Chemistry of Nitrogen Mustards
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Questions and Answers

The electrophilicity of nitrogen mustards is related to their ability to form?

  • Covalent bond
  • Chloride anion
  • Aziridinium cation (correct)
  • Ammonium cation
  • What is an orally administered alkylating agent?

    Temozolomide

    The following structure modification leads to?

  • COOH group improves stability
  • One of the fast-acting & least toxic N mustards
  • Improve selectivity and decrease cytotoxicity (correct)
  • Replacement of CH3 with phenyl group improves reactivity
  • This reaction shows?

    <p>Metabolism of an alkylating agent</p> Signup and view all the answers

    Which chemical motif is responsible for oral bioavailability?

    <p>Unknown</p> Signup and view all the answers

    Which chemical motif is responsible for targeting effect?

    <p>Unknown</p> Signup and view all the answers

    Which structure is the main alkylator of DNA?

    <p>Unknown</p> Signup and view all the answers

    This reaction results in?

    <p>Activation of cyclophosphamide and formation of toxic acrolein</p> Signup and view all the answers

    This structural modification leads to?

    <p>Improve stability</p> Signup and view all the answers

    This compound can cross the BBB and is used orally for treatment of brain tumors.

    <p>Temozolomide</p> Signup and view all the answers

    Which chemical compounds are used as prophylactic against toxicity of acrolein?

    <p>A &amp; C</p> Signup and view all the answers

    Comparing structure, A and B, which one is designed to have less affinity to CYP?

    <p>Unknown</p> Signup and view all the answers

    Which structure corresponds to a chemoprotectant compound used in combination with cis-platinum complexes?

    <p>Unknown</p> Signup and view all the answers

    Which of these is not a reversible proteasome inhibitor?

    <p>Option 2</p> Signup and view all the answers

    In the body, via a sequence of reactions, capecitabine is converted into which molecule (drug)?

    <p>5-fluorouracil</p> Signup and view all the answers

    The fluorine on fludarabine phosphate confers what type of activity (or property)?

    <p>Resistance to deaminase</p> Signup and view all the answers

    Which enzyme will very effectively phosphorylate this drug - Gemcitabine?

    <p>Deoxycytidine kinase</p> Signup and view all the answers

    This is the activated form of fluorouracil – which enzyme does it inhibit?

    <p>Thymidylate Synthase</p> Signup and view all the answers

    What is the active form of the prodrug cyclophosphamide?

    <p>4-hydroxycyclophosphamide</p> Signup and view all the answers

    Which enzyme is responsible for the first activation step of gemcitabine?

    <p>Deoxycytidine kinase</p> Signup and view all the answers

    This reaction is carried out by which enzyme?

    <p>Thymidylate Synthase</p> Signup and view all the answers

    Pemetrexed has been used in several cancers beyond the leukemia/lymphoma types. Which enzyme does it preferentially inhibit?

    <p>Thymidylate Synthase</p> Signup and view all the answers

    Nitrogen mustards react with DNA through the formation of which reactive intermediate?

    <p>Aziridinium ion</p> Signup and view all the answers

    This drug better resembles which form of folic acid?

    <p>Dihydrofolate</p> Signup and view all the answers

    Most modifications of the folic acid structure to make antifolates are made on which part of the molecule?

    <p>Pteridine ring</p> Signup and view all the answers

    Which of the following drugs is less prone to activation?

    <p>Drug C</p> Signup and view all the answers

    Fluorouracil (when converted to active drug) could be very effective at inhibiting thymidylate synthase if combined with which of the following drugs?

    <p>Drug B</p> Signup and view all the answers

    Which of these drugs will cause more extensive & less repairable DNA damage?

    <p>Drug A</p> Signup and view all the answers

    Carboplatin is a platinum analog that has which of the properties below when compared to cis-platin?

    <p>10-fold slower</p> Signup and view all the answers

    For which enzyme will this drug be more selective?

    <p>Thymidylate Synthase</p> Signup and view all the answers

    The presence of the fluoride on fludarabine led to?

    <p>Decreased deamination to inactivate the drug</p> Signup and view all the answers

    Which one of the following is the reactive species generated from temozolomide?

    <p>Methyldiazonium ion</p> Signup and view all the answers

    For mercaptopurine patients, genotype must be determined to avoid myelosuppression, which could result from low or deficiency of the following enzyme?

    <p>Thiopurine-S-methyl transferase</p> Signup and view all the answers

    Pemetrexed is a folate analog that shows what type of affinity to folyl polyglutamate synthesis as compared to Methotrexate?

    <p>Higher</p> Signup and view all the answers

    Which is true of crosslinking agents?

    <p>It only takes one cross-link to damage the DNA and prevent a cell from dividing.</p> Signup and view all the answers

    Study Notes

    Electrophilicity of Nitrogen Mustards

    • Electrophilicity is linked to the formation of Aziridinium cation.
    • Useful as alkylating agents due to their reactivity.

    Orally Administered Alkylating Agents

    • Certain agents can be administered orally, facilitating patient compliance.

    Structure Modifications

    • COOH group enhances stability of compounds.
    • Modifications can increase selectivity and decrease cytotoxicity.
    • Substituting CH3 with phenyl increases reactivity in nitrogen mustards.
    • Some structural changes can result in fast-acting and low-toxicity compounds.

    Reactions and Metabolism

    • Reactions can deactivate alkylating agents or modify them to improve stability.
    • The metabolism of alkylating agents is crucial for therapeutic effect.

    Chemical Motifs

    • Certain chemical structures contribute to oral bioavailability, targeting effect, and specific reactivity towards DNA.

    Key Alkylators

    • Specific structures are identified as main alkylators of DNA, critical for inhibiting cell division and overcoming cancer.

    Cyclophosphamide

    • Activation leads to toxic acrolein, which poses further health risks.
    • Deactivation pathways can also yield toxic products.

    Structural Modifications

    • Alterations in structure can result in loss of activity or improved stability.
    • Some modifications slow down metabolism, enhancing drug efficacy.

    Brain Tumor Treatment

    • Compounds capable of crossing the Blood-Brain Barrier (BBB) are utilized for treating brain tumors.

    Prophylactic Compounds

    • Certain chemical compounds serve as prophylactic agents against toxic effects, like those from acrolein.

    CYP Affinity

    • Comparison between structures can reveal which compounds are designed for reduced affinity to Cytochrome P450 enzymes.

    Chemoprotectants

    • Structure identification is essential for compounds used in conjunction with cis-platinum complexes for cancer treatment.

    Proteasome Inhibitors

    • Distinguishing between reversible and non-reversible proteasome inhibitors is key in targeting cancer.

    Capecitabine Metabolism

    • Converted to active drug through a sequence of reactions, critical for therapeutic applications.

    Fludarabine Phosphate Activity

    • The presence of fluorine confers resistance to deaminases, enhancing drug longevity and effectiveness.

    Gemcitabine Activation

    • Deoxycytidine kinase phosphorylates Gemcitabine effectively, enhancing its action against tumors.

    Thymidylate Synthase Inhibition

    • Active form of fluorouracil inhibits thymidylate synthase, a key enzyme in DNA synthesis.

    Nitrogen Mustards Reactivity

    • These compounds generate reactive intermediates that interact with DNA, leading to crosslinking.

    Folate Analog Modifications

    • Most modifications to create antifolates occur on specific parts of the folic acid structure for optimal activity.

    Enzyme Affinities

    • Understanding enzyme selectivity helps in designing effective therapeutics with reduced side effects.

    Temozolomide's Reactive Species

    • Identifying the reactive species from temozolomide is crucial for understanding its mode of action.

    Mercaptopurine Genotyping

    • Patients may require genotyping to prevent myelosuppression due to enzyme deficiencies.

    Pemetrexed Affinity

    • Pemetrexed shows higher affinity for folyl polyglutamate synthesis compared to Methotrexate, positioning it for enhanced therapeutic use.

    Crosslinking Agents

    • Just one cross-link can significantly damage DNA, inhibiting cell proliferation and establishing a therapeutic window for cancer treatment.

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    Description

    Test your knowledge on the electrophilicity of nitrogen mustards and their structural modifications. This quiz covers the effects of various groups on stability, selectivity, and reactivity of these alkylating agents. Perfect for students studying medicinal chemistry or pharmacology.

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