Organic Chemistry in Medicine

Organic Chemistry in Medicine: Making Drugs

Background: Medicinal Chemistry and Drug Pricing

  • Martin Shkreli (Pharma Bro):
    • Former CEO of Turing Pharmaceuticals. Acquired exclusive rights to Daraprim in the US around ten years ago.
    • Daraprim: An anti-malarial and anti-parasitic drug used to treat toxoplasmosis (parasitic infection often acquired from cats).
    • Price hike: Increased the price from $13.50 per pill to over $700 per pill.
  • Daraprim:
    • Small molecule drug with an aromatic ring and nitrogens (heteroaromatic).
    • Discovered in 1952, in medical use in 1953.
    • On the World Health Organization's list of essential medicines.
    • Cost: 5-20 US cents per dose in most of the world.
    • Post-Shkreli price hike: $75,000 for a course of treatment in the US.
  • Synthesis by Students:
    • In 2016, a group of students from Sydney Grammar synthesized Daraprim for $20 USD.
    • Produced 3.7 grams of the molecule.
  • Shkreli's Downfall:
    • Sentenced to seven years in prison for defrauding investors, not directly for the price hike.
    • Ordered to pay $64,600,000 for an illegal scheme to monopolize the life-saving drug.
  • The Price of Drugs:
    • Raises the question of the true cost of drug development and production.

The Cost of New Drugs

  • Estimates:
    • 2004: "The $800,000,000 Pill" - Estimated cost of drug development.
    • 2014: CNN article put the value at $2,500,000,000.
    • Current estimates hover around $2,500,000,000.
  • Reasons for High Cost:
    • Lengthy process with no guarantee of success.
    • Costs account for the failure rate of drug molecules in clinical trials.
Stages of Drug Development
  • Preclinical Phase:
    • Scientists discover and innovate new chemical entities.
    • Focus on molecules with promising activity against a target or disease.
    • Limited knowledge about safety, toxicity, and pharmacokinetics (fate of the drug in the body).
    • Synthetic chemistry plays a key role in molecule discovery.
  • Clinical Trials
    • Aimed to determine safety and efficacy in humans
    • Phase One:
      • Involves healthy volunteers.
      • Determines safety and dosing; looks at the safety window of the drug.
      • Compounds may fail if they have intolerable adverse effects.
    • Phase Two:
      • Small numbers of patients with the target disease.
      • Initial reading of efficacy and further exploration of safety.
      • Double-blind study: patients receive either a placebo or the active therapeutic.
      • A common failure point for drugs.
    • Phase Three:
      • Large trials involving thousands of patients.
      • Further determines safety and efficacy.
Costs and Success Rates
  • Cost Distribution:
    • Clinical and preclinical phases are both costly, approximately $1 billion each.
    • The cost has increased, potentially exponentially, over time.
  • Success Rate:
    • Low success rates are a key factor driving high costs.
    • Example: Starting with 10,000 candidate molecules:
    • 10,000 initial candidate molecules
    • 250250 show promise in the biological model
    • 1010 qualify for tests on humans (phase one trial)
    • 20%20\% of drugs that start phase one are approved
    • 10,000→250→10→210,000 \rightarrow 250 \rightarrow 10 \rightarrow 2 (0.02% success rate).
    • Around 26 new chemical entities enter the market each year.

Sources of Medicinal Agents

  • Top Pharmaceuticals Over Time:
    • Analysis of top pharmaceutical products reveals trends in drug types.
      • The list of top 5 pharmaceuticals is dynamic changing every year. The changes reflect pop culture and political events around the globe.
    • 2012: Mostly small molecules.
    • 2022: Inclusion of COVID vaccines and antibodies (for immunology and cancer treatment).
      • Antibody-drug conjugates emerge as another class of therapeutics.
      • The COVID vaccines were developed extremely fast compared to the typical 10-15 year development time.
    • 2023: COVID vaccines decrease in market share.
      • Ozempic gains popularity as a weight loss drug (semaglutide, a modified peptide hormone).
Natural Products
  • Natural Products as Sources:
    • Natural products (from plants, animals, etc.) are a valuable source of medicinal agents.
    • Earliest therapies (e.g., opium from poppy seeds) were natural products.
    • Chemical synthesis tools now allow modification and diversification of natural product scaffolds.
    • Semaglutide (Ozempic) is an example where chemical modifications enhanced the therapeutic viability of a natural peptide hormone.
Types of Medicinal Agents
  • Small Molecules:
    • Aspirin (acetylsalicylic acid) as an example.
  • Proteins:
    • Erythropoietin (EPO), used to enhance red blood cell count; infamously used for doping in sports.
    • Molecular weight measured in Daltons (grams per mole).
  • Peptides:
    • Intermediate in size between proteins and small molecules.
    • Composed of amino acids and have protein-like structural features.
    • Can be more specific in target binding, reducing side effects.
    • Cheaper to produce than larger proteins.
    • Example: Semaglutide (Ozempic).

Peptide Chemistry

  • Peptides with a Bad Rap:
    • Concerns about non-validated growth hormone releasing peptides being used for muscle development.
    • Risk due to lack of clinical validation and guarantee of safety/purity.
Insulin
  • Insulin as a Peptide Success Story:
    • Isolated in 1922, a major advancement over using ground-up ox pancreas.
    • Primary structure determined by Frederick Sanger (Nobel Prize, 1958).
    • 3D structure determined by Dorothy Hodgkin (X-ray crystallography).
    • Complex structure with two chains of amino acids (A and B) linked by disulfide bonds.
    • Topologically complex compared to small molecules.

Peptide Assembly: Amino Acids and Amide Bonds

  • Amino Acids:
    • Contain an amine and a carboxylic acid group.
    • Have a stereogenic center (alpha chirality).
    • R group makes each amino acid unique.
    • Can be denoted by L or D (antiquated Fischer projection system) rather than R or S.
  • L and D Amino Acids:
    • L amino acids are generally naturally incorporated into proteins by ribosomes.
    • D amino acids can be present in natural products via enzymatic modification.
    • For purposes, best to assign as R and S, but note that historically L and D are also important.
  • Amino Acid Diversity:
    • Variable at the R group, leading to a diverse set of side chains (aliphatic, aromatic, acidic, amines, alcohols, etc.).
    • Requires highly specific chemical reactions when doing chemistry on peptides or proteins.
  • Essential Amino Acids:
    • Cannot be made by the body and must be consumed in the diet.
    • Essential amino acids are important for building muscle and protein; often found in supplements.
  • Tryptophan Highlight:
    • Aromatic amino acid, allegedly high in turkey, precursor to melatonin and serotonin.

Amide Bond Formation

  • Condensation Reaction: Joining of a carboxylic acid and an amine, losing water.
  • Protecting groups mask specific groups. Amino acids are protected on nitrogen and carboxylic acids using a terbutyl group, facilitating bond formation.
  • Activation of Carboxylic Acid:
    • The activation does not happen spontaneously and is facilitated by using an acid chloride.
Mechanism of Amide Bond Formation Using Acid Chloride
  • Acid Chlorides as Electrophiles:
    • Chlorine is electronegative, inducing a dipole around the central carbon.
  • Mechanism:
    • Amine lone pair acts as nucleophile, attacking the electrophilic carbonyl carbon.
    • Carbonyl double bond breaks, electrons pushed to oxygen.
    • Base deprotonates the nitrogen.
    • Lone pair on oxygen reforms carbonyl, chloride leaves as leaving group.

Solid Phase Peptide Synthesis

  • Solid Phase Synthesis:

    • An efficient iterative method using immobilized amino acids tethered to a bead or resin
    • Polystyrene resin with chemical linkers (e.g., Merrifield resin with benzyl chloride group).
    • Reactions carried out and impurities can be washed away due to the immobilisation of the amino acids on the bead.
    • Discovered by Bruce Merrifield in 1959.

  • Process:

    • Load amino acid onto the resin, protect reactive groups.
    • Deprotect to generate a free amine.
    • Couple the next amino acid.
    • Wash off byproducts and impurities.
    • Repeating this process allows the growing peptide chain tethered to that resin bead.

  • Advantages:

    • Efficient purification (impurities washed away).
    • Can be automated.

  • Peptide Chain Elongation

    • You can then deprotect and keep adding amino acids to elongate the peptide chain.
    • This creates a growing chain of amino acids connected by amide bonds on the bead so that you can keep adding over and over again.

  • Characterization: The original idea had limited community support because you weren't able to characterize the individual intermediate phases.

    • It's now the most efficient method used for synthesis.
      • One can put the peptide in a machine and have a robot do the process.
      • Easy reactions and filtrations in sequence.

  • Applications now include:

    • The use of automated peptide machines.
    • Merrifield synthesized insulin in a few days.

  • Examples of marketed therapeutics: Contain polyamide backbones and the technology is so beautiful because molecules that have these characteristics contain unlimited flexibility to couple, deprotect and extend the peptide by incorporating what wasn't originally in the natural products.

  • Graph of Progress:

    • Chart of efficiency in peptide creation over time.
    • Emil Fisher made the dipeptide, plateaued until CBZ groups.
    • Got slightly better in solutions.
    • During the 1960's when solid phase synthesis was hit, one was able to get into the smallest proteins in order to make what looks like insulin.
    • Key Question: There are limitations with current solid phase system that we will discuss.