Chem Basis: Steroids 4

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kyleannkelsey
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268525
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Chem Basis: Steroids 4
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2014-03-30 20:48:17
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Chem Basis Steroids
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Chem Basis: Steroids 4
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Chem Basis: Steroids 4
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  1. What type of substitution at C9 and C6 will enhance gluco and mineralo corticoid activity?
    Alpha Halogens (like F)

  2.  Substitution at this point has what effect on the molecule?
    Tends to decrease mineralo activity

  3. What are the significant characteristics of this group?
    • Site of metabolism
    • Protection can be achieved by creating an ester

  4. What groups are accommodated at this point?
    OH or F are required for Mineralo and Gluco acitivty

  5. This group is significant for what reasons?
    • Required for gluco activity
    • Can be metabolized reversibly to a weakly active ketone

  6.  What is the significance of this group?
    • Methyl protects against inactivating metabolism
    • Provides steric hindrance to A ring reduction to a 5B-H, 3a-OH metabolite
    • 70% reduction in this reaction
    • Enhanced receptor affinity leading to 10x increase in GC activity and string MC activity

  7.  What is the significance of the 3-keto and delta 4,5?
    Essential for Gluco and Mineralo activity

  8. What is the significance of this additional double bond between 1 and 2?
    • Extends the resonance
    • Stabilizes the A ring
    • Electronically inhibits A ring reduction
    • Additional sp2 carbons flatten the A ring for 3-5x GC activity enhancement
    • Reduces MC activity by 0.6-0.8x

  9. A Delta 1, 4, 6 compound, has what characteristics beyond a delta 1, 4 compound?
    • Extended resonance into the B ring
    • Increases GC activity

  10. A halogen at this location (9a) would have what effect on the molecule and through what mechanism?
    • Enhanced GC activity by e- withdraw on the 11B-OH, increasing the –OH’s affinity for H bonding to the receptor
    • Electronic pull decreased Oxidation of 11B-OH by 67%
    • F at this position would enhance MC activity

  11.  When would you see an F at this position and when would you see a Cl?
    • Cl would be for topical only due to enhanced lipophilicty over F
    • F would be used for enhanced GC or MC activity

  12. How can you enhance Mineralocorticoid activity?
    • Add a 9a-F or a 12a-F
    • Increased 300-800 fold with these adjustments and no MC abolishing groups

  13. Would a 9 beta or 12 beta Flourine enhance mineralcorticoid activity?
    No, need to be alpha, because MC receptor interactions are with the alpha face
  14. Functional groups at what positions are used to abolish MC activity at therapeutic doses?
    • C6 and C16

  15. What effect does a 16a-OH have on this molecule?
    • Abolishes MC activity
    • Decreases glucocorticoid affinity
    • Slows oxidation to the inactive 17-keto steroid by 70%
    • The two effects above = Glucocorticoid activity increases due to a 2-fold increase in DOA
    • Lipophilic pocket on GC receptor repels this group

  16. What effect does a 16a or 16B-CH3 have on this molecule?
    • Abolishes MC activity
    • Lipophilic pocket on the GC receptor accepts the C16-CH3 (a or B form) to form a hydrophobic bond
    • Increases GC activity 12x over no C16 substiuent
    • Slows C17 inactivation

  17. How does the GC activity compare between a steroid with a 16a-OH and one with a 16-CH3?
    16-CH3 in either a or B form, promotes a 6-fold increase in glucocorticoid activity over the 16a-OH

  18. What effects does a 6a-CH3 group impart?
    • Abolishes MC activity
    • Provides a slight increase in GC activity resultant of an increase in DOA due to steric inhibition of A ring reduction

  19. What effects does a 6B-CH3 group impart?
    • Does not abolish MC activity, slight increase in MC activity
    • Slight Increase in GC activity due to DOA, as a result of steric inhibition of A ring reduction

  20. What effects does a 6a-F group impart?
    2-fold increase in glucocorticoid potency over the 6a-CH3
  21. Order the possible groups at C6 from most to least GC activity enhancing:
    F > Beta CH3 > alpha CH3
  22. Order the possible groups at C6 from most to least MC activity abolishing:
    alpha CH3 > Beta CH3 or F
  23. In what way can you use a topical steroid to treat psoriasis (a disease normally resistant to steroids)?
    Use an occlusive dressing
  24. Topical corticoids are all highly hyro or lipo –philic?
    Lipophilic
  25. What type of structures are particularly common in topical steroids?
    Lipophilic esters, diesters, acetonides, and halogenated molecules (C21)
  26. Can systemic steroids have a C21 halogen?
    No, strictly OH (or ester that is hydrolyzed to and OH)

  27. Mometasone has a furan ring part of the ester at the –C17 α-OH, what effect does this have?
    Enable it to penetrate into the skin and stay there (not penetrate to the systemic circulation)

  28. Amcinonide has a cyclopentane forming the diether of the Hexacetonide, what effect does this have?
    Enable it to penetrate into the skin and stay there (not penetrate to the systemic circulation)

  29. Alcometasone has a unique C7 α-Cl, what effect does this have?
    Enable it to penetrate into the skin and stay there (not penetrate to the systemic circulation)

  30. Fluticasone has a unique C20 fluoro methyl thio ester group, what effect does this have?
    Enable it to penetrate into the skin and stay there (not penetrate to the systemic circulation)
  31. Will topical corticoids be used for GC or MC activity?
    GC only
  32. Functional groups with what type of activity will usually be found on topical corticoids?
    • GC enhancing groups
    • MC diminishing groups at 6 or 16
  33. Fluid retention can occur if only a small amount of topical corticosteroid penetrates the skin and reaches the blood stream, groups with what action can diminish this effect?
    MC diminishing groups (at 6 and 16)

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