Cancer Drug Discovery PM3PY2

Course Title and Number

• PM3PY2 Cancer Drug Discovery and Development

Lecturer

• Professor Helen Osborn
• Email: [email protected]

Aims of Lectures

• To illustrate the importance of plants and natural products in cancer drug discovery
• To explain how pre-existing chemistry knowledge is used in drug development from natural products (functional group chemistry, prodrugs, semi-synthesis, structure-activity relationships, total synthesis)
• To highlight the advantages and disadvantages of natural products in drug discovery
• To integrate knowledge from other modules (Part 1 and 2)
• To demonstrate the application of pharmacy science in medicine design
• To identify strategies to contribute to research and development for better health outcomes
• To explain how to communicate with patients about their prescribed treatments

Introduction

• Cancer remains a significant global health concern with growing incidence
• There is an urgent need for new cancer therapies with limited side effects.
• Plants produce diverse bioactive compounds, potentially providing a source of novel cancer-fighting agents.

Plants as Sources of Anticancer Drugs

• Plants have historically been a valuable source of anticancer drugs.
• The National Cancer Institute (NCI) conducted substantial research on natural anticancer agents from the 1960s to the 1980s, screening thousands of plant extracts.
• NCI continues free compound library screening. Screening of 114,000 extracts from 35,000 species was conducted covering multiple tumor types between 1960 and 1982.

Examples of Natural Product-Based Anticancer Drugs

• Vinblastine (Velban)
• Vincristine (Oncovin)
• Etoposide
• Teniposide
• Taxol (Paclitaxel)
• Navelbine (Vinorelbine)
• Taxotere (Docetaxel)
• Topotecan (Hycamtin)
• Irinotecan (Camptostar)

Specific Examples to Be Discussed

• Camptothecin
• Taxol
• Podophyllotoxin
• Vinca alkaloids
• Alkaloids
• Cyanogenic alkaloids

Challenges and Advantages of Natural Product-Based Drug Development

• Challenges:
  • Complexity of natural product structures and isolation processes
  • Limited quantities of active compounds
  • Potential for toxicity
• Advantages:
  • Potential for novel drug targets
  • Rich source of lead compounds
  • Potential for optimization and improved pharmacokinetics
  • Potential for semi-synthesis to overcome availability issues

Camptothecin

• In 1957, the Cancer Chemotherapy National Center (US) screened 1000 ethanolic plant extracts and found high activity in an extract of Camptotheca acuminata.
• 20Kg of wood and bark were collected and extracted, resulting in a compound that was active in a mouse leukemia life-prolongation assay.
• Isolation involved a slow, laborious process (3 months for assay results, compared to 12 hours today).
• Key component isolated is Camptothecin, a highly unsaturated α-hydroxylactone (ester).

Camptothecin: Mechanism of Action

• Camptothecin inhibits topoisomerase I (an enzyme involved in DNA replication and repair)

New Derivatives of Camptothecin

• Irinotecan (1994): reduced toxicity of camptothecin, and used for metastatic colorectal cancer
• Topotecan (1996): effective for metastatic ovarian cancers.

Taxol

• Isolated from the Pacific Yew ( Taxus brevifolia) in the 1960s.
• Initial isolation was challenging and inefficient; very little Taxol was found per kg of yew tree.
• Using extraction and partitioning of solvents, a very small amount was found: 0.5g isolated from 12 kilograms of yew bark.
• Key components are extracted through plant material and separated into aqueous and chloroform solutions.
• Taxol's structure has been elucidated (presence of hydroxyl groups).
• Taxol inhibits mitosis and stabilizes microtubules, preventing depolymerization.

Taxol- Nearly Lost!

• Initial interest in taxol waned after the publication of its structure and early isolation difficulties.
• Renewed interest triggered by the discovery of taxol's unique mode of action in inhibiting mitosis, stabilizing microtubules and inhibiting depolymerization.

Taxol Reprived!

• Taxol's unique structure and mechanism of action made it a desirable development candidate
• Subsequent semi-synthetic production of taxol derivatives like Taxotere and Docetaxel led to more accessible and better pharmaceutical properties and solutions
• Further development, focusing on semi-synthesis reduced reliance on the plant resource.

Semi-Synthetic Approach

• Using biosynthetic intermediates as starting materials rather than the final compound leads to increased efficiency in isolation and synthesis
• This avoids the need to harvest the complete product
• Efficient conversion of biosynthetic intermediates into the final compound through chemical synthesis

Advantages of Semi-Synthesis

• Higher yield for the intermediate compared with the final product
• Easier synthesis of analogues, which can aid in probing relationships between structure and activity (SAR).
• Optimization for pharmacokinetics (solubility, bioavailability, etc.)
• Example: Semi-synthetic taxanes are better suited for oral administration compared to taxol and have better pharmacological properties for drug resistant cancers

Total Chemical Synthesis

• Total chemical synthesis involves assembling the final compound from simpler chemical building blocks.
• Although potentially useful to create multiple derivatives across a range of structures, scaling-up synthesis is challenging

Podophyllum

• Podophyllum peltatum (commonly known as May-apple) contains podophyllin, a resinous extract
• Traditionally used topically to treat skin cancers
• Podophyllin is highly irritant and cannot be administered systemically
• Major component of podophyilln is podophyllotoxin

Isolation of Active Compounds

• Initial mixture of podophyllum yielded low but measurable amounts of podophyllotoxin
• Methods improved, allowing isolated quantity increase to 2g
• Further modifications to methods reduced impurity of final product

Semi-Synthetic Analogues of Podophyllotoxin

• Modifications of podophyllotoxin gave etoposide and tenoposide, dramatically increasing potency
• These are effective treatments for small cell lung cancer

Madagascar Periwinkle

• Catharanthus roseus is native to Madagascar and now cultivated widely
• Produces the important anti-cancer alkaloids vincristine and vinblastine

Structures of Vinca Alkaloids

• Vincristine and vinblastine are structurally complex and difficult to synthesise, hence semi-synthesis of the alkaloids
• Both inhibit mitosis
• They work by binding to tubulin to prevent spindle formation required to divide chromosomes

Therapeutic Uses of the Vinca Alkaloids

• Vinblastine: widely used for treating various cancers, with side effects including hair loss and myelosuppression
• Vincristine (Oncovin) effective against multiple cancers
• Vinorelbine is a more potent alternative with a wider use case and combination possibilities

Alkaloids

• Alkaloids can mimic carbohydrate structures
• These structures are prevalent amongst a diverse range of microorganisms
• Several structural classifications of alkaloids occur in diverse plants

Natural Cyanohydrins and Cyanogenic Glycosides

• Natural cyanohydrin structures occur in plants as constituents like bitter almonds and cassava as well as the glycoside
• In plants this chemical structure is coupled to a sugar molecule, producing a non-toxic cyanogenic glycoside
• Hydrolysis of the glycoside produces hydrocyanic acid (HCN)

Mode of Action and Prodrug Development

• Cyanogenic glycosides are converted to hydrocyanic acid by hydrolysis and are potentially toxic
• Prodrugs are designed to deliver the cyanogenic glycoside to cancer cells where it can be converted to HCN

Conclusions

• Plants are a significant source of lead compounds for anticancer therapies.
• Semi-synthetic approaches can increase production quantity and efficiency over total synthesis
• The diversity of plant compounds and novel extraction methods offers great potential for future discovery