Analyse a molecule Flashcards
What is the number we use to approximate N,O,C molecular weight?
15
What must we think about when given a molecule to analyse?
1) Molecular weight
2) Volatility
3) Polarity
4) Distribution
5) Metabolism
6) Excretion
What is oxidation?
When carbon atoms gain bonds to more electronegative atoms (often oxygen)
What is reduction?
When carbon atoms lose bonds to more electronegative atoms (such as oxygen) and instead gain bonds to hydrogen.
What is the rule of thumb about volatility, VOC
Boiling point below 250 is VOC
Use reference pentadecane C15H32 which has boiling point 270
What is the rule of thumb about uptake in intestines?
Molecular weight below 500 can get uptaken, above 500 is too large
How should we think about volatility?
Relate it to boiling points of corresponding hydrocarbon.
Eg. pentadecane (C15H32) has a boiling point of 270, use this as reference
What is the risk of VOC?
Risk of inhaling
Average polarity if…
a molecule has around one heteroatom in every 5 atoms (not sure about this one)
Oxidation of alkyl/methyl group
Alcohol (OH) to aldehyde (COH) to carboxylic acid (COOH)
Carboxylic acid can undergo which phase II reaction?
Conjugation with glycine (most simple amino acid) NH2CH2COOH
Oxidation of the nitrogen NH
NH to NOH
NOH can undergo which phase II reaction?
Sulphated, conjugation with OSO3 makes nitrogen an electrophile
Double bounds can undergo which phase I reaction?
Epoxidation
An epoxidised benzene reacting with water forms…
two OH groups which can be made into autoquinon
A Michael acceptor has…
double bond single bond double bond to oxygen
Carboxylic acid when H removed is very polar and will therefore be distributed by … and excreted in …
Distributed by the blood and excreted by the kidneys
Flat molecules are toxic because of…
intercalation. Planar molecules toxic as such in DNA (already toxic before metabolised)
Nitrogroup can be reduced to…
nitroso and hydroxylamin
Carboxylic acid on aromatic ring is often conjugated with… and forms…
Conjugated with glycine and forms hippyric acid
Acetals are not stable under … conditions
acidic conditions (an exception is if it is part of five/six member ring)
Nitrogroup gets reduced to
N=O and then NOH2
Hydroxylamine HNOH on benzene is toxic when it undergoes which phase II reaction?
When conjugated with OSO3 making N an electrophile (it gets a positive charge)
NO2 and NH2 form the same two products in the body, which?
N=O and HNOH
What is a benzene with an NH2 group called?
Anillin
Why is anillin toxic?
Aniline damages hemoglobin, a protein that normally transports oxygen in the blood. The damaged hemoglobin can not carry oxygen. It converts FeII to FeIII which is inactive.
Epoxides can react in which phase II reaction?
Conjugation with glutathione (GSH)
When a molecule is of average polarity it is distributed in…
blood and fatty tissue
What are the physical and chemical properties when we analyse a molecule?
1) Molecular weight
2) Volatility
3) Polarity
What is a hydroxylamine
HNOH on benzene
What is a nitrosocompound?
N=O on benzene
The reduction of the nitrosocompund N=O on benzene becomes HNOH on benzene and uses what as its reducing agent which makes it toxic?
It uses FeII to reduce and FeII becomes FeIII which is inactive and cannot carry oxygen.
Hydroxylamine (HNOH on benzene) undergoes which phase II reaction?
It gets sulphated (conjugated with OSO3) to make it more water soluble but this makes N electrophilic
What are phase I reactions?
Oxidation, reduction, hydrolysis
What are phase II reactions?
Conjugations with glycine, OSO3 or GSH
More notes:
Enzyme (common) reacts with the drug: (UDP-glucuronosyltransferase, UGT) found in SER adds on glucuronide (super polar). In a glucuronidation reaction.
Enzyme glutathione S transferase. Transfers a glutathione molecule onto the drug. Makes it super charged and polar. Very important antioxidant.
Enzyme sulphur transferase SLT. adds on a sulphate group OSO3.
Enzyme NAT N-acetyl transferase adds on an acetyl group.
Phase I reactions
Phase I: for example oxidation/hydroxylation at carbons next to ether oxygens, with subsequent hemiacetal hydrolysis;
epoxidation of phenyl rings; epoxide hydrolysis; nitro reductions.
Phase II reactions
Phase II: for example conjugation of the carboxylic acid with an amino acid such as glycine; conjugation of a phenol
(from phase I) with glucuronic acid; conjugation of a phenol (from phase I) with sulfate; opening of an epoxide with glutatione; conjugation of a hydroxylamine (from phase I reduction two steps from the nitro) with glucuronic acid;
conjugation of a hydroxylamine (from phase I reduction two steps from the nitro) with sulfate.
How do we determine whether a molecule is hydrophilic or hydrophobic?
It is hydrophobic/lipophilic if it has only one or less hydroxyl or amino group per 8 carbons
What makes a molecule polar (hydrophilic)?
Functional groups that are, or are
converted to, charged groups at physiological pH, such as sulfates, carboxylates and aliphatic amines
make a molecule highly polar. That hydrogen bond donors (HBD, these are also HBA) such as the
hydroxyl group, primary and secondary amines and amides also convey a fair dose of polarity. Other oxygen and nitrogen functional groups such as esters, ketones, ethers (HBA, dipols) also provide polarity but to a lesser extent.
What functional group/heteroatoms make a molecule hydrophobic?
A group of heteroatoms that contribute to increased hydrophobicity are the halogens. The more
halogenated a molecule is, the more it prefers to distribute into a lipophilic phase. Often, this goes
hand in hand with metabolic resistance making heavily halogenated compounds an environmental
problem as they tend to accumulate in top predators of the food chain.
What is an aliphatic compound?
An aliphatic compound is an organic compound containing carbon and hydrogen joined together in straight chains, branched chains, or non-aromatic rings. It is one of two broad classes of hydrocarbons, the other being aromatic compounds
What is dehalogenation?
In organic chemistry dehalogenation is a set of chemical reactions that involve the cleavage of C-halogen bonds. Dehalogenations come in many varieties, including defluorinaion, dechlorination, debromination, and deiodination.
Generation of ROS in which one electron is added in each step down:
Dioxygen in “normal” ground-state O2
Superoxide anion O-O.
Hydrogen peroxide HOOH
Water and hydroxy radical HOH OH.
Water (Unreactive and NOT ROS) HOH HOH
Down: reduction
Up: oxidation
What is lipid peroxidation?
Membranes are frequently the target for ROS and other radicals
Unsaturated fatty acids are oxidised by radical processes
Membranes and membrane components are damaged
Enzymes on the membrane are damaged
Harmful electrophiles are formed
