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  • Edit as necessary… When talking about artificial rubber, I made a big deal about how WWII was a real source of technological innovation out of necessity. When the Japanese have cut off your latex supply to Indonesia, you need to come up with an alternative. Similarly, the Germans needed airplane fuel, and this is why Freidel and Crafts developed their alkylation reaction (to alkylate benzene, which was in good supply, to xylene, which was in short supply but made the better airplane fuel) At the time, Peruvian imports of quinine were threatened, which motivated Woodward to develop a synthesis, and that was Doering’s PhD thesis. Lipton told me that it has recently been shown, however, that Doering’s synthesis was flawed. Doering never actually completed the synthesis, he only got to an intermediate that had previously been shown to be convertible to quinine. Stork has recently shown that the intermediate Bill made actually cannot be converted to quinine, as it was believed. I told Mark that I’d never admit that about my great-grandfather.
  • Maybe a time to pull out our tonic water again? I don’t know what kind of demo to do, other than to drink some 
  • Edit as necessary… When talking about artificial rubber, I made a big deal about how WWII was a real source of technological innovation out of necessity. When the Japanese have cut off your latex supply to Indonesia, you need to come up with an alternative. Similarly, the Germans needed airplane fuel, and this is why Freidel and Crafts developed their alkylation reaction (to alkylate benzene, which was in good supply, to xylene, which was in short supply but made the better airplane fuel) At the time, Peruvian imports of quinine were threatened, which motivated Woodward to develop a synthesis, and that was Doering’s PhD thesis. Lipton told me that it has recently been shown, however, that Doering’s synthesis was flawed. Doering never actually completed the synthesis, he only got to an intermediate that had previously been shown to be convertible to quinine. Stork has recently shown that the intermediate Bill made actually cannot be converted to quinine, as it was believed. I told Mark that I’d never admit that about my great-grandfather.
  • This is what I got from Kavita, so that’s why I attribute it to chemical biologists.
  • I actually found some reading that talks about these ideas. I have made it the assigned reading available on WebCT
  • This research comes from the Lilly laboratories and Purdue’s own Dr. Steven Byrn an international expert in polymorphism. He is in the pharmacy department and runs SSCI in the Purdue Research park. Note that not only are the colors different (The red, orange, yellow “ROY”), but the crystal habit is different too. You can see the needles, prisms, and plates. In the Cambridge structural Database in May 1999 the authors discovered using C, H, N, O, F, and S that 291 systems were dimorphic, 27, trimorphic, 3 had four polymorphs, and none had 5 or more. This ROY system exhibits a high degree of polymorphism.
  • FDA = Food and drug administration.
  • Take quotations from a series of press conferences held to allay the public’s fears and perhaps mistrust. This series of quotations demonstrates many aspects of the nature of polymorphism: inability to predict, appearance of new forms, differences in properties, desire to control polymorph, frustration in losing control, total lack of knowledge of new form(s), etc. This is a drug given to HIV patients and it is a protease inhibitor.
  • Random cancer stats
  • What is cancer and how do we treat it now. Hair cells, bone marrow, and stomach lining cells are fast growing cells, which is why chemotherapy causes the side effects it does
  • OK, this is the most complicated slide, but it is important to understand. There is a protein called bcr-abl (pronounced B-C-R-Able) that causes leukemia. Normally, bcr-abl isn’t a problem, because it is only present as the bcr and abl components. However, the problem starts when the bcr and abl get “fused” to create bcr-abl (I don’t know why the fusion occurs, but that is what is shown at the top of the slide. The two components (the oligomerization domain and the tyrosinekinase domain) get fused together, and that creates bcr-abl). Bcr-abl is a phosphorylating agent, that adds phosphorous to tyrosine in GRB-2 and SHC proteins (surface proteins on a cell). Phosphorylation of these proteins causes the cells to start reproducing rapidly (proliferation), mainly by changing the adhesion properties to the surface proteins (that is the altered adhesion part). Also, the phosphorylation inhibits apoptosis, which is when cells die due to lack of oxygen. So, the cells start proliferating out of control, and the cell death mechanism is blocked. That makes them cancerous (oncogenic) On the left, i am just pointing out some of the secondary structure of the protein. I don’t know what the substrate is that is docked there
  • This is an animated slide. I like the way the substrate keeps bouncing off when the inhibitor is present 
  • OK, so the fusion can’t be stopped. But GLEEVEC does stop the phosphorylation step by inhibiting the binding of the RGB-2 and SHC substrates. Gleevec binds the active site even more tightly than the substrates. No phosphorylation, no oncogenic growth
  • This shows the H bonding sites, and how Gleevec sits in the active site
  • _Technically_ Gleevec is an “inhibitor” because it acts on an enzyme (bcr-abl is a phosphorylation catalyst), but antagonist and inhibitor are very similar in function, so I wanted to use the general language
  • They’ll see dopamine agonists in their homework
  • The colored effects are more important enough to overcome concerns about the other things (a little constipation is not a big deal if you need pain relief)
  • The colored effects are more important enough to overcome concerns about the other things (a little constipation is not a big deal if you need pain relief)
  • Opoid receptors are membrane proteins. The hydrophobic sections are alpha-helices in the cell membranes, and the hydrophilic sections sit above and below. This is one protein (not heptameric)
  • It is not a coincidence that enkephlins look like endorphins. In fact, enkephlins are the agonists, but are generated by cleaving the endorphin. This enkephlin is met-enkephlin, because the C terminus is methionine. The other common enkephlin is leu-enkephlin (which has a leucine there) So trauma/stress triggers the formation of endorphins, which cleave into enkephlins, which trigger opioid activity
  • I know heroin is hydrolyzed. I’m not sure about codeine. I suspect that the anisole is convered to the phenol, but since it is very slow, codeine isn’t as potent as the others. Note the substitution at the hydroxy groups is the only difference between these three.
  • Transcript

    • 1. Chemistry 115 Lecture 20 Outline Molecular Shape and Drug Discovery Molecular Shape Drug discovery process Shape of drug molecules/polymorphism Curing Cancer QUIZ in Recitation this Friday: Chapter 10 EXAM Next week (April 4, 7pm)
    • 2. 3-D Molecular Shape and Vision
      • Rhodopsin is responsible for vision.
      • Rhodopsin consists of 11- cis -retinal covalently bonded to a large protein.
      • Note how 11- cis -retinal “fits” into the protein to allow it to bond.
    • 3. 3-D Molecular Shape and Vision
      • When light strikes the molecule, the shape will change via a rotation around the 11-12 bond.
    • 4. 3-D Molecular Shape and Vision
      • When the shape changes, the molecule no longer “fits” with the protein, and they separate.
      • This change in shape and separation from the protein contributes to the electrical signal that travels through your neurons as “vision.”
    • 5. Molecular Shape and Drugs
      • Molecular shape affects the interaction of drugs in your body
      • In order to develop useful drugs, chemists at pharmaceutical companies:
        • synthesize different potential drugs
        • Work to understand the drug targets (proteins)
        • Use chemical knowledge to find protein/drug interactions.
        • Let’s start with a disease example, Malaria:
    • 6. Malaria
      • Malaria is caused by parasitic protozoa (genus: Plasmodium) and is transferred to humans by mosquitoes
      • Symptoms: VERY high fever (107°!), nausea, delirium
      • There are an estimated 100 – 200 MILLION cases of malaria worldwide each year (80% are in Africa)
      • 1 – 1.5 millions deaths per year
      • Used to treat syphilis prior to antibiotics.
    • 7.
      • Peruvian Indians used bark from the Cinchona tree (found in the Andes) to treat fever; it also was found to cure malaria
      • Europeans started harvesting Cinchona bark (almost to extinction) and sending it back to Europe
      • The active ingredient in the
      • Cinchona bark is quinine,
      • isolated in 1820
      • Quinine cures malaria by
      • killing the parasite (it binds
      • to proteins in the body that
      • the parasites need).
      Treatment of Malaria: Quinine
    • 8. Interesting Facts about Quinine
      • The British Army developed tonic water in order to get their soldiers to take quinine to fight malaria (it’s not known who was the first to add gin)
      • Although quinine can be obtained from tree bark, it was first synthesized artificially in 1944 by RB Woodward and W Doering (not a coincidence that it was during WWII – natural supplies were cut off)
    • 9. Many drugs are discovered in the same way as quinine
      • Aspirin – salicylic acid (not aspirin) was obtained by chewing on Willow bark. Alfred Bayer in Germany discovered that the acetyl ester was more effective for pain relief, and called it “aspirin” (the trademark was lost when the US seized all domestic German assets after WWI)
      • Mold in a petri dish led to the discovery of penicillin
      • Taxol is an anti-cancer drug that is obtained from the bark of Yew trees
      • Countless potential drugs are isolated from plants, algae, and even things like sea sponges.
      • In all these cases, the general approach is
      • Find some unusual natural product test it against a wide
      • range of diseases and
      • see if it does any good
    • 10. This approach to drug discovery is what chemical biologists call “Forward Chemical Genetics” Phenotype Reduces Fever Aspirin Cyclooxegenase 2 Forward chemical genetics requires screening of a very large number of possibilities, hoping that one is successful Find the active agent Figure out what it does
    • 11. Reverse Chemical Genetics: Design a drug to target the cause of the disease Understand the basis for the problem Develop a strategy for preventing the disease from occurring Use chemical approaches (e.g. agonist, antagonist) to solve the problem! The development of Gleevec for the treatment of CML is an example of reverse chemical genetics: the mechanism of cancer formation/growth was discovered, and the information was used to develop a therapy to prevent it from happening
    • 12. Designing a drug
      • There are many challenges to drug design
        • mechanism of the disease
        • create a drug with appropriate chemical properties
        • proper physical properties to act within the body
        • form to introduce into the body
    • 13. Drug Development Pipeline Combinatorial chemistry Phase 3 Phase 2 Phase 1 Preclinical Discovery # compounds 1M 100 10 2 1 Total cost: <$500M/drug Phase 3 most expensive
    • 14. Chemical and physical properties of good drugs
      • Restrictions on the types of chemical and physical properties of drug molecules.
      • Summed up in Lipinski’s “Rules of 5”
      • The important considerations are
        • Hydrogen bonding ability: determines the ability of the drug to bind properly into the receptor site; too many H-bonding sites cause the drug to bind non-specifically
        • Size: if the molecules are too big, they aren’t adequately soluble
        • Hydrophobicity: they have to dissolve sufficiently in water
    • 15. 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile “ROY” Reference: Yu, L.; Stephenson, G. A.; Mitchell, C. A.; Bunnell, C. A.; Snorek, S. V.; Bowyer, J. J.; Borchardt, T. B.; Stowell, J. G; Byrn, S. R. J. Am. Chem. Soc. 2000, 122, 585. 6 polymorphic forms
    • 16. Acetaminophen polymorphs Growing crystals of the pain-relieving drug acetaminophen on different polymer surfaces will yield different crystal structures. One polymer gives rise to tiny prisms (right); another, miniature monoliths (left).
    • 17. Solid State Chemistry of Drugs, or why pharmaceutical companies worry about polymorphism
      • $ - Many drugs receive patents and FDA approval for only a single crystalline form, or polymorph.
      • Arrangement of molecules in a crystal determine its physical properties
        • Melting point, density, dissolution rate
      • Physical properties of a drug can affect its performance.
    • 18. Characterization
      • X-ray diffraction (demonstrating non-equivalence of forms)
        • FDA definitive evidence of polymorphism.
      • Other experimental evidence
        • Microscopy (look at crystal structure),
        • Thermal analysis (melting points), and
        • Spectroscopy (IR, ssNMR)
    • 19. The Ritonavir Story
    • 20. Warning?
      • “ There was no gradual trend. Something occurred that that caused the new form to occur…There was no early warning.”
      • “ We, quite honestly, have not been able to pinpoint the precise conditions which led to the appearance of the new crystal form. We now know that the new form is, in fact, more stable than the earlier form, so nature would appear to favor it…Form II is new.”
        • This is very bad news, if they have found a more stable form, then the less stable form will become very difficult to make.
      Quotes from Abbott Labs:
    • 21. Ritonavir - The solution proposed
    • 22. Can we cure cancer?
      • Over one million people get cancer each year
      • Approximately one out of every two American men and one out of every three American women at some point during their lifetime.
      • Although 77% of all cancers are diagnosed in people age of 55 and older, anyone can get cancer at any age
      Statistics from the American Cancer Society
    • 23. What are the ways we treat cancer?
      • Surgery
        • Physical removal of cancerous tumor
      • Radiation
      • Chemotherapy
        • Destroys all rapidly dividing cells – that includes cancer cells, but also
          • Cells in your hair (hair loss)
          • Bone marrow (fatigue)
          • Stomach lining (nausea)
      • Biologic therapies
    • 24. Biologic Therapies for Cancer Treatment
      • Biologic therapies use the body's immune system to fight cancer or to lessen the side effects of some cancer treatments.
        • interfering with cancer cell growth
        • acting indirectly to help healthy immune cells control cancer
        • helping to repair normal cells damaged by other forms of cancer treatment.
    • 25. Chemotherapy-based approaches to stopping cancer growth
      • If we know what causes the cancer to form in the first place, it may be possible to create a drug that will stop it from happening
      • EXAMPLE: Chronic myeloid leukemia (CML) and Gleevec ®
        • Leukemia is a cancer of the blood or bone marrow characterized by an abnormal proliferation of blood cells, usually white blood cells. CML is a form of chronic (slowly developing) leukemia characterized by increased and unregulated production of predominantly myeloid cells in the bone marrow.
    • 26. The Bcr-Abl protein: the cause of Chronic Myeloid Leukemia (CML) Part of the bcr-abl protein Alpha-Helices! Beta-sheets
    • 27. The “lock and key” approach to inhibition
      • We can envision the activity of Gleevec as like putting the wrong key into a lock, to prevent anyone from using the right key
      Normal binding between the protein and the substrate is like a key going into a lock. Turn the key, and the door opens (the substrate gets modified) The inhibitor is shaped liked the substrate but doesn’t undergo the modification. It just stays stuck in the door, preventing the substrate from entering protein substrate protein substrate inhibitor
    • 28. Gleevec: a bcr-abl inhibitor Bcr-abl is a phosphorylating agent: it adds phosphorous to proteins. Gleevec prevents the substrate from binding, so phosphorylation can’t occur, and cancer doesn’t form.
    • 29. Structure of Gleevec® Class: Phenylaminopyrimidines, C 30 H 35 N 7 SO 4 MW=589.7 • CH 3 SO 3 H
    • 30. How does Gleevec fit into the lock? Intermolecular forces! Hydrogen bond donors Hydrogen bond acceptors
    • 31. One form of cancer down, thousands to go…
      • Although Gleevec is a wonderful success in treating cancer (more than 95% of CML patients treated with Gleevec have their leukemia cured), it is essentially specific to that one form of cancer.
      • Other forms of cancer have different mechanisms for formation and growth. We need to find different drugs to cure them.
      • It takes time and money
    • 32. Agonist vs Antagonist
      • Gleevec can be considered an example of an antagonist because it prevents the active agent from doing what it normally does
      • An agonist is a drug that gets the active agent to do its normal function without having its usual trigger around
    • 33. Common “agonists” include
      • “ dopamine agonists“ used to treat Parkinson’s symptoms by triggering dopamine receptors
      • Asthma inhalents trigger bronchodilation
      • Penicillin – mimics a dipeptide
      • “ mood altering drugs”
      Opiates, substances created by our bodies in order to fight pain, are agonists. Opioid receptors are triggered in response to trauma/stress(i.e. pain): for example, you get your toe smashed, it hurts, but the pain subsides. That’s due to opioid receptor activity.
    • 34. Morphine
      • An agonist that triggers activity of μ -opioid receptors in the brain and top of the spinal cord causing
        • Analgesia
        • sedation
        • Reduced blood pressure
        • Itching
        • Nausea
        • Euphoria
        • Decreased respiration
        • Miosis (constricted pupils)
        • Decreased bowel motility often leading to constipation.
    • 35. Morphine
      • An agonist that triggers activity of μ -opioid receptors in the brain and top of the spinal cord causing
        • Analgesia
        • sedation
        • Reduced blood pressure
        • Itching
        • Nausea
        • Euphoria
        • Decreased respiration
        • Miosis (constricted pupils)
        • Decreased bowel motility often leading to constipation.
    • 36. Morphine as an opioid agonist Morphine is an example of an opioid alkaloid: a natural occurring product (usually isolated from plants) with a nitrogen containing ring
    • 37. The opioid receptor: a membrane protein The active site (where opiates bind to the receptor) is not well known
    • 38. Endogenous (in the body) opioids: peptide structures Endogeneous substances are substances substances created by our bodies Endogenous Opioids Enkephlins Endorphins
    • 39. Other drugs are similar to morphine, and have a similar activity heroin Difficult to convert to OH much more easily converted to OH codeine Wedge bond, not H-bond
    • 40. Summary
      • Molecular Shape plays an important role in:
        • Vision, Smell
        • Drug action
      • Drug discovery process is challenging, 2 methods:
        • Forward chemical genetics: find the drug, then find out why it works
        • Reverse chemical genetics: figure out what causes disease, and then design a drug to fix it
        • Molecular structure, shape, and crystal structure are all important determinants of the drug’s success
      • Optimizing a drug for a specific disease takes lots of chemical knowledge, hard work, luck!

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