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HIV / IN and LEDGF/p75 interaction inhibitor design , synthesis and biological activity of cinnamic aldehyde synthesis and study

Author: LiuJie
Tutor: LiJian
School: East China University of Science and Technology
Course: Medicinal Chemistry
Keywords: Computer-aided drug design HIV-1 intergrase Lens epithelium-derived growth factor (LEDGF/p75) Interface inhibitor Cinnamaldehydes Small organo-molecular catalysis Cascade reaction Synthetic methodology
CLC: R914
Type: Master's thesis
Year: 2011
Downloads: 75
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Abstract


The dissertation contains two chapters.Chapter 1 regards the design, synthesis and biological evaluation of inhibitors targeting the interaction between integrase and cellular LEDGF/p75. In view of prone mutations associated with HIV-1 drug resistance, discovering anti-HIV-1 drugs with new pharmacological mechanisms are the hot topic today. HIV intergrase (HIV/IN) is one of the three key enzymes in HIV-1 life cycle, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration of viral-DNA into host chromosome mediated by HIV/IN. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. Based on active conformation of the lead compound D77 discovered previously by us and pharmacophore model, the SPECS database, consisting of approximately 280,000 compounds, was screened. The four classes of scoffolds (classes A-D) were selected to be synthesized according to the scoring data of virtual screening and structural similarity. Totally, twenty-six target molecules were synthesized, and thirty-five compounds (including nine key intermediates) were evaluated by yeast two-hybrid technology based assay. The results indicated that three compounds (M7-8:IC50= 82.52μM, D3:IC50= 186μM, and D10:IC50= 166μM) could potently inhibit the IN-LEDGF/p75 interaction. The activity of the most potent inhibitor (M7-8) is more than that of the lead compound (D77, IC50> 100μM). On the basis of biological results, we can deduce the preliminary structure-activity relationships (SARs) of A-D series compounds, which give some valuable clues for further design of inhibitors targeting HIV-1 integrase interaction with LEDGF/p75, and might supply useful structural information for further anti-HIV agent discovery.Chapter 2 concerns the development of synthetic methods of cinnamaldehydes catalyzed by Pd(OAc)2.Cinnamaldehydes are highly synthetic useful building blocks in organic synthesis due to their easy versatility of transformation of functional groups. Despite several approaches to prepare cinnamaldehydes have been disclosed over the years, it is noteworthy that most of the described methods suffer from preparation process or poor yields, whereas others demand some harsh reaction conditions. So we develop the two effective strategies in the synthesis of versatile cinnamaldehydes:(1) Inspired of the modified Saegusa oxidation proposed by our group, we have developed an improved amine-Pd(OAc)2 co-catalytic system for the direct Saegusa oxidation reaction of unmodified aldehydes to a,(3-unsaturated aldehydes in moderate to good yields (44-72%). The use of simple o-anisidine in place of (S)-diphenylprolinol made the process more simple and cost-effective; (2) We have developed a new and practical Pd-catalyzed cascade Heck-Saegusa reaction for one-pot synthesis of useful cinnamaldehydes using readily available aryl iodides and allyl alcohol under mild reaction conditions (Pd(OAc)2 (0.2 equiv), aminocatalysis (0.2 equiv); O2 (1 atm), DMSO/DMF(v/v=1:1)). The cascade reactions are compatible with a variety of functional groups on aryl ring and even with the heterocycles in good yields (57-82%). These research results in Chapter 2 have extended the application fields about organometallic and small organo-molecular co-catalyzed reactions, and aslo provided novel and simply strategies in the preparation of cinnamaldehydes.

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