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PHA111 > Peptide Synthesis > Flashcards

Peptide Synthesis Flashcards

1
Q

what are natural peptides commonly used as and give examples?

A

signalling molecules + substrates

  • peptide hormones - LH, prolactin, GH, insulin, vasopressin, oxytocin, cholecystokinin
  • neurotransmitters + neuropeptides
  • snake, ant, spider venoms
  • toxins from microbes + aquatic life
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2
Q

give examples of some peptides + peptidomimetics in clinical use?

A
  • goserelin (prostate cancer)
  • saquinavir (HIV/AIDS)
  • gramicidin (antibacterial)
  • insulin (diabetes)
  • interferons
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3
Q

why do we synthesise peptides + analogues?

A

investigate biological systems + biochem pathways

inhibit/change pathways

improve on nature -> higher potency, greater specificity

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4
Q

condensation reactions are not …. useful

A

synthetically

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5
Q

describe block protection briefly?

A
  • block amine of aa1
  • block acid of aa2
  • condense using dehydrating agent
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6
Q

how do carbodiimides work?

A
  • protonated carbodiimides = v electrophilic
  • adduct contains good leaving group
  • urea bi-prod = v stable + precipitates from solution
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7
Q

give examples of protecting groups?

A
  • amino protecting groups (N protection)
  • carboxyl protecting groups
  • solid phase peptide synthesis
  • side chain protecting groups
  • orthogonal protection strategies
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8
Q

describe N protection briefly?

A
  • need to make N non-nucleophilic

- remove lone pair availability

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9
Q

what are the most common N-protecting groups?

A

carbamates

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10
Q

what does the choice of carbamate depend on?

A

functional group sensitivity

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11
Q

when would you use Boc?

A

acid sensitive

protected amino acid (tertiarybutyloxycarbonyl)

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12
Q

when would you use Cbz?

A

reduction sensitive

protected amino acid (benzyloxycarbonyl)

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13
Q

when would you use Fmoc?

A

base sensitive

protected amino acid
fluorenyloxycarbonyl

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14
Q

what is the most common reagent in boc protection?

A

di-tert-butyldicarbonate

boc anhydride

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15
Q

what is the source of Cbz?

A

benzyloxycarbonyl chloride

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16
Q

when is Cbz protection unsuitable?

A

for Cys, Met, Lys

17
Q

if R1 = H, what is the product in Cbz protection?

A

Cbz - Gly

18
Q

what is the source of Fmoc?

A

succinimidyl ester because = good leaving group

19
Q

if R1 = H, what is the product in Fmoc protection?

A

Fmoc-Gly

20
Q

why are mild bases used in Fmoc protection?

A

strong bases cause racemisation of AA

end up with 1:1 mix of D and L isomers

get peptides with non-natural stereoisomers = inactive

21
Q

if you have a methyl/ethyl group, what do u hydrolyse with?

A

hydroxide

22
Q

if you have a tertiary butyl group, what do u hydrolyse with?

A

TFA

23
Q

if you have a benzyl group, what do you hydrolyse with?

A

hydrogenate

24
Q

what are the advantages of SPPS?

A
  • automation
  • rapid + reliable
  • easy purification: wash beads
  • cheap
  • many different applications
25
Q

give examples of reactive side chains?

A
  • N-containing (lys, arg, his)
  • carboxylate (asp, glu)
  • alcohol (ser, thr)
  • thiol (cys)
26
Q

what is the orthogonal protection strategy?

A

when you can use the same protecting groups already considered

but NOT the same group being used to protect the end chain

to maintain protection throughout

27
Q

orthogonal protection issues?

A
  • if using tBoc on N-terminus
    can’t use tBoc/tButyl on side chains —> deprotect at same time as N-terminus
  • if using Fmoc on N-terminus
    can’t use Fmoc on side chains —> deprotect at same time as N-terminus
  • potentially harmful/inactive if administered
28
Q

describe orthogonal protection -Fmoc?

A
  • use tboc, cbz, Me ester, Et ester, thioester, benzyl ester / benzyl ether on side chains
  • amine terminus deprotects with base
  • side chains remain protected throughout synthesis

side chains deprotect with appropriate reagent

29
Q

describe orthogonal protection -tBoc?

A

can use all reagents but NOT tbutyl

Cbz rarely used as N-protecting agent due to terminal AA needing hydrogenation

also incompatible with industrial scale + issues with resins

PHA111 (30 decks)

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