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Chemistry 2 > Chemistry Y7: Applied Organic Chemistry > Flashcards

Chemistry Y7: Applied Organic Chemistry Flashcards

1
Q

What are important factors in the intermolecular interactions with receptor proteins?

A
  • Charge
  • Polarity
  • Shape
  • Size
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2
Q

How are Amino Acids made?

A

The condensation reaction between the acid group of one molecule and the amine group of another molecule

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3
Q

What determines how an AA reacts?

A

The R group

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4
Q

what are the natural alpha AAs?

A

Glycine, alanine, valine, leucine, isoleucine, methionine, proline

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5
Q

What are the polar AAs with uncharged R groups?

A

Serine, cysteine, threonine, asparagine, glutamine

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6
Q

What are the polar AAs with +vely charged R groups?

A

Lysine, arginine, histidine

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7
Q

What are the polar AAs with -vely charged R groups?

A

Aspartate, glutamate

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8
Q

What are the aromatic R group AAs?

A

Phenylalanine, tyrosine, tryptophan

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9
Q

which AA doesn’t have a chiral centre?

A

Glutamine

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10
Q

Why is PKa imortant for R groups?

A

Ka= Acidity constant
PKa = log of Ka
How much equilibrium lies more acidic or basic

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11
Q

What does it mean if PKa =pH?

A

That HA is deprotonated by 50%

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12
Q

How can you stabilise the protonated form of Arginine?

A

By resonance

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13
Q

What is the henderson Hasselbalch equation?

A

For acids:
pH = pKa + log10 [A-]
/[HA]

[A-]/[HA] =10^(pH-pKa)

For bases:
pH = pKa + log10 [B]/[BH+]
[B]/[BH+] = 10^(pH=pKa)

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14
Q

Why is histidine an excellent catalyst

A

[B]/[BH]
=10^ (7-7)
=1
Equal amounts of BH+ and B at pH=7
-Can easily lose or gain a proton

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15
Q

Why does cysteine have a lower pKa (pKa=10) than serine (pKa=15)?

A
  • Cysteine is more readily deprotonated.
  • Because S atom is larger and less electronegative than the O atom
  • SO for solvation to occur no H-bonds are broken for cysteine, unlike serine
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16
Q

What are enzymes?

A

*Proteins that act as catalysts in biological systems
* Unchanged after the reaction
* Substrates fit into active sites - then converted into products
* AA side chains help substrate to fit into active site

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17
Q

What is formed when a receptor protein binds with a signalling compound?

A

An R-S complex
-Creates a response (e.g. nerve impulse)

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18
Q

TGF-alpha-cancer complexes

A

EGFT is formed. (an R-S complex)
* Causes phosphorylation
* Process in gene transcription/ cell cycle progression
=Cell proliferation, inhibition of apoptosis, angiogenesis

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19
Q

What is EGFR and what does it do to serine/threonine?

A

Epidermal growth factor receptor
* Tyrosine kinase, once activated EGF binds to EGFR to phosphorylate Serine / Threonine

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20
Q

What do activated (phosphorylated) kinases do?

A

They relay and amplify signals

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21
Q

What does over expression of EGFR do?

A

Results in permanently activated kinase = inappropriate growth signal
=Causes CANCER

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22
Q

What does MEK stand for

A

Mitogen-activated protein kinase
Serine/tyrosine/threonine protein kinase

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23
Q

What does RAF stand for?

A

Rapidly accelerated fibrosarcoma
Threonine specific protein kinase

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24
Q

What does ERK stand for?

A

Extracellular signal-regulated kinse
Serine/ threonine specific protein kinase

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25
Q

What are the binding interactions?

A
  1. Electrostatic (ionic)
  2. Dipole-Dipole, esp H-bonding
  3. Hydrophobic interactions between non-polar side chains
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26
Q

If LP on Nitrogen is delocalised, what does that mean?

A

The nitrogen is non-basic

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27
Q

What is the Hydrophobic effect?

A

Hydrophobic groups tend to aggregate together to reduce exposure to water

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28
Q

What molecules can bind to the hydrophobic pocket of an enzyme/receptor?

A

Non-polar groups

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29
Q

What interactions are involved in ACh binding to a receptor?

A
  • ELectrostatic
    *Dipole-Dipole
    *Hydrophobic interactions
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30
Q

What is ACh?

A

It is a neurotransmitter. It binds to receptors leading to nerve impulses

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31
Q

What doe the ACh binding site look like?

A

-ACh receptor active site has 2 hydrophobic pockets

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31
Q

What are ACh inhibitors?

A

Atropine binds to the active site of the ACh receptor and blocks nerve signal
-Functions as an ACh antagonist

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32
Q

What can rapidly hydrolyse ACh? and what is it’s function

A

Acetylcholinesterase
* It prevents continuous nerve impulses

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33
Q

What is ACh hydrolysed into?

A
  1. Acetic acid and choline
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34
Q

What is neostigmine?

A

It is the reversible inhibitor of ACh esterase
* It reduces the rate of ACh hydrolysis
* Treatment for myasthenia Gravis (Muscle weakness)

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35
Q

What is irreversible ACh esterase inhibition?

A

Sarin: A lethal nerve agent
* Eventually causes the lungs to drown in mucous
* It blocks ACh entirely = continuous nerve impulses = Asphyxiation

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36
Q

How does atropine work as an antidote for sarin?

A

Atropine blocks the ACh receptor (competitive inhibitor)

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37
Q

What are nitrogen mustards?

A

They are genotoxic agents that cross-link DNA (inter-strand)
* Burn skin and airways
* It reacts with Nu N of guanine in DNA and damages cells

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38
Q

How does Nitrogen mustards cross-linking with DNA work?

A

In GC rich regions of DNA

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39
Q

(S)-Melphalan (nitrogen mustard) used in cancer treatment

A
  • It is mainly zwitteionic (overall neurtal) at pH =7
    =Polar
    =Water soluble
    -Able to reach target cancer cells
  • Similarity to (S)-phenylalanine means that transported into rapidly dividing cells
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40
Q

How does glutathione production result in cancer cell resistance?

A
  • Resistance to (S)-melphalan
  • Glutathione is a Nu that destroys the electrophilic aziridinium ion(s) produced by (s)-melphalan
  • The drug is unable to damage cancer cells
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41
Q

what are alkaloids?

A

Natural products that contain basic nitrogen
* Mainly produced by plants and marine organisms

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42
Q

What makes a Nitrogen LP basic?

A

They are available, they aren’t being used in the aromaticity
Usually SP3 hybridised

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43
Q

What makes a Nitrogen LP non-basic?

A

They aren’t available - used up in aromaticity
Usually SP2 hybridised

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44
Q

What is the 4n+2 rule?

A

In aromatic systems there are 4n+2 electrons (n has to be a whole number)

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45
Q

How do you make an amine from a ketone?

A

Reductive amination
Ketone -> Imine -> amine

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46
Q

What are imines?

A

Analogues to ketones and tautomerise to give enamines?

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47
Q

what influences equilibriums between enols and enamines

A

influenced by adjacent conjugating groups and intramolecular hydrogen bonding

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48
Q

How can you form enamines using ketones?

A

Dialkylamines react with ketones to produce iminium ions that can form enamines by loss of a proton

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49
Q

How can you synthesise analogues of imines

A

condensation (acid-catalysed)

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50
Q

What is the Mannich reaction?

A

An iminium ion (often generated from formaldehyde in a separate step) reacts with the enol form of a ketone/ aldehyde

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51
Q

What does a high enol content make ketones

A

good substrates

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52
Q

What ketones are preferable

A

Symmetrical ketones
Ketones that can enolise in any one direction
* Otherwise regiosiometric mixtures can result

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53
Q

What does the intramolecular mannich reaction produces

A

Cyclic amine

54
Q

What is tropinone

A

It is an alkaloid and a precursor for the synthesis of atropine

55
Q

What are stereoisomers

A

*Compounds with the same molecular formula and structural formulae
*Different 3D arrangement of 4 groups around the central C atom

56
Q

If a compound has 2 stereo genic centres ho many stereoisomers are there?

A

4

57
Q

What are enantiomers?

A

*Non-superimposable mirror images
*All stereo centres different
*Identical physical properties but different biological effects

58
Q

What are Diastereomers?

A
  • Isomers with no mirror-image relationship
  • can have same or different stereo centres
  • Different physical properties
  • Can be separated (e.g. chromatography
59
Q

How do we assign a chiral centre R or S

A
  • Priority based on atomic mass
  • Double bonds take priority over single bonds
  • Lowest priority viewed at the back
  • Count 1st to 4th priority and check direction of rotation
    Clockwise= R
    Anticlockwise = S
60
Q

What was wrong with Thalidomide?

A

*It was sold as a racemic mixture to treat morning sickness
* One of the enantiomers was lethal to unborn babies

61
Q

What is a racemisation?

A

A racemic drug (racemate) is a 50:50 mixture of enantiomer
* Drugs must be a single enantiomer
*Racemision can occur if the stereo genic centre is next to a carbonyl group

62
Q

How do you separate a racemic mixture?

A

With a chiral resolving agent
* This gives a salt
* Which can then be separated by crystallisation

63
Q

What are approaches to finding new drugs?

A

Screening natural products
Testing fragments
Screening combinatorial libraries

64
Q

Describe screening combinatorial libraries (SCL)

A
  1. identify biological target e.g. microtubule assembly
  2. Develop robust assay e.g. high-throughput screening assay
  3. Identify lead compound e.g. screen combinatorial libraries
65
Q

How is an electronic detector used in drug discovery?

A

Attach electronic detector to beads: machine will detect what sequence of reactions that bead has been through

66
Q

Other than an electronic detector what can you attach to beads in SCL

A

You can use a reporter group on the bead (e.g. DNA/ peptide sequence)
*This gives automated messages about the reaction pathways the bead has been on.

67
Q

Why aren’t natural products often pharmaceuticals?

A

Issues with polarity/ cross reactions

68
Q

What are related structures of natural products called?

A

Analogues

69
Q

why might an analogue be better than a natural product?

A

It may have higher activity

70
Q

what assessments can you perform to assess analogues?

A

Structure-activity-relationship (SAR)
-Use quantitative SAR (QSAR)

71
Q

what does QSAR do?

A

it relates activity to structure
can be used as a predictive device

72
Q

what can you use to understand ligand-protein binding?

A
  1. X-ray crystallography - Shows how the drug binds to the protein, whether hydrophobic pockets are occupied and which functional groups are important for binding
  2. Saturation-transfer different NMR (STD-NMR)
73
Q

How do you optimise the drug candidate?

A

Diversity oriented synthesis (DOS)

74
Q

What is diversity oriented synthesis?

A
  • combines natural product with a combinatorial approach
  • Start with structure that has known activity and set about increasing diversity
    -Putting on groups
    -Changing stereochemistry
75
Q

Why is DOS better than combinatorial library?

A

*Combinatorial leaves you with similar structures
*DOS = large libraries rapidly
= more diversity in structures
*DOS= more privileged structures (potential ligands for multiple enzymes)

76
Q

How do you create a DOS library?

A
  • Synthesis is short, branching and complexity generating
    *Incorporate diversity
77
Q

How can you introduce diversity to libraries?

A
  1. building blocks
  2. stereochemistry
  3. functional groups
78
Q

what are the ways to cover as much chemical space as possible?

A
  1. Volume
  2. Charge
  3. Number of bonds
  4. Barriers to rotation
79
Q

Give examples of privileged structures

A

Indoles and Purines

80
Q

What does hydrophilic mean?

A

water loving

81
Q

what do hydrophilic compounds contain?

A

“Water loving’ polar groups
-they dissolve in polar solvents

82
Q

What do hydrophobic compounds contain?

A

‘Fat loving’ non-polar compounds
-They dissolve in non-polar solvents (e.g. octanol)

83
Q

Why are too hydrophobic compounds bad?
Why are too hydrophilic compounds bad?

A
  1. They get trapped in fatty acids. The drug wont be soluble in (aq) media e.g. blood
  2. struggle to get across membranes. Wont be soluble in lipids.
84
Q

What is hydrophobicity?

A

The measure of ability of a drug to pass through hydrophobic membranes into a cell
* How a compounds partitions between octanol and water

85
Q

What is the equation for hydrohpobicity?

A

Partition coefficient = p
p= [drug in octanol]/ [Drug in water]

86
Q

What does a large P value mean?
What does a small P value mean? Partition coefficient.

A

Large p = hydrophobic (non-polar)
Small p = Hydrophilic (polar)

87
Q

What is the log calculation for hydrophobicity?

A

LogP = Log10[drug in octanol]/ [Drug in water]

88
Q

what is the optimum LogP value for anaesthetics?

A

2.30
-given by QSAR

89
Q

What is unlikely to cross a cell membrane -NH2 or -NH3

A

NH3 as it is protonated making it too hydrophyllic (polar) to dissolve in the phospholipid bilayer of the membrane

90
Q

At pH 7 what do AAs exist as? What does this mean?

A

Zwitterions
* Ionic = low P value = water soluble
* cant diffuse across cell membranes
*Require facilitated transport by AA carrier protein

91
Q

How do you treat parkinson’s?

A

L-DOPA

92
Q

What is the solubility of aspirin?

A

Insoluble as it is a carboxylic acid

93
Q

How do you make aspirin soluble?

A

Form the carboxylate via ionisation reaction
-Acetal group is removed
-Esterases cleave off the ester group to give active from of the drug

94
Q

At pH 7, Why does DOPA cross the blood brain barrier while dopamine cannot?

A
  • Both DOPA and dopamine are too hydrophilic to cross the barrier
  • However, DOPA mimics an AA and is therefore carried across by facilitated transport
95
Q

What are phase transfer catalysts?

A

They facilitate the transfer of reagent between (aq) and (organic) phases

96
Q

What are crown ethers?

A

Crown ethers are a class of cyclic chemical compounds that consist of repeating ether units (O-CH2-CH2-O) forming a ring, which resembles a crown.

97
Q

What is an example of an (aq) soluble oxidising agent?

A

Potassium permanganate
18-crown-6 (organic)

98
Q

What can complexed potassium permanganate do?

A

It is organic soluble so can oxidise organic compounds in organic solvents

99
Q

What are examples of phase transfer catalysts?

A

Quaternary ammonium salts
* Ammonium hydroxide (water soluble)
* Tetrabutylammonium Hydrogen sulfate
(soluble in aq and organic)

100
Q

What type of reactions can Quaternary ammonium salts catalyse?

A

Nu reaction of cyanide with alkyl halides

101
Q

Why would a non-polar solvent promote a forwards reaction?

A

If a reagent in the RDS is not soluble in non-polar (water soluble)

102
Q

Why is the trigonal bipyramidal transition state for the Sn2 reaction stabilised by a non-polar solvent?

A
  • The charge is more dispersed in transition state than starting material.
    *Energy to reach the TS (Ea) is minimised using a non-polar solvent
103
Q

What does it mean when we say phospholipids are amphiphilic?

A

They have both hydrophilic and hydrophobic characteristics

104
Q

What type of molecule are the non-polar tails of phospholipids made from?

A

non-polar tails of phospholipids are fats
-Fatty acids

105
Q

What do polyene antibiotics bind to in fungal cell membranes? What does this lead to?

A
  1. Erogosterol (NOT human equivalent which is cholesterol)
  2. Creates pores in the membrane - leading to leakage of essential ions
    * Cell death
    * Cholesterol is present in mammalian cells, but ergosterol is not
    *Antifungals do not bind strongly to cholesteol
106
Q

What can carcinogenic polycystic aromatics do?

A

they can intercalate DNA and are carcinogenic
-Via metabolic oxidation
-Guanine then acts as a Nu
-Intercalated DNA damages cells

107
Q

what are UVC, UVB and UVA?

A

all UV radiation
* UVC blocked by O3 (oxone)
*UVB main cause of skin cancer
*UVA causes skin ageing by penetrating deep into the skin

108
Q

absorption of Uv radiate excited electrons into what phase

A

From HOMO to LUMO

109
Q

What does increasing conjugation do to the HOMO-LUMO energy gap

A

Reduces it which decreases the energy of absorption and increases the wavelength of absorption (increasing LambdaMAX)

110
Q

Is zwitterions have more conjugation what does that make them better at?

A

Absorbing UVA and UVB

111
Q

Is is better for suncream to be water-soluble or non-polar soluble

A

non-polar soluble

112
Q

what is the biggest difference between normal cells and abnormal cancer cells?

A

The rate of division

113
Q

What are common side effects of chemotherapeutic agents?

A

Hair loss, Blood cell damage, damage to cells in mouth, stomach and intestine

114
Q

What are the main type of chemotherapeutics?

A
  1. Alkylating agents
  2. antimetabolites
  3. Anti-microtubule agents
  4. Topoisomerase inhibitors
  5. Cytotoxic agents
  6. Angiogenesis inhibitors
  7. Protein kinase inhibitors
115
Q

What do Alkylating agents do?

A

They react with amine, carboxyl, hydroxyl, thiol and phosphate groups critical for cell function or division

116
Q

What are examples of alkylating agents

A

*Nitrogen mustards
*Nitrosoureas- form diazo compounds (v reactive)
*Tetrazines- Form diazonium ions
*Aziridines- V reactive w Nus
*Platinum complexes- React with and cross -link DNA

117
Q

What are antimetabolites?

A

They are analogues of natural DNA building blocks

118
Q

What are the antimetabolites of deoxycytidine?

A

Gemcitabine- is phosphorylates and added to DNA chain, after addition no more bases can be added
Decitabine - Is incorperated into DNA during replication and inhibits the enzyme methyltransferase, preventing methylation in that sequence

119
Q

What is 5-fluorouracil, and what does it do?

A

An antimetabolite
-Acts as a primary inhibitor of thymidylate synthase (which converts dUMP to dTMP)
-Rapidly dividing cancer cells are deprives of essential bases as dTMP blocks enzyme

120
Q

What is methotrexate and what does it block?

A

An antifolate
-Inhibits the enzyme Dihydrofolate reductase (essential for formation of purine bases)

121
Q

What are topoisomerase inhibitors?

A

Topoisomerase I and II are enzymes that produce breaks in the unwound DNA chain during replication or transcription
-Preventing cell replication

122
Q

What is Camptothecin?

A

A topoisomerase inhibitor, inhibiting topoisomerase I
-Has poor solubility
-Topotecan is a synthetic water-soluble analogue

123
Q

What does dozorubicin do?

A

It intercalates between base pairs and stabilised the topoisomerase II complex after it has broke the DNA chain
-Preventing DNA chain from being released

124
Q

What are cytotoxic Antibiotics?

A

Generally just agents that interrupt cell division

125
Q

What does bleomycin do?

A

It binds Fe2+ or Cu+ in the presence of oxygen
-Forms a peroxide = generation of free radicals that damage DNA

126
Q

What does Actinomycin D to?

A

it intercalates DNA during transcription and prevents elongation of RNA and RNA polymerase

127
Q

The cell cycle and cancer:
What happens in mitosis, synthesis phase and apoptosis?

A

Mitosis: Spindle forms, division occurs
Synthesis: full copy of nuclear DNA is made
Apoptosis: is cell death

128
Q

What do antimitotic agents do?

A

Damage rapidly dividing cells in mitosis
-Damages cancer cells

129
Q

What are anti-microtubule agents?

A

They greatly increase or decrease microtubule stabily
-This halts cell division and leads to apoptosis
-Inhibit formation of new cells

130
Q

What is Vincristine and what does it do?

A

A DRUG THAT CAN INHIBIT MICROTUBULE FORMATION
*Structurally related anti-cancer agent vinbblastin produced by same plant

131
Q

What are epothilones?

A

They are a series of structurally related macrolactones isolated from soil
-They have better water solubility than taxol
= solubilising agents not required

132
Q

What is taxol mode of action?

A
  • Microtubules are polymers formed between alpha and beta tubulin (proteins)
    Microtubules have critical role in mitosis (cell division)

so MOA is,
Normal assembly of microtubules is reversible
*Taxol causes inapropriate assembly of MT even in absence of GTP and Mg2+ (energy source)
*Mitosis stalls

133
Q

How does Taxol damage cancer cells?

A

Creates stable microtubules, which stalls in mitosis and so leads to cell death

Chemistry 2 (7 decks)

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