Medicinal Plants & Natural Drug Molecules Notes

The same molecule can be a toxin or a medicine depending on the dosage.
Digoxin (from foxglove leaves):
- Cardiac glycoside (terpenoid).
- High dose: vomiting, cardiac arrest, death.
- Low dose: treats congestive heart failure (CHF) and related edema.
- Plant source: Digitalis purpurea.
Morphine (from opium poppy capsule latex):
- Alkaloid (nitrogenous compound).
- Highly addictive; caused the Opium Wars.
- Overdose: respiratory failure, death.
- Central nervous system depressant for severe pain relief.
- Plant source: Papaver somniferum.

Fossil records:
- Evidence of use by Neanderthals (50,000 years ago.)
- Neanderthals used early versions of penicillin and aspirin.
- Evidence found by examining plaque on Neanderthal teeth.
Written documents:
- Sumerian clay tablet (4,000 years old).
- Papyrus Ebers (ancient Egyptian medicine).
- 本草綱目 (Bencao Gangmu) - a comprehensive traditional Chinese medicine book.

Still used by 60% of the world population.
Examples of herbal medicine ingredients: 木이버섯, 모과, 살구씨, 팔각, 치자, 오가지, 오미자, 구기자, 산수유, 맥문동, 감국, 햇녹차, 녹차, 홍화이트, 홍화씨, 헛개열매, 헛개나무, 장미차, 잔대, 유근피, 치커리, 봉일, 익모초, 인진쑥, 둥

Accounts for >40% of China's pharmaceutical market.
Annual turnover is >190 billion yuan.
Governmental funding aims to:
- Facilitate TCM inheritance & innovation.
- Promote TCM internationalization.
- Modernize & standardize TCM by identifying bioactive compounds.

Produce physiological effects in living cells & tissues.
Many are secondary metabolites produced under stress, including:
- Terpenoids.
- Phenolics.
- Nitrogenous compounds (alkaloids).

Types of Stress:
- Chemical.
- Physical.
- Climatic (warming, UV radiation, drought).
Effects of Stress
- Photosynthetic tissues induce PSMS biosynthesis.
- PSMS react with PSMS.
- Increased PSMS, decreased VOCs, high C/N ratio.
Volatile Terpenoids (Isoprene, MT, SQT):
- Increase in production: Drought, UV, Warming
Phenolics (Tannins, Phenolic acids, Flavonoids):
- Increase in production: UV
Resin Acids
- Increase in production: Warming
Salicylates
- Increase in production: Warming

An alkaloid isolated from bark of fever tree in 1820.
Antimalarial effect of bark powder discovered by a Spanish Jesuit priest in Peru in the 17th century.
Source: Cinchona sp.
Mechanism: Kills Plasmodium in bloodstream & prevents infection of red blood cells.
Tonic water:
- Soda & sugar mask bitter taste of quinine.
- Effective but with side effects (blurred vision, nausea).
- Quinine level later reduced in soft drinks.
Production:
- Total synthesis is cost-ineffective.
- Extraction from fever tree bark is primary source, but high demand causes deforestation.

A terpenoid from leaves of sweet wormwood.
Kills Plasmodium effectively with fewer side effects.
Also shows anti-inflammatory & anti-cancer effects.
Source: Artemisia annua.
Rapid response but short-acting.
Needs prolonged therapy to reduce recurrence.
Monotherapy may lead to drug resistance.
Artemisinin-based Combination Therapy (ACT):
- Completes clearance of Plasmodium.
- Hinders development of resistance.
- Artemisinin + a long-acting antimalarial drug.
Production:
- Extraction:
  - Inconsistent natural harvest.
  - Long lead time (~15 months) from cultivation.
  - Low yield (0.01 – 0.8%).
- Total synthesis:
  - Short lead time, but low yield & high cost.
  - Scheme 1. First total synthesis of artemisinin by Schmid and Hofheinz.
- Semi-synthesis:
  - Pathway is known.
  - Medium lead time.
  - High cost.
  - Uses Saccharomyces cerevisiae Fermentation + Photochemistry.
- Biosynthesis:
  - Higher yield.
  - Under development.
  - Transgenic plant, Hairy roots, Transformed callus, Transgenic cell suspension culture.

Malignant tumor with abnormal cell growth & potentials to spread to other parts.
Process:
- Normal skin cells transforming into a tumor.
- Tumor growing and invading underlying tissues.
- Cancer cells invading blood vessels.
- Cancer cell traveling to other parts of the body.

Caused by genetic mutation:
- Hyperactive oncogenes.
- Inactive tumor suppressor genes.
- Inactive DNA repair genes.
Effects of mutation:
- Reprogram metabolism.
- Secrete TGF-B.
- Produce own growth factors (Bombesin-like peptides).
- Sustained proliferation signalling.
- Evade destruction by immune cells.
- Uncontrolled replication.
- Angiogenesis (↑ VEGFR-A): Endothelial cell migration & proliferation.
- Resistance to cell death.
- Metastasis & invasion: Alter cell morphology & adherence.

One of the first plant-derived anticancer agents.
An alkaloid from leaves of Madagascar periwinkle.
Antimitosis by preventing microtubule formation.
Source: Catharanthus roseus.
Production:
- Very low yield (<0.0003%) from extraction.
- Possible total synthesis & biosynthesis to increase yield.
- Mainly by semi-synthesis from 2 natural precursors with higher yield, using coupling and oxidation.

Search for plant biosynthesis genes
- Madagascar periwinkle (Catharanthus roseus), Happy tree (Camptotheca acuminata), Pacific yew (Taxus brevifolia), Mayapple (Podophyllum peltatum), Opium poppy (Papaver somniferum), Hemp (Cannabis sativa)
Enzyme function validation
Systems biology - Synthetic biology - Metabolic engineering
Transfer in a microbial model
- DNA assembly
- Genetic transformation
Improvement of the metabolic flux
- Enzyme engineering
- Balancing co-factors
Optimization of the fermentation strategy
- Media optimization
- Co-culture
Semisynthesis is an option if high enough precursors are available.

Extraction:
- Growth rate.
- Bioactive compound concentration.
Total synthesis:
- Chirality (R vs S):
  - Chiral molecule with non-superposable mirror image.

Semi-synthesis:
- Suitable precursor.
Biosynthesis:
- Optimal conditions.
- Potential contamination.
Other considerations:
- Usage & demand.
- Chemical complexity.
- Cost effectiveness.