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Saquinavir

Organic Chemistry II Final Project Presentation
by

Gina Lu

on 8 May 2013

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Transcript of Saquinavir

Saquinavir N O NH H N 2 O O N H N NH O HIV Background Infects CD4+ T cells apoptosis by CD8 T cells
Integrates viral RNA into host cell DNA
No cure for HIV
High genetic variability due to fast replication (1010/day)
Reverse transcription is error prone high mutation rate
How hosts die: various infections due to loss of immunity 34.2 million people infected globally
Death by AIDS fell to 1.7 million due to antiretroviral therapy
Africa makes up of 70% of all HIV-infected people
More than 8 million people go through antiretroviral therapy
Examples: Protease inhibitor, Reverse transcriptase inhibitor, integrase inhibitor, etc. HIV Statistics (2011) Anti-retroviral drug used for HIV therapy
Protease inhibitor
Prevents viral replication by binding to the active site of HIV-1 Protease
HIV-1 Protease: Cleaves poly-protein into mature proteins of HIV
Trade Name: Invirase (capsule) Saquinavir Designer: Donald Jeffries
Invirase (hard capsule): approved Dec. 6, 1995
Approval Time: 3.2 months
Fortovase (soft gel): approved Nov. 7, 1997
Approval Time: 5.9 months
No longer marketed - lack of demand
Used in conjunction with other HIV therapeutic drugs
Saquinavir/Ritonavir;
Saquinavir/Lopinavir History of Saquinavir Diarrhea, stomach pain, nausea, vomiting
Fatigue, back pain, fever
Rash, peeling skin
Loss of appetite, slow heartbeat, fainting Side-Effects Image From : https://commons.wikimedia.org/wiki/File:HIV-budding-Color.jpg Image From : http://www.who.int/healthinfo/statistics/indhivprevalence/en/ Sources : http://www.huffingtonpost.com/2012/07/18/hiv-aids-numbers-statistics-worldwide_n_1682936.html Sources : http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm118915.htm
http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/hivandaidsactivities/ucm124862.htm Sources : http://www.huffingtonpost.com/2012/07/18/hiv-aids-numbers-statistics-worldwide_n_1682936.html Sources : http://www.aidsinfonet.org/fact_sheets/view/443 Sources : http://courses.chem.indiana.edu/c582/documents/hivproteasemechanismandinhibitors.pdf Current Synthesis Scheme Step 1 Hydrogenation Conversion to Amides:
Carboxylic acid Derivatives Step 2 Step 3 Step 4 Hydrolysis of Amides:
Reverse Fischer Esterification Step 5 Nucleophilic
Substitution Step 6 Hydrolysis of Amides Step 7 Our Synthesis Scheme: Modular Approach Module A Module B Module C Synthesis of Module A Step 1: Hydrogenation and Formation of Acyl Chloride Mechanism: Formation of Acyl Chloride Formation of Iminium Ion Attack by the Carboxylic Acid Step 2: SN2 Attack by Amine DCC-coupled
Protein Synthesis Step 8 Hydrolysis of Amides Synthesis of Module A Synthesis of Module B Step 1: SN2 Amine Attack Synthesis of Module B Step 2: Epoxidation (Mitsunobu Reaction Analogue) Mechanism: Mitsunobu Reaction Step 9 DCC-coupled
Protein Synthesis Module B: Alternative Pathway
(Better Regioselectivity) Step 1: Cross-Claisen Condensation Module B: Alternative Synthesis Saquinavir Step 2: Reaction with Sulfuryl Chloride Jeffrey Chen
Dennis Guo
Annette Ko
Gina Lu
Abby Shin
Tammy Ying Module B: Alternative Synthesis Step 3: Reduction and Formation of the Epoxide Final Synthesis of Saquinavir
From Modules Step 1: Ring Opening and Leaving of Amine Image From : http://en.wikipedia.org/wiki/HIV-1_protease Final Synthesis of Saquinavir From Modules Step 2: DCC Coupling to Form Amide Product Potential Side Reactions of DCC Coupling Minimized Through Addition of N-Hydroxysuccinimide Cost and Duration of the Original Synthesis DCC-coupled
Peptide Synthesis Cost and Duration of the Proposed Synthesis Alternative History, Applications, and Method of Synthesis Comparison of the Three Syntheses Conclusion This step will form numerous side products
Some of these unwanted products are cytotoxic
However, side reactions are minimized through addition of N-hydroxysuccinimide. [1]
Will allow scale-up of process. Impact on health care
Flaws of proposed synthesis
Solutions
Scale up?
Minimal side reaction
Cytotoxic products minimized Price
(tens of dollars) Time (hours) Yield (%) Original Synthesis Our Synthesis Alternative Synthesis 180
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0 Sources : http://www.drugsyn.org/Saquinavir.htm Sources : www.scifinder.com Image : http://livingwithcfs.com/understanding-antidepressant-withdrawal/pills/ [1] https://www.thieme-connect.com/ejournals/html/10.1055/s-0031-1290663 Thank you for your time! Questions? Image From : http://blog.massagetoday.com/wibb/2012/03/23/bridging-the-gap-referring-other-cam-disciplines/happy-patients/ Image : http://lowerabdominalpainrelief.com/wp-content/uploads/2013/03/sexy-women-stomach-pain.jpg http://en.wikipedia.org/wiki/Mitsunobu_reaction Acknowledgments Dr. Danith Ly
Dr. Susan Graul
Matthew Mackenzie
Elizabeth Rastede
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