Nigranoic Acid

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Nigranoic Acid

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1. Nigranoic Acid Origin, Structure, and Uses By Martin Schulte

2. Nigranoic Acid The major structural features include the cyclopropane ring attached to the triterpenoid rings. Also, there are the two carboxylic acids present at each end of the molecule. Finally, there are the double bonded carbons. At the bottom is IUPAC name that reflects the stereochemistry and the optical properties. From ACD/I-Labs services.The major structural features include the cyclopropane ring attached to the triterpenoid rings. Also, there are the two carboxylic acids present at each end of the molecule. Finally, there are the double bonded carbons. At the bottom is IUPAC name that reflects the stereochemistry and the optical properties. From ACD/I-Labs services.

3. Origin Schisandra sphaerandra Native to China Used in traditional Chinese Folk medicine Used as a sedative and tonic for over 2000 years. Increase energy, suppress cough, treat stomach disorders, and treat fatigue. Its traditional use made it an attractive plant for pharmaceutical research. In the 1970ís it was found to be hepatoprotective. Researchers found that it lowered serum glutamic-pyruvic transaminase (SGPT), a liver enzyme released into the blood stream as a result of liver damage. Used to treat hepatitis.Used as a sedative and tonic for over 2000 years. Increase energy, suppress cough, treat stomach disorders, and treat fatigue. Its traditional use made it an attractive plant for pharmaceutical research. In the 1970ís it was found to be hepatoprotective. Researchers found that it lowered serum glutamic-pyruvic transaminase (SGPT), a liver enzyme released into the blood stream as a result of liver damage. Used to treat hepatitis.

4. Schisandra sphaerandra Schisandra species have been found to be a good source of a number of biologically active compounds. A number of lignanes have been isolated as well as several triterpenoid acids.Schisandra species have been found to be a good source of a number of biologically active compounds. A number of lignanes have been isolated as well as several triterpenoid acids.

5. Extraction and Isolation Isolated from petroleum ether extract Separated using column chromatography, presumably with increasing EtOAC gradient Used bioassay guided fractionation to determine the active component Fractions showing biological activity were combined and purified using column chromatography Recrystallized compound in pet ether Nigranoic acid was found a white needles after the recrystallization. Found to be about 2.5% of the plant stems. Nigranoic acid was found a white needles after the recrystallization. Found to be about 2.5% of the plant stems.

6. Structure Determination 13CNMR 1HNMR IR DEPT Mass Spec. MF: C30H46O4 (470.3393 vs. 470.3396) Computer Modeling They used a variety of techniques to determine the structure of nigranoic acid. They used a variety of techniques to determine the structure of nigranoic acid.

7. 1H-NMR Spectrum The H-NMR was not as useful due to the overlap of chemical shifts. 11.77 corresponds to the carboxylic acid protons. 0.90 and 0.87 correspond to two tertiary methyl groups (26 and 34) and 0.96 corresponds to a one secondary methyl group (position 24). The shifts at 0.62 and 0.34 correspond to the two hydrogen atoms on carbon 22. The actual data lists these shifts at 0.63 and 0.34 ppm, respectively. The shifts at 4.79 and 4.94 are the two hydrogen atoms (39 and 40, respectively) attached to the double bonded carbon. Finally, the shifts around 6.00 ppm are from hydrogen 21. This spectrum is a prediction based on the structure of the molecule. From ACD Labs/I-Labs software. It does not correspond exactly to the observed chemical shifts.The H-NMR was not as useful due to the overlap of chemical shifts. 11.77 corresponds to the carboxylic acid protons. 0.90 and 0.87 correspond to two tertiary methyl groups (26 and 34) and 0.96 corresponds to a one secondary methyl group (position 24). The shifts at 0.62 and 0.34 correspond to the two hydrogen atoms on carbon 22. The actual data lists these shifts at 0.63 and 0.34 ppm, respectively. The shifts at 4.79 and 4.94 are the two hydrogen atoms (39 and 40, respectively) attached to the double bonded carbon. Finally, the shifts around 6.00 ppm are from hydrogen 21. This spectrum is a prediction based on the structure of the molecule. From ACD Labs/I-Labs software. It does not correspond exactly to the observed chemical shifts.

8. 13C-NMR Spectrum The C-NMR was also a prediction based on the structure by ACD/I-Labs software. It does correlate almost exactly with what was observed experimentally. The shifts to the far right are from the carboxylic acids. Moving left, the next four peaks correspond to the double bonded carbon atoms. The large peak at 36.73 is the result of identical overlap from carbons 14 and 10.The C-NMR was also a prediction based on the structure by ACD/I-Labs software. It does correlate almost exactly with what was observed experimentally. The shifts to the far right are from the carboxylic acids. Moving left, the next four peaks correspond to the double bonded carbon atoms. The large peak at 36.73 is the result of identical overlap from carbons 14 and 10.

9. 13C-NMR (CH3 Only) This NMR shows only the terminal methyl groups. The shifts at 18.67 and 19.85 correspond to the methyl off of the five-membered ring. The methyl groups off of the double bonded carbons are at 20.41 and 21.92.This NMR shows only the terminal methyl groups. The shifts at 18.67 and 19.85 correspond to the methyl off of the five-membered ring. The methyl groups off of the double bonded carbons are at 20.41 and 21.92.

10. 13C-NMR (CH2 Only) The most prominent line is the peak at 112.20. This is the terminal double bonded CH2 group. Again this is a very complex spectrum that tells us little.The most prominent line is the peak at 112.20. This is the terminal double bonded CH2 group. Again this is a very complex spectrum that tells us little.

11. 13C-NMR (CH Only) The peak at 143.04 in the alkene region corresponds to carbon 17. The peak at 52.79 is carbon 11, part of the five membered ring systemThe peak at 143.04 in the alkene region corresponds to carbon 17. The peak at 52.79 is carbon 11, part of the five membered ring system

12. 13C-NMR (C Only) Finally, the C only spectrum shows the two carboxylic acids as well as the two double bonded regions. The cyclopropane carbons (3 and 5) are at 21.88 and 27.99, respectively. The middle peaks correspond to the carbons shared between the five- and six-membered rings (7 and 8)Finally, the C only spectrum shows the two carboxylic acids as well as the two double bonded regions. The cyclopropane carbons (3 and 5) are at 21.88 and 27.99, respectively. The middle peaks correspond to the carbons shared between the five- and six-membered rings (7 and 8)

13. Potential Uses Advances in HIV Drug Therapy Using bioassays designed to identify HIV inhibitors, they identified nigranoic acid as a possible drug therapy for HIV infection.Using bioassays designed to identify HIV inhibitors, they identified nigranoic acid as a possible drug therapy for HIV infection.

14. Drug Targets Common drug targets for HIV include inhibition of certain enzymes needed for viral replication. These include integrase, protease, and reverse transcriptase. Another investigated target are the proteins found on the viral membrane. However, these are difficult to target due to the high mutation rate of the virusí genetic material.Common drug targets for HIV include inhibition of certain enzymes needed for viral replication. These include integrase, protease, and reverse transcriptase. Another investigated target are the proteins found on the viral membrane. However, these are difficult to target due to the high mutation rate of the virusí genetic material.

15. Potential Uses Advances in HIV Drug Therapy Inhibits HIV-1 Reverse Transcriptase It was found the Nigranoic acid is an effective inhibitor of the reverse transcriptase enzymeIt was found the Nigranoic acid is an effective inhibitor of the reverse transcriptase enzyme

16. HIV Life Cycle Reverse transcriptase is one of the early enzymes activated after infection of the cell. For those who are not familiar, RT produces a DNA copy from an RNA template. This is the exact opposite of most organisms who make RNA from a DNA template. Once the DNA copy is made, integrase incorporates the newly made DNA into the host organismís DNA. Once integration has happened, the host cell machinery transcribes host DNA along with viral DNA. The transcribed DNA is then translated into proteins. This is where protease comes in. It cleaves the protein precursors into active viral proteins that are packaged and excreted from the cell to infect other cells. Reverse transcriptase is one of the early enzymes activated after infection of the cell. For those who are not familiar, RT produces a DNA copy from an RNA template. This is the exact opposite of most organisms who make RNA from a DNA template. Once the DNA copy is made, integrase incorporates the newly made DNA into the host organismís DNA. Once integration has happened, the host cell machinery transcribes host DNA along with viral DNA. The transcribed DNA is then translated into proteins. This is where protease comes in. It cleaves the protein precursors into active viral proteins that are packaged and excreted from the cell to infect other cells.

17. Potential Uses Advances in HIV Drug Therapy Inhibits HIV-1 Reverse Transcriptase DDDP 96.7% inhibition at 200 mg/mL RDDP 99.4% inhibition at 200 mg/mL No effect on RNAse H 6.8% inhibition at 200 mg/mL DNA-dependant DNA polymerase, RNA-dependant DNA polymerase, catalytic subunits on reverse transcriptase. RNAse H is the protease protein DNA-dependant DNA polymerase, RNA-dependant DNA polymerase, catalytic subunits on reverse transcriptase. RNAse H is the protease protein

18. Disadvantages Active against DNA polymerase b Moderately active against RNA polymerase Weakly active against mutant reverse transcriptase DNA polymerase B, crucial for DNA repair. RNA polymerase, crucial for the synthesis of proteins. However, modifications to the compound could possibly be made which would minimizes these unwanted effects.DNA polymerase B, crucial for DNA repair. RNA polymerase, crucial for the synthesis of proteins. However, modifications to the compound could possibly be made which would minimizes these unwanted effects.

19. References IUPAC name provided by ACD/I-Labs Service 1H- and 13C-NMR provided by ACD/I-Labs Service Picture of Schisandra sphaerandra from Harvard University Herbaria Website (http://brimsa.huh.harvard.edu/cms-wb/specimens.jsp?barcode=39169) Sun, H.D., et. al. (1996). Nigranoic Acid, a Triterpenoid from Schisandra sphaerandra That Inhibits HIV-1 Reverse Transcriptase. J. Nat. Prod. 59, 525-527. Chen, Y., et. al. (2003). Triterpenoids fro Schisandra henryi with Cytotoxic Effect of Leukemia and Hela Cells In Vitro. Arch. Pharm. Res. 26,11. 912-916.

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