Cancer Drug Discovery PM3PY2
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Questions and Answers

What was the primary advantage of Irinotecan compared to CPT?

  • Lower solubility than CPT.
  • Effectiveness against skin cancer.
  • Reduced toxicity. (correct)
  • Increased potency against lung cancer.

    • What is the significance of the 9-Amino and 10,11 methylenedioxy compounds in relation to cancer treatment?

  • They are primarily used in treating skin cancers.
  • They enhance the potency of Taxol.
  • They showed great potency against human colon cancer xenografts. (correct)
  • They are ineffective against human colon cancer.

    • Which of the following statements is true about Topotecan?

  • It is significantly less soluble than CPT.
  • It acts as a prodrug metabolized in vivo to a more potent form. (correct)
  • It is only effective against colorectal cancer.
  • It was approved in 1994 for lung cancer treatment.

    • What was the initial amount of Taxol extracted from the 146 grams of material?

    <p>0.5 grams. (D)</p> Signup and view all the answers

    In what year was Topotecan approved for use in treating metastatic ovarian cancer?

    <p>1996 (A)</p> Signup and view all the answers

    Which plant was identified as a source of Taxol in the NCI screening program?

    <p>Taxus brevifolia. (B)</p> Signup and view all the answers

    How many partitions were used during the isolation process of Taxol?

    <p>400 partitions. (D)</p> Signup and view all the answers

    What was the extraction yield of Taxol from the total amount of material processed?

    <p>0.004%. (A)</p> Signup and view all the answers

    Which alkaloid is marketed as Velban?

    <p>Vinblastine (B)</p> Signup and view all the answers

    What is the primary mechanism through which vinca alkaloids inhibit cell division?

    <p>Preventing spindle formation (A)</p> Signup and view all the answers

    Which of the following cancer types is NOT treated by vincristine?

    <p>Advanced testicular cancer (A)</p> Signup and view all the answers

    What are the primary side effects of vinblastine?

    <p>Hair loss and nausea (D)</p> Signup and view all the answers

    Vinorelbine is a semisynthetic vinca alkaloid primarily used to treat which type of cancer?

    <p>Ovarian cancer (C)</p> Signup and view all the answers

    Which compound is NOT a type of vinca alkaloid?

    <p>Artemisinin (B)</p> Signup and view all the answers

    What structural feature do alkaloids mimicking monosaccharides possess?

    <p>A nitrogen atom in the ring (D)</p> Signup and view all the answers

    Which class is NOT one of the five structural classes of sugar-mimicking alkaloids?

    <p>Tetrazoles (C)</p> Signup and view all the answers

    What is the main advantage of using natural product-based anticancer drugs?

    <p>They often have unique mechanisms of action. (A)</p> Signup and view all the answers

    Which of the following best describes the initial discovery process for camptothecin?

    <p>It required extensive extraction from Camptotheca acuminata. (B)</p> Signup and view all the answers

    What is the effect of the lactone (ester) group in camptothecin?

    <p>It is crucial for the drug's therapeutic efficacy. (D)</p> Signup and view all the answers

    Which of the following is NOT one of the specific examples of natural product-based anticancer drugs mentioned?

    <p>Curcumin (B)</p> Signup and view all the answers

    What is the primary mechanism of action for camptothecin?

    <p>Inhibition of topoisomerase I. (D)</p> Signup and view all the answers

    What significant limitation was associated with the initial testing of camptothecin?

    <p>The long duration of assay result retrieval. (B)</p> Signup and view all the answers

    Which natural product described is known for its treatment of mouse leukemia?

    <p>Camptothecin (D)</p> Signup and view all the answers

    Which of the following substances is a part of the vinca alkaloids?

    <p>Vincristine (A)</p> Signup and view all the answers

    How do alkaloids potentially contribute to cancer treatment?

    <p>By inhibiting glycosidase enzymes related to cancer cell properties. (B)</p> Signup and view all the answers

    What characteristic do cyanogenic glycosides possess when bound to glucose?

    <p>They are non-toxic while bound. (D)</p> Signup and view all the answers

    What occurs upon hydrolysis of cyanogenic glycosides?

    <p>They yield sugar and release toxic HCN. (A)</p> Signup and view all the answers

    What is a potential benefit of using prodrugs in cancer therapy?

    <p>They deliver active agents directly to the tumor site. (A)</p> Signup and view all the answers

    What characteristic of taxol's chemical structure contributes to its complexity and difficulty of synthesis?

    <p>Large number of chiral centers (B)</p> Signup and view all the answers

    What major advantage do natural products offer in drug development?

    <p>They contain complex structures not always found in synthetic alternatives. (B)</p> Signup and view all the answers

    Which statement is true regarding lead compounds from plants for anti-cancer therapies?

    <p>Some lead compounds can be modified to create synthetic drugs. (B)</p> Signup and view all the answers

    Why was taxol's development initially halted in 1971?

    <p>Insufficient concentrations in plants (C)</p> Signup and view all the answers

    What is a significant challenge in developing drugs from natural products?

    <p>The excessive complexity of their structures. (C)</p> Signup and view all the answers

    What specific modification to taxol's structure is crucial for its antitumor activity?

    <p>Ester group at C-13 (C)</p> Signup and view all the answers

    Which mechanism of action for taxol was discovered by Susan Horowitz's group?

    <p>Stabilization of microtubules (D)</p> Signup and view all the answers

    Why are surface carbohydrates significant in tumour cells?

    <p>They confer metastatic properties to tumor cells. (B)</p> Signup and view all the answers

    What was one major reason for the revival of interest in taxol after initial setbacks?

    <p>Evidence of effectiveness in melanoma models (A)</p> Signup and view all the answers

    Which of the following describes the synthesis of taxol in 1994?

    <p>Completed in 26 steps (C)</p> Signup and view all the answers

    What significant development allowed the supply issues of taxol to be addressed?

    <p>Semi-synthesis using abundant metabolites (C)</p> Signup and view all the answers

    Which structural feature of taxol contributes to its classification as a highly functionalized molecule?

    <p>Multiple types of functional groups such as esters and amides (A)</p> Signup and view all the answers

    What is the primary benefit of using a semi-synthetic approach in drug development?

    <p>It reduces reliance on natural resources by utilizing biosynthetic intermediates. (B)</p> Signup and view all the answers

    Why is it difficult and expensive to fully synthesize certain drugs?

    <p>Many drugs contain complex structures that require substantial resources to synthesize. (C)</p> Signup and view all the answers

    How does extracting a biosynthetic intermediate differ from extracting the final product?

    <p>It is usually more fruitful to extract the intermediate than the final complex compound. (D)</p> Signup and view all the answers

    What role does 10-deacetylbaccatin III play in the production of paclitaxel?

    <p>It is a natural compound used to initiate the synthesis of paclitaxel. (C)</p> Signup and view all the answers

    What is a significant drawback of obtaining active components from natural sources?

    <p>The extraction processes can be tedious, time-consuming, and wasteful. (C)</p> Signup and view all the answers

    For which of the following drugs is the semi-synthetic approach not commonly applied?

    <p>Aspirin (A)</p> Signup and view all the answers

    Which of the following statements about the semi-synthetic approach is true?

    <p>It helps in studying structure-activity relationships by allowing analogues to be synthesized. (C)</p> Signup and view all the answers

    What is the environmental impact of extracting taxol from yew trees?

    <p>It leads to deforestation, requiring the cutting down of multiple trees for a single treatment. (D)</p> Signup and view all the answers

    Study Notes

    Course Title and Number

    • PM3PY2 Cancer Drug Discovery and Development

    Lecturer

    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

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    PM3PY2 Cancer Drug Discovery Natural Products PDF

    Description

    This quiz explores the role of plants and natural products in cancer drug development, emphasizing the chemistry involved in the process. It covers key concepts like structure-activity relationships, synthesis methods, and the integration of pharmacy science in medicine design. Prepare to enhance your understanding of strategies for better health outcomes.

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