Organic Chemistry in Medicine Notes

Organic Chemistry in Medicine

• The lecture discusses organic chemistry in medicine, focusing on pharmaceuticals rather than illicit substances.

• The lecture recording may have visual issues, but a proper video will be uploaded later.

Background: Medicinal Chemistry and Drug Pricing

• Martin Shkreli (Pharma Bro):

  • Former CEO of Turing Pharmaceuticals. Purchased exclusive rights to Daraprim in the U.S.

  • Daraprim: Anti-malarial and anti-parasitic drug used to treat toxoplasmosis (parasitic infection from cats).

  • Shkreli increased the price from $13.50 per pill to over $700 per pill in 2015.

• Daraprim Details:

  • Small molecule drug with a heteroaromatic ring (contains nitrogens in the aromatic ring).

  • Discovered in 1952, in medical use in 1953.

  • On the World Health Organization's list of essential medicines.

  • Costs 5-20 US cents per dose in most of the world.

  • Shkreli's price hike resulted in a cost of $75,000 for a course of treatment in the US.

• Synthesis of Daraprim:

  • In 2016, a group of students from Sydney Grammar synthesized 3.7 grams of Daraprim for $20.

• Shkreli's Downfall:

  • Sentenced to seven years in prison for defrauding investors, not directly for the price hike.

  • Ordered to pay $64.6 million for illegally monopolizing a life-saving drug.

• Key Question: What determines the price of a drug and the cost of pharmaceutical development?

Cost of New Drugs

• Book: The $800 Million Pill (2004) - estimated cost of drug development at that time.

• CNN article (2014): Estimated cost at $2.5 billion.

• Current estimates hover around $2.5 billion to develop a new pharmaceutical drug.

• Why so expensive? Lengthy process with no guarantee of success.

• Cost accounts for the fact that not every drug molecule will be successful through the clinic.

Phases of Drug Development

• Preclinical Phase:

  • Innovation and discovery of the molecule.

  • Development of new chemical entities with promising activity.

  • Little is known about safety, toxicity, pharmacokinetics (fate of the drug in the body).

  • Focus on molecule discovery through synthetic chemistry.

• Clinical Trials:

  • Phase One:

    • Involves healthy volunteers to determine safety and dosing.

    • Determines the safety window/limit of the drug.

    • Compounds may fail at this stage due to adverse effects.

  • Phase Two:

    • Used to get an initial reading of efficacy and further explore safety.

    • Involves small numbers of patients with the target disease.

    • Uses double-blind study (placebo vs. active therapeutic), where neither participants nor doctors know who receives what.

    • A common fail point for drugs.

  • Phase Three:

    • Larger trial to determine safety and efficacy in large numbers of patients (thousands).

*Graph of Cost Over Time:
Shows almost exponential increase in cost of clinical and preclinical phases over time.

Success Rate of Drug Development

• Very small percentage of drug molecules make it to the clinic.

• Example:

  • 10,000 initial candidate molecules made by synthetic chemists.

  • 250 show some promise in a biological model (cell assay or animal model).

  • 10 qualify for tests on humans (Phase One trial).

  • 20% of drugs that start Phase One are eventually approved for marketing.
    *Formula for success rate:
    $Success Rate = (2/10000) * 100 = 0.02 \%$

• Approximately 26 new chemical entities enter the market each year worldwide.

Sources of Medicinal Agents

• Top 200 Pharmaceutical Products:

  • Dominated by small molecules. This is changing over time.

• Evolution Over Time:

  • 2012: Mostly small molecules. Hydrocodone (pain reliever) was number one.

  • 2022: Included COVID vaccines and antibodies (for immunology and cancer treatment). Emergence of antibody-drug conjugates.

  • 2023: COVID vaccines market share decreased. Ozempic (weight loss drug) entered the market (Semaglutide - peptide hormone initially for diabetes treatment).

• Ozempic:

  • Semaglutide is a peptide hormone, a variant of a peptide hormone originally used for diabetes.

  • Regulates appetite and blood sugar levels.

  • Marketed as a weight-loss drug.

  • Side effect: "Ozempic face" (loss of fat including buccal fat).

• Natural Products:

  • Key source of medicinal agents throughout history (e.g., Sumerians using opium).

  • Chemical synthesis tools allow diversification from natural scaffolds (as seen with Ozempic).

Categories of Medicinal Agents

• Small Molecules:

  • Example: Aspirin (acetylsalicylic acid).

• Proteins:

  • Example: EPO (erythropoietin) - used to enhance red blood cell count.

  • Molecular weight measured in Daltons (grams per mole).

• Peptides:

  • Intermediate in size between small molecules and proteins.

  • Have structural features of proteins.

  • More specific targets, potentially fewer side-effects.

  • Cheaper to produce than larger proteins.

  • Example: semaglutide

• Peptides and Bad Reputation:

  • Growth hormone-releasing peptides were used to enhance muscle development, but lacked clinical validation.

  • Peptides have a good side: e.g., life-saving and beneficial properties, namely insulin.

Insulin: A Peptide Example

• Isolated in 1922, a significant advancement from injecting ox pancreas material.

• Primary structure (amino acid sequence) determined by Fredrik Sanger (Nobel Prize in 1958).

• Three-dimensional structure determined by Dorothy Hodgkin (x-ray crystallography).

• Insulin consists of two chains of amino acids (A and B) linked by disulfide bonds between cysteines.

• Complex topology in a way that a small molecule cannot be.

Peptide Chemistry: Assembly and Components

• Amino Acids:
  Has an amine group and a carboxylic acid group.
  Have alpha chirality at the alpha carbon position (between the amine and the acid).
  The R group is what makes each amino acid unique.
  Can assign priority to the groups: amine (1), carboxylic acid (2), R group (3).

• Stereochemistry:
  $S$ configuration is when 1-2-3 numbering goes in a counter clockwise direction.
  $R$ would be the opposite configuration.
  The terms $L$ or $D$ are also used, the most time amino acids are labelled with $L$ or $D$ and it's a historical naming thing.
  L glyceraldehyde, the $OH$ group is on the left-hand side and the most oxidized group (aldehyde) is always positioned at the top when drawing the compound.
  $L$ amino acids are those that are generally naturally incorporated by proteins while D amino acids aren't incorporated by the ribosome but can still be present in natural products.
  Most $L$ amino acids are $S$.

• Amino Acid Variability:
  Diversity of side chains (aliphatic, aromatic, acidic, amines, alcohols).
  Essential amino acids must be consumed in diet.

• Tryptophan:
  Essential amino acid allegedly present in high contents in turkey that may make you sleepy.
  Precursor to melatonin and serotonin.
  Not only used in protein synthesis.

• Peptide Bonds (Amide Bonds):
  The reaction drawn to condense carboxylic acid and an amine won't work as is, you'll need to control reactivity.
  Overall transformation is just condensation.

  Forming Amide Bonds (cont) How Nature Assemble Amino Acids

• Nature's Method (Ribosome):

  • mRNA template and tRNA molecules.

  • Ribosome positions the incoming amino acid (with a free amine) next to the growing chain linked to tRNA by an activated ester.

  • Proximity effect: positioning a nucleophile (amine) right next to electrophile (activated ester).

• Protecting groups:
  Masks reactivity of compounds.
  For example, amino acid protected on the nitrogen with a $Boc$ group (tert-butyl oxycarbonyl). That blocks off the reactivity of that amine.
  Carboxylic acids blocked with tert-butyl groups can facilitate bond formation exclusively between the amine and carboxylic acid between two groups.

  Reactivity & Mechanisms

• Acid chlorides:
  The lone pair in the amine acts as a nucleophile reacting with electrophilic carbonyl carbon, so the amine reacts with the carbon and pushes electrons up onto the oxygen in the final step.
  $Cl^-$ or chloride, a leaving group, is a stable anion that gets lost as a byproduct.

Solid Phase Peptide Synthesis Overview

*   Takes advantages of the iterative sequences of amino acids to make multiple amide bonds for each peptide.
*   One reactive component gets tethered a immobilized bead or resin. One of the resin used is Merrifield resin.
*   Resins have chemical linkers that allow you to attach an amino acid.

Advantage: the molecule of interest is immobilized and anything that is an impurity in liquid form can be washed away.

• Process Steps:
  1. Have loaded acid to resin.
  2. Deprotect.
  3. Couple next amino acid to the chain.
  4. Wash off all byproducts and impurities.
  5. Get a growing peptide chain linked a resin bead.
  Discovered by Merrifield, his original paper was initially rejected because of not being able to characterize intermediates.
  6. Bruce would ultimately win the Nobel Prize in 1959.
  Iterative process of coupling deprotection coupling deprotection that a robot can do.

  Solid Phase Peptide Synthesis Applications

• Merrifield synthesized insulin in a few days, with 51 amino acids.
  Necessity that he was discovered, it took him 11 months to make a pentapeptide and was impractical.

• Many drugs today have polyamide backbones (sequences of amino acids).
  Advantage of solid phase; you can perform things that nature can't do.

Graph Over time How we Become Efficient at Making Peptides of Bigger and Bigger Size

• A graph shows that when solid phase hit, it allowed eke into the smallest protein size.

Limitations to this synthesis system exist and we cannot move past that barriet.