Approaches to Drug Discovery from Natural Products: Organic Chemistry Study Notes

Abbreviations and Key Terms

Definitions

• NCE (New Chemical Entity): A newly discovered molecule with potential therapeutic effects.

• SCE (Single Chemical Entity): A sample containing only one molecule.

• CCE (Complex Chemical Entity): A sample containing many molecules, usually in one extract.

• NPs (Natural Products): Chemical compounds produced by living organisms, often with medicinal properties.

Critical Factors for Drug Discovery

Key Considerations

• Receptor Activity and Selectivity: Drugs must interact specifically with biological targets.

• Biological Issues: Includes routes of administration, metabolism, and transporter issues.

• Physico-chemical Issues: Ionisation potential (pKa), solubility (log P).

• Lipinski's Rule of 5: Guidelines for drug-likeness:

  • Less than 5 hydrogen bond donors

  • Less than 10 hydrogen bond acceptors

  • Molecular weight less than 500 Da

  • LogP less than 5

• Chemical Issues: Synthesis and stability of the compound.

• Patentability: Ability to protect intellectual property.

Natural Products: Challenges and Exceptions

Comparison Table

Critical Factors (Books)	Natural Products (Reality)
Specific receptor activity and selectivity	Many NPs are 'multitarget' or 'dirty' molecules
Metabolism/transporter issues	Difficult to ascertain if extracts are used (CCE)
Solubility/log P	NPs often defy 'Rule of 5' by providing high MW, poor water solubility
Formulability	Many NPs are impossible to synthesize
Synthesis/stability	Natural molecules cannot be easily patented (need modifications)

Case Studies: Successful Natural Products

Salicylic Acid (Aspirin)

• Source: Salicin from Willow bark

• Properties: Soluble in water and organic solvents, small/simple structure, no chiral centers, easy synthesis

• Indications: Pain, fever, prevention of cardiovascular diseases and colon cancer

• Mechanism: COX-1 inhibition

• Equation: $\text{Salicin} \rightarrow \text{Salicylic Acid} \rightarrow \text{Aspirin}$

Taxol (Paclitaxel)

• Source: Yew bark

• Properties: Complex structure, many chiral centers, difficult synthesis, low natural yield

• Indications: Ovarian, breast, lung, and pancreatic cancer

• Mechanism: Tubulin stabilization

Strategies for Natural Product Discovery

Modern and Classic Approaches

• High Throughput Screening (HTS): Automated testing of large chemical libraries

• Ethnopharmacology: Using traditional knowledge to identify bioactive compounds

• Observation of Toxic Effects: Studying poisons for therapeutic potential

• Observation of Beneficial Food Effects: Linking diet to health outcomes

• Chemoinformatics and AI: Computational prediction of bioactivity

• Serendipity: Accidental discoveries

Main Steps of Modern Drug Discovery from Natural Products

Workflow

1. Select part of the plant, microbe, fungi, or animal

2. Extract using appropriate solvents

3. Fractionate the extract

4. Test each fraction in a bioassay

5. Further fractionate for maximum effect

6. Identify composition using spectroscopy (UV, IR, NMR, MS) and chromatography

Example: Discovery of Taxol

Process Overview

1. Screening: 650 plant extracts tested for activity against cancer cells; Yew bark identified as a hit

2. Bio-directed Isolation: Extraction and fractionation using ethanol and chromatography

3. Yield: 0.5 g active compound from 12 kg bark (0.004% yield)

4. Structure Elucidation:

   • UV spectroscopy

   • IR spectroscopy

   • Elemental analysis

   • Mass spectrometry

   • NMR spectroscopy

   • X-ray diffraction

Analytical Techniques in Natural Product Chemistry

NMR Spectroscopy

• Application: Identifies aromatic and aliphatic regions, functional groups, and molecular structure

• Example: $\text{Chemical shift (\delta)}$ values indicate environment of protons in Taxol

Modern Screening of Chemical Libraries

Key Points

• Chemical libraries contain thousands to millions of samples (SCE or CCE)

• Samples are barcoded and screened by robots using bioassays

• Robotic chromatography systems (2D column chromatography) accelerate purification

How to Make a Chemical Library with Natural Products

Steps

1. Collection (wild plants) or harvest (domesticated plants)

2. Select part of the plant

3. Extract

4. Fractionate

5. Store fractions for future screening

Classic Ethnopharmacological Drug Discovery

Quinine from Jesuit's Tree

• Source: Bark of Cinchona tree

• Application: First drug for malaria; also used in tonic water

• Derivatives: Chloroquine and others synthesized for improved efficacy

Classic Observation of Toxic Effects

Medicines from Animals

• Example: Bothrops jararaca snake venom induces hypotension

• Teprotide: Peptide from venom, not orally active due to hydrolysis in stomach

• Captopril: Synthetic drug resembling teprotide, used for hypertension

Gel Filtration Chromatography

• Separates peptides based on size, not polarity

• No molecular forces between molecules and stationary phase

• Small molecules retained in gel pores; large molecules excluded

Classic Observation of Physiological Effects of Food Components

Case Studies

• ALD and Lorenzo's oil

• Hypertension and milk

• Diabetes and chlorophylls, coffee, and others

• Garlic and leukaemia

• Physalins and cancer

References and Further Reading

• Gray, Alexander I. et al. Natural Products Isolation in Modern Drug Discovery Programs.

• Heinrich M. et al. Fundamentals of Pharmacognosy and Phytotherapy.

• Wall ME, Wani MC. Camptothecin and taxol: Discovery and chemistry.

• Videos: Drug development at Roche, The Yew Tree, Medicines from the Ocean.

Additional info:

• Some slides include independent learning prompts and reference materials for further study.

• Tables and diagrams have been described and recreated in text and HTML format for clarity.