Dissertation > Excellent graduate degree dissertation topics show

The Construction of Similar D/E Ring Moiety of Betulinic Acid on Steroidal Scaffold via Diels-Alder Reaction and Preliminary Bioactivity Test

Author: ZhangZuo
Tutor: ChenZuo；XiaPeng
School: Fudan University
Course: Medicinal Chemistry
Keywords: Betulinic acid Anti- HIV-1 activity Steroidal 2,2 - dimethyl succinic anhydride Synthesis
CLC: R93
Type: Master's thesis
Year: 2008
Downloads: 84
Quote: 0
Read: Download Dissertation

Abstract


Betulinic acid (betulinic acid) is the University of North Carolina School of Pharmacy in the late 1990s from the extraction and separation in the Myrtaceae plant has obvious anti-HIV-1 activity (EC 50 = 1.4μM, TI = 13) pentacyclic triterpenoids, University of North Carolina School of Pharmacy in its structure on the basis of their 3 - hydroxy different the ester structural modification and biological activity observed, found that derivatives of PA-457 anti- HIV-1 activity (EC 50 <3.5 × 10 -4 μM, TI> 20000) significantly improved. While Mayaux et al on of the C-28 side chain of the betulinic acid for the structural modification of the synthesis of a series of amide derivatives, wherein IC 9564 of HIV-1 inhibitory activity, the best therapeutic index (EC the 50 = 0.053μM, IC 50 > 10μM). The two types of the betulinic acid derivative is neither HIV reverse transcriptase inhibitors, nor is the mechanism of protease inhibitors. C-3 side chain modified derivatives can specifically disrupt CA precursor (p25) is cleaved into the mature CA (p24), so that the assembly completed virus particles defect, no ability to infect, i.e. blocked in the late stage of the viral life cycle, HIV- 1 replication; while the C-28 side-chain modified derivatives by targeting the HIV-1 envelope glycoprotein capsular membrane mediated membrane fusion to inhibit HIV-1, i.e. to play an earlier stage in the viral life cycle of the active anti-viral fusion . The betulinic acid sources are mainly dependent on plant extracts or semi-synthetic, large-scale production of raw materials is one of the issues need to be addressed. Our group in the long-term in-steroidal and anti-viral (including HIV-1) in the drug research, for the first time found that some simple steroidal compound has a significant inhibition of HIV activity. The purpose of this project is to convenient source, and easy to carry out chemical modification of steroid skeleton as the nucleus, and birch acids triterpenoids similar pentacyclo structure, and in the corresponding active site (corresponding to the C-skeleton of betulinic acid 3, C-20 and C-28) modified structural skeleton compounds study steroidal anti-HIV-1 activity and structure-activity relationship. The article pregn-dehydropregnenolone acetate as raw materials, the use of a D-ring α, β-unsaturated carbonyl group, the 20 - position of a carbonyl group converted to hydroxy after the elimination or direct the enolate structure diene structure, and then with carboxyl Diels-Alder cycloaddition reaction occurred dienophiles or ester group, successfully building the E-ring of the steroid and the introduction of the free carboxyl group, and betulinic acid structure pharmacophore introduced in the 3 - 3 ', 3'- dimethyl ester structure, to obtain the objective compound. Full Total synthesis of compounds 35, 21 new compounds have not been reported. 12 target compound in the synthesis of the E-ring side chain of the steroidal 3 target compound having a free carboxyl group, 6 for the 3 - position side chain to the 3 ', 3'-dimethylbutoxy esters, 3 at the 3 - position, both having an E-ring side chain free carboxyl side chains into 3 ', 3'-dimethoxy butanedioate the target compound. HIV biological activity of some of the compounds synthesized in this paper and the target compounds were detected. However, due to the HIV biological activity was measured in foreign countries, a longer period, on hand has been active data are very limited, and most of the various design routes starting some of the simple structure of the intermediate steps, the reference is not meaningful, specific structure-activity and then discuss and research analysis required to obtain all of the target compounds active feedback. Some of the compounds synthesized in this thesis, the detection of the biological activity of the vascular endothelial growth factor, and the censorship 11 compounds have varying degrees of inhibitory activity, especially the compound 46 (EC 50 = 0.0472 mM TI = 18.51) and 25 (EC 50 = 0.0121 mM, TI = 10.03) activity and selectivity than the positive control 2-ME (EC 50 = .4964 mM, TI = 3.33). The 11 compounds in the structural differences of 16, 17 and 20, but with a certain activity, indicate the existence of a further modification space, also hinted there may be more than one point of integration with the target. Therefore, this provide a reference for further in-depth study of structure-activity relationships. Article in synthetic research to explore the three synthetic route preliminary research and discussion of the behavior of chemical compounds and reactions. a) the through the transformation-steroidal D-ring △ 16 -α, β-unsaturated carbonyl, completed a successful build betulinic acid the pentacyclic structure synthesis route, while the smooth introduction of the E-ring side chain free carboxyl, lay the foundation for the E ring C-20 further substituents modified. b) in the steroid nucleus D ring △ 16 -α, β-unsaturated carbonyl group reactive study found that the reaction of the C-18 angular methyl group 20 - bit larger steric effects. In the use of methyl magnesium iodide the △ 16 -α, β-unsaturated carbonyl group by a Grignard addition and sodium borohydride reduction reaction, since the C-18 angular methyl the impact such that a considerable amount of reagent from the steric hindrance of relatively small C-16 offensive, and generates half of the amount of 1,4 - addition byproducts: We the smaller reagent or more reactive reagent solutions through the use of molecular volume △ 16 -α, β-unsaturated carbonyl selective addition problems. c) The papers were also groping two apply to steroidal △ 16 -17 - tert-alcohol △ 16 -17 - secondary alcohol elimination reaction conditions. On △ 16 -17 - tertiary alcohols higher yield in weak alkaline conditions and under acidic conditions are to get rid of product; while △ 16 -17 - secondary alcohols, 10% H 2 SO 4 / Dioxane (wt / wt) conditions can get a better yield of elimination product.

Related Dissertations

  1. Studies on the Synthesis and Technology of Dipentaerythritol and Its Derivative,TQ223.164
  2. Synthesis and Characterization on Semi-Aromatic Polyamides Containing Benzoxazole Units,O633.5
  3. Hydrothermal Synthesis of Oxide Hollow Spheres,TB383.4
  4. Video Coding Research Based on Texture Characteristics,TP391.41
  5. Poetic alienation : graphics,J506
  6. Urothermal Synthesis, Structure and Characterization of Functional Coordination Polymers,O631.3
  7. The Total Synthesis of a Flavonoid Glycoside Apigenin-7-O-β-D-glucuronide,R284.1
  8. Atovaquone analogues Design, Synthesis and antitumor activity of,R914
  9. Synthesis and Seperation of 1,1’-binaphthol,O625.3
  10. Flexible,rigid,Synthesis and characterization of mixed ligand complexes,O621.1
  11. Synthesis and Performance Study of Bisphenol AP-based Polybenzoxazines,TQ320.1
  12. Study on the Synthetic Process of Vat Pink R,TQ616.2
  13. Study on the Mechanism of Night Temperature to Grain Filling of Inferior in Rice,S511
  14. Gold-catalyzed Addition Reaction of Sulfonates and Alkynes and Study of Synthesis and Bioactivity of (E)-3-phenyl-substituted Acrylic Acids,R914
  15. Synthesis and Identification of P22/P221 Polypeptides of IBDV Ligand Epitope and Screening CEF Library,S852.65
  16. The Properties and Synthesis of Photochromic Indole-Substituted Fulgides,O626
  17. Curing Mechanism and Properties of Fluorenyl Epoxy Resin,TQ323.5
  18. Study on Antioxidant Activities and Lipase-catalyzed Transesterification of Lard to Produce L-ascorbyl Fatty Acid Esters,TS202.3
  19. Syntheses of Novelbenzopyran Compounds Containing Fluorine and Induced Resistance to TMV,S435.72
  20. Research on the Physiology Mechanism of Grain Filling of inferior Grain during Day and Night Chemical Regulations,S511
  21. Expression of β-Catenin in Pig’s Ovary and the Effect of β-Catenin on Porcine Granulosa Cells Apotosis and Steroidogenesis Related Enzyme,S828

CLC: > Medicine, health > Pharmacy > Pharmacognosy (natural pharmacy )
© 2012 www.DissertationTopic.Net  Mobile