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PSFC2 > Case Study 2 - Benzodiazepines and Combinatorial Chemistry > Flashcards

Case Study 2 - Benzodiazepines and Combinatorial Chemistry Flashcards

1
Q

Ring A and drawing

A

Ring A involved in pie-pie stacking in the receptor protein

Exchanging ring A for a heterocyclic ring leads to lower anxiolytic activity

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2
Q

Ring B drawing

A

slide 5

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3
Q

Ring C and drawing

A

• Ring C may contribute to steric or hydrophobic interactions

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4
Q

What Is Combinatorial Chemistry?

A
  • A process where groups of starting materials are reacted together to make every available product
  • Mixtures of products are obtained – a library
  • Useful for making very diverse mixtures of compounds with drug-like properties for screening
  • One set of starting materials may be fixed on a solid support – solid-phase synthesis
  • Can be totally automated, increase productivity
  • Introduces diversity in lead compound structure
  • Rational versus Irrational drug design
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5
Q

What Is A Compound Library?

A
  • A collection of compounds prepared for testing
  • A library contains very little of each compound
  • Several types of library can be prepared:
  • Virtual: in silico
  • General: no bias for a target
  • Discovery: a library with drug-like features
  • Focused: designed to inhibit a target family
  • Targeted: designed to inhibit a specific target
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6
Q

Orthodox synthesis:

A

A+B –> AB

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7
Q

Making a Simple Library

A
  • Parallel synthesis, spatially addressable

* 96- or 384-well plates, ready for HTS

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8
Q

‘Mix And Split’ Library Synthesis

A
  • Substrates are attached to a solid support
  • Reactions are driven to completion by using excess reagent
  • Screening issues
  • Positive results must be deconvoluted
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9
Q

Solid Phase Organic Chemistry 1 - methodology

A
  • The development of automated solid-supported peptide synthesis revolutionised peptide research
  • The automated methodology has been adapted to make many peptides in parallel
  • All of the chemistry required has been worked out so combinatorial synthesis of peptides is easy
  • The methodology can also be applied to the synthesis of any small-molecule library using combinatorial chemistry on a solid support
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10
Q

Solid Phase Organic Chemistry

• Wang linker

A
  • Suitable for a base-labile protecting group strategy
  • Requires 1% - 95% TFA for cleavage
  • Reveals CO2H
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11
Q

Screening Compound Libraries

A
  • Screen the library in solution
  • Must cleave all compounds from the support
  • Possibility of false or misleading hits
  • Must resynthesize all compounds in an active library
  • Screen individual compounds in solution
  • Separate the beads manually
  • Requires a method for identifying active structures
  • Screen compounds still attached to the support
  • Colorimetric/ fluorimetric assay
  • Support can restrict the conformation of the product
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12
Q

Hit Structure Determination

A
  • The active hit must be prepared on a larger scale once activity has been found
  • Structure determination can be the rate-limiting step
  • Ideally, the structure of the hit would be determined whilst the compound is still anchored to the solid support
  • Nanomolar quantities of the hit can not be characterised easily using spectroscopy so some other methodology, chemical or otherwise, is required to trace the hit structure
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13
Q

Matrix Metalloproteinase (MMP) Enzymes

A
  • A family of zinc-dependant enzymes
  • Degradation and remodeling of the extracellular matrix
  • Important therapeutic targets with indications in cancer, arthritis, autoimmunity, and cardiovascular disease
  • Selectivity is important for therapy
  • Diketopiperazine (DKP) enzyme inhibitors chosen as lead compounds following de novo drug design
  • Solid-phase combinatorial synthesis chosen as a route to develop a diverse array of analogues for screening
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14
Q

Benzodiazepines

A

Class A

Class B

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15
Q

Benzodiazepines Class A

A

Clonazepam Diazepam
Lorazepam
Oxazepam Temazepam

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16
Q

Benzodiazepines Class B

A

Alprazolam
Estazolam
Midazolam
Triazolam

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17
Q

Clonazepam

A 
Class A
R1 - H
R3 - H
R7 - NO2
X - Cl
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18
Q

Diazepam

A 
Class A
R1 - CH3
R3 - H
R7 - Cl
X - H
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19
Q

Lorazepam

A 
Class A
R1 - H
R3 - OH
R7 - Cl
X - Cl
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20
Q

Oxazepam

A 
Class A
R1 - H
R3 - OH
R7 - Cl
X - H
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21
Q

Temazepam

A 
Class A
R1 - CH3
R3 - OH
R7 - Cl
X - H
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22
Q

Alprazolam

A

Class B
R - CH3
X - H
Y - N

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23
Q

Estazolam

A

Class B
R - H
X - H
Y - N

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24
Q

Midazolam

A

Class B
R - CH3
X - F
Y - CH

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25
Q

Triazolam

A

Class B
R - CH3
X - Cl
Y - N

26
Q

Ring A - position 7

A

An electronegative group in position 7 markedly increases the functional anxiolytic activity

27
Q

Ring A - position 6,8,9

A

Substituents in 6, 8 or 9 positions decrease anxiolytic activity

28
Q

Ring B - position 1

A

• Alkylation of the amide nitrogen in position 1 with sterically undemanding groups does not affect activity significantly

29
Q

Ring B - position 2

A
  • A proton accepting group in position 2 of Ring B is essential, coplanar with Ring A
  • Substituting sulfur or oxygen in position 2 does not affect anxiolytic activity significantly
30
Q

Ring B - position 3

A
  • Substitution on the methylene group at position 3 has no effect on anxiolytic (agonist) activity but decreases antagonist activity
  • The stereochemistry of hydroxylation at position 3 does not affect activity
  • The stereochemistry at position 3 may be important for steric interactions at the receptor with one enantiomer being favoured
31
Q

Ring B - position 4,5

A

• The 4-5 C=N bond is essential for in vivo activity

32
Q

Ring C - position 2

A

Substitution at position 2’ is not detrimental to agonist activity

33
Q

Ring C - position 4

A

Substitution at position 4’ is unfavourable due to steric interactions

34
Q

Oxazepam metabolism S

A

Oxazepam S –> (UGT2B15) S-oxazepam glucuronide

70 - 85%

35
Q

Oxazepam metabolism R

A

Oxazepam R –> (UGT1A9, UGT2B7) R-oxazepam glucuronide

15-30%

36
Q

Metabolism of Alprazolam

A

CY3A5, CYP3A4 –> Hydroxylation –> Glucuronidation –> Elimination

37
Q

Metabolism of Triazolam

A

CY3A5, CYP3A4 –> Hydroxylation –> Glucuronidation –> Elimination

38
Q

Metabolism of Midazolam

A

CYP3A4 –> Hydroxylation –> UGT1A4, UGT2B7 UGT2B4 –> Glucuronidation –> Elimination

UGT1A4 –> Glucuronidation –> Elimination

39
Q

Metabolism of Flurazepam

A

Hydroxylation/ alkylation –> Glucuronidation –> Elimination

40
Q

Metabolism of Bromazepam

A

CYP1A2, CYP2D6 –> Hydroxylation –> Glucuronidation –> Elimination

41
Q

Metabolism of Lorazepam

A

UGT2B15 –> Glucuronidation –> Elimination

42
Q

Metabolism of Clonazepam

A

NAT2 –> Acetylation –> Elimination

43
Q

Metabolism of Diazepam

A

CYP2C19 –> Nordazepam

CYP3A4 –> Tempazepam –>

44
Q

Metabolism of Nordazepam

A

CYP3A4 –> S-oxazepam

45
Q

Metabolism of Temazepam

A

CYP2C19 –> R-oxazepam

46
Q

difference in oxazepam and diazepam

A

oxazepam has an extra OH next C=O

47
Q

difference in flurazepam and quazepam

A

quazepam has C=S instead of C=O in flurazepam

quazepam has N-CF3 instead of N-CH2-CH2-N in flurazepam

48
Q

difference in estazolam, triazolam, temazepam

A

triazolam has extra CH3 bound to N ring than estazolam

temazepam has an extra C=O and -OH bound to N ring than triazolam

49
Q

Solid Phase Organic Chemistry 2 - each substrate

A
  • Each substrate is attached to a polymer bead
  • All reactions are driven to completion by using an excess of reagent
  • The final products are separated easily from the reaction mixture by filtration
  • By-products and excess reagents can be washed off the solid support, leaving pure product to be cleaved from the bead
50
Q

Solid Phase Organic Chemistry 3 - polymeric support

A
  • The polymeric support must be insoluble and inert to the reaction conditions employed
  • The means of linking the substrate to the solid support must allow efficient and selective cleavage of some or the entire quantity of product from the solid support
  • A protecting group strategy must be used which allows selective protection and deprotection of all reactive groups in the building blocks to be used and the supported substrate
51
Q

Solid Phase Organic Chemistry 4 - most widely used

A
  • The most widely used solid supports are cross-linked polystyrene beads
  • The local environment around the polystyrene bead can limit the range of possible reactions
  • Sheppard’s resin is a polyamide and provides a more suitable environment for peptide synthesis
  • Tentagel resin has polyethylene glycol residues tethered to polystyrene beads
  • The surface environment of Tentagel beads is hydrophilic but also like a polar organic solvent
52
Q

Solid Phase Organic Chemistry 5 - linker group

A
  • The linker group provides a means by which the substrate is attached to the polymer bead
  • The linker dictates what chemistry the growing substrate will withstand, the conditions required to release the library from the solid phase and what functionality will be revealed
  • Merrifield resin, developed for peptides: requires HF to cleave the product from the bead, reveals CO2H
53
Q

Fluoroquinolone Antibiotics

A

Ciprofloxacin
Levofloxacin
Gatifloxacin
Moxifloxacin

54
Q

Fluoroquinolone Synthesis

A

Diagram - slide 27

55
Q

SPOS Fluoroquinolone Synthesis

A

Diagram - slide 30

56
Q

Library DKP-1

A

L-cysteine gives 19 x 18 = 342 compounds
D-cysteine gives 19 x 18 = 342 compounds

Library DKP-1: Total of 684 compounds in pools of 19 DKPs

57
Q

Library DKP-2

A

L-cysteine gives 19 x 18 = 342 compounds
D-cysteine gives 19 x 18 = 342 compounds

Library DKP-2: Total of 684 compounds in pools of 19 DKPs

58
Q

Most selective inhibitor for Collagenase 1

A

R1 : PhCH2

R2 : p-CH3OC6H4

59
Q

Least selective inhibitor

A

R1 : n-Butyl

R2 : C6H11

60
Q

Best candidate for optimisation for Gelatinase B Inhibitor

A

R1 : C6H11CH2

R2 : p-CH3OC6H4

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