Chemistry Y7: Applied Organic Chemistry Flashcards
(134 cards)
1
Q
What are important factors in the intermolecular interactions with receptor proteins?
A
- Charge
- Polarity
- Shape
- Size
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
3
Q
What determines how an AA reacts?
A
The R group
4
Q
what are the natural alpha AAs?
A
Glycine, alanine, valine, leucine, isoleucine, methionine, proline
5
Q
What are the polar AAs with uncharged R groups?
A
Serine, cysteine, threonine, asparagine, glutamine
6
Q
What are the polar AAs with +vely charged R groups?
A
Lysine, arginine, histidine
7
Q
What are the polar AAs with -vely charged R groups?
A
Aspartate, glutamate
8
Q
What are the aromatic R group AAs?
A
Phenylalanine, tyrosine, tryptophan
9
Q
which AA doesn’t have a chiral centre?
A
Glutamine
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
11
Q
What does it mean if PKa =pH?
A
That HA is deprotonated by 50%
12
Q
How can you stabilise the protonated form of Arginine?
A
By resonance
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)
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
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
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
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)
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
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
20
Q
What do activated (phosphorylated) kinases do?
A
They relay and amplify signals
21
Q
What does over expression of EGFR do?
A
Results in permanently activated kinase = inappropriate growth signal
=Causes CANCER
22
Q
What does MEK stand for
A
Mitogen-activated protein kinase
Serine/tyrosine/threonine protein kinase
23
Q
What does RAF stand for?
A
Rapidly accelerated fibrosarcoma
Threonine specific protein kinase
24
Q
What does ERK stand for?
A
Extracellular signal-regulated kinse
Serine/ threonine specific protein kinase
25
What are the binding interactions?
1. Electrostatic (ionic)
2. Dipole-Dipole, esp H-bonding
3. Hydrophobic interactions between non-polar side chains
26
If LP on Nitrogen is delocalised, what does that mean?
The nitrogen is non-basic
27
What is the Hydrophobic effect?
Hydrophobic groups tend to aggregate together to reduce exposure to water
28
What molecules can bind to the hydrophobic pocket of an enzyme/receptor?
Non-polar groups
29
What interactions are involved in ACh binding to a receptor?
* ELectrostatic
*Dipole-Dipole
*Hydrophobic interactions
30
What is ACh?
It is a neurotransmitter. It binds to receptors leading to nerve impulses
31
What doe the ACh binding site look like?
-ACh receptor active site has 2 hydrophobic pockets
31
What are ACh inhibitors?
Atropine binds to the active site of the ACh receptor and blocks nerve signal
-Functions as an ACh antagonist
32
What can rapidly hydrolyse ACh? and what is it's function
Acetylcholinesterase
* It prevents continuous nerve impulses
33
What is ACh hydrolysed into?
1. Acetic acid and choline
34
What is neostigmine?
It is the reversible inhibitor of ACh esterase
* It reduces the rate of ACh hydrolysis
* Treatment for myasthenia Gravis (Muscle weakness)
35
What is irreversible ACh esterase inhibition?
Sarin: A lethal nerve agent
* Eventually causes the lungs to drown in mucous
* It blocks ACh entirely = continuous nerve impulses = Asphyxiation
36
How does atropine work as an antidote for sarin?
Atropine blocks the ACh receptor (competitive inhibitor)
37
What are nitrogen mustards?
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
38
How does Nitrogen mustards cross-linking with DNA work?
In GC rich regions of DNA
39
(S)-Melphalan (nitrogen mustard) used in cancer treatment
* 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
40
How does glutathione production result in cancer cell resistance?
* 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
41
what are alkaloids?
Natural products that contain basic nitrogen
* Mainly produced by plants and marine organisms
42
What makes a Nitrogen LP basic?
They are available, they aren't being used in the aromaticity
Usually SP3 hybridised
43
What makes a Nitrogen LP non-basic?
They aren't available - used up in aromaticity
Usually SP2 hybridised
44
What is the 4n+2 rule?
In aromatic systems there are 4n+2 electrons (n has to be a whole number)
45
How do you make an amine from a ketone?
Reductive amination
Ketone -> Imine -> amine
46
What are imines?
Analogues to ketones and tautomerise to give enamines?
47
what influences equilibriums between enols and enamines
influenced by adjacent conjugating groups and intramolecular hydrogen bonding
48
How can you form enamines using ketones?
Dialkylamines react with ketones to produce iminium ions that can form enamines by loss of a proton
49
How can you synthesise analogues of imines
condensation (acid-catalysed)
50
What is the Mannich reaction?
An iminium ion (often generated from formaldehyde in a separate step) reacts with the enol form of a ketone/ aldehyde
51
What does a high enol content make ketones
good substrates
52
What ketones are preferable
Symmetrical ketones
Ketones that can enolise in any one direction
* Otherwise regiosiometric mixtures can result
53
What does the intramolecular mannich reaction produces
Cyclic amine
54
What is tropinone
It is an alkaloid and a precursor for the synthesis of atropine
55
What are stereoisomers
*Compounds with the same molecular formula and structural formulae
*Different 3D arrangement of 4 groups around the central C atom
56
If a compound has 2 stereo genic centres ho many stereoisomers are there?
4
57
What are enantiomers?
*Non-superimposable mirror images
*All stereo centres different
*Identical physical properties but different biological effects
58
What are Diastereomers?
* Isomers with no mirror-image relationship
* can have same or different stereo centres
* Different physical properties
* Can be separated (e.g. chromatography
59
How do we assign a chiral centre R or S
* 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
What was wrong with Thalidomide?
*It was sold as a racemic mixture to treat morning sickness
* One of the enantiomers was lethal to unborn babies
61
What is a racemisation?
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
How do you separate a racemic mixture?
With a chiral resolving agent
* This gives a salt
* Which can then be separated by crystallisation
63
What are approaches to finding new drugs?
Screening natural products
Testing fragments
Screening combinatorial libraries
64
Describe screening combinatorial libraries (SCL)
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
How is an electronic detector used in drug discovery?
Attach electronic detector to beads: machine will detect what sequence of reactions that bead has been through
66
Other than an electronic detector what can you attach to beads in SCL
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
Why aren't natural products often pharmaceuticals?
Issues with polarity/ cross reactions
68
What are related structures of natural products called?
Analogues
69
why might an analogue be better than a natural product?
It may have higher activity
70
what assessments can you perform to assess analogues?
Structure-activity-relationship (SAR)
-Use quantitative SAR (QSAR)
71
what does QSAR do?
it relates activity to structure
can be used as a predictive device
72
what can you use to understand ligand-protein binding?
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
How do you optimise the drug candidate?
Diversity oriented synthesis (DOS)
74
What is diversity oriented synthesis?
* 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
Why is DOS better than combinatorial library?
*Combinatorial leaves you with similar structures
*DOS = large libraries rapidly
= more diversity in structures
*DOS= more privileged structures (potential ligands for multiple enzymes)
76
How do you create a DOS library?
* Synthesis is short, branching and complexity generating
*Incorporate diversity
77
How can you introduce diversity to libraries?
1. building blocks
2. stereochemistry
3. functional groups
78
what are the ways to cover as much chemical space as possible?
1. Volume
2. Charge
3. Number of bonds
4. Barriers to rotation
79
Give examples of privileged structures
Indoles and Purines
80
What does hydrophilic mean?
water loving
81
what do hydrophilic compounds contain?
"Water loving' polar groups
-they dissolve in polar solvents
82
What do hydrophobic compounds contain?
'Fat loving' non-polar compounds
-They dissolve in non-polar solvents (e.g. octanol)
83
Why are too hydrophobic compounds bad?
Why are too hydrophilic compounds bad?
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
What is hydrophobicity?
The measure of ability of a drug to pass through hydrophobic membranes into a cell
* How a compounds partitions between octanol and water
85
What is the equation for hydrohpobicity?
Partition coefficient = p
p= [drug in octanol]/ [Drug in water]
86
What does a large P value mean?
What does a small P value mean? Partition coefficient.
Large p = hydrophobic (non-polar)
Small p = Hydrophilic (polar)
87
What is the log calculation for hydrophobicity?
LogP = Log10[drug in octanol]/ [Drug in water]
88
what is the optimum LogP value for anaesthetics?
2.30
-given by QSAR
89
What is unlikely to cross a cell membrane -NH2 or -NH3
NH3 as it is protonated making it too hydrophyllic (polar) to dissolve in the phospholipid bilayer of the membrane
90
At pH 7 what do AAs exist as? What does this mean?
Zwitterions
* Ionic = low P value = water soluble
* cant diffuse across cell membranes
*Require facilitated transport by AA carrier protein
91
How do you treat parkinson's?
L-DOPA
92
What is the solubility of aspirin?
Insoluble as it is a carboxylic acid
93
How do you make aspirin soluble?
Form the carboxylate via ionisation reaction
-Acetal group is removed
-Esterases cleave off the ester group to give active from of the drug
94
At pH 7, Why does DOPA cross the blood brain barrier while dopamine cannot?
* 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
What are phase transfer catalysts?
They facilitate the transfer of reagent between (aq) and (organic) phases
96
What are crown ethers?
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
What is an example of an (aq) soluble oxidising agent?
Potassium permanganate
18-crown-6 (organic)
98
What can complexed potassium permanganate do?
It is organic soluble so can oxidise organic compounds in organic solvents
99
What are examples of phase transfer catalysts?
Quaternary ammonium salts
* Ammonium hydroxide (water soluble)
* Tetrabutylammonium Hydrogen sulfate
(soluble in aq and organic)
100
What type of reactions can Quaternary ammonium salts catalyse?
Nu reaction of cyanide with alkyl halides
101
Why would a non-polar solvent promote a forwards reaction?
If a reagent in the RDS is not soluble in non-polar (water soluble)
102
Why is the trigonal bipyramidal transition state for the Sn2 reaction stabilised by a non-polar solvent?
* 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
What does it mean when we say phospholipids are amphiphilic?
They have both hydrophilic and hydrophobic characteristics
104
What type of molecule are the non-polar tails of phospholipids made from?
non-polar tails of phospholipids are fats
-Fatty acids
105
What do polyene antibiotics bind to in fungal cell membranes? What does this lead to?
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
What can carcinogenic polycystic aromatics do?
they can intercalate DNA and are carcinogenic
-Via metabolic oxidation
-Guanine then acts as a Nu
-Intercalated DNA damages cells
107
what are UVC, UVB and UVA?
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
absorption of Uv radiate excited electrons into what phase
From HOMO to LUMO
109
What does increasing conjugation do to the HOMO-LUMO energy gap
Reduces it which decreases the energy of absorption and increases the wavelength of absorption (increasing LambdaMAX)
110
Is zwitterions have more conjugation what does that make them better at?
Absorbing UVA and UVB
111
Is is better for suncream to be water-soluble or non-polar soluble
non-polar soluble
112
what is the biggest difference between normal cells and abnormal cancer cells?
The rate of division
113
What are common side effects of chemotherapeutic agents?
Hair loss, Blood cell damage, damage to cells in mouth, stomach and intestine
114
What are the main type of chemotherapeutics?
1. Alkylating agents
2. antimetabolites
3. Anti-microtubule agents
4. Topoisomerase inhibitors
5. Cytotoxic agents
6. Angiogenesis inhibitors
7. Protein kinase inhibitors
115
What do Alkylating agents do?
They react with amine, carboxyl, hydroxyl, thiol and phosphate groups critical for cell function or division
116
What are examples of alkylating agents
*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
What are antimetabolites?
They are analogues of natural DNA building blocks
118
What are the antimetabolites of deoxycytidine?
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
What is 5-fluorouracil, and what does it do?
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
What is methotrexate and what does it block?
An antifolate
-Inhibits the enzyme Dihydrofolate reductase (essential for formation of purine bases)
121
What are topoisomerase inhibitors?
Topoisomerase I and II are enzymes that produce breaks in the unwound DNA chain during replication or transcription
-Preventing cell replication
122
What is Camptothecin?
A topoisomerase inhibitor, inhibiting topoisomerase I
-Has poor solubility
-Topotecan is a synthetic water-soluble analogue
123
What does dozorubicin do?
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
What are cytotoxic Antibiotics?
Generally just agents that interrupt cell division
125
What does bleomycin do?
It binds Fe2+ or Cu+ in the presence of oxygen
-Forms a peroxide = generation of free radicals that damage DNA
126
What does Actinomycin D to?
it intercalates DNA during transcription and prevents elongation of RNA and RNA polymerase
127
The cell cycle and cancer:
What happens in mitosis, synthesis phase and apoptosis?
Mitosis: Spindle forms, division occurs
Synthesis: full copy of nuclear DNA is made
Apoptosis: is cell death
128
What do antimitotic agents do?
Damage rapidly dividing cells in mitosis
-Damages cancer cells
129
What are anti-microtubule agents?
They greatly increase or decrease microtubule stabily
-This halts cell division and leads to apoptosis
-Inhibit formation of new cells
130
What is Vincristine and what does it do?
A DRUG THAT CAN INHIBIT MICROTUBULE FORMATION
*Structurally related anti-cancer agent vinbblastin produced by same plant
131
What are epothilones?
They are a series of structurally related macrolactones isolated from soil
-They have better water solubility than taxol
= solubilising agents not required
132
What is taxol mode of action?
* 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
How does Taxol damage cancer cells?
Creates stable microtubules, which stalls in mitosis and so leads to cell death
