medical intermediates. These rearch provided some new templates to discover new chemical entities for drug development.

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