Chemistry of alkaloids (spring)

Question 1

name common alkaloids and draw their structure

Answer 1

Question 2

where do alkaloids come from?

Answer 2

They occur naturally and are produced by plants, fungi and animals

Question 3

Why produce alkaloids?

Answer 3

Nicotine is a secondary metabolite of various plants (high concentrations in tobacco plants, but also found in other members of Solanaceae). Toxic to insects, so thought to be an insect antifeedant (produced by the plant in response to herbivory). One of the first compounds to be used as an insecticide.

Senecionine is one example of an alkaloid found in high concentrations in Jacobaea vulgaris. Toxic to a number of mammals (grazing stock such as cows and horses particularly susceptible). Fresh plants tend to be avoided, but problems can occur when ragwort ends up dried in hay or silage. Senecionine is hepatotoxic. Some insects preferentially feed on plants containing high levels of pyrrolizidine alkaloids such as senecionine. The alkaloids accumulate in the skin of the caterpillars, protecting them from predation

Question 4

Alkaloids for defense?

Answer 4

Alkaloids are found in animals:

Puffer fish

• Family: Tetraodontidae (over 30 species)
• Weapon of choice: Tetrodotoxin

Golden poison frog

• Phyllobates terribilis
• Weapon of choice: multiple different alkaloids including Batrachotoxin

Question 5

the structure of alkaloids?

Answer 5

Contain nitrogen, usually in a heterocyclic ring

Basic (alkaline) in nature; alkaloids form salts with acids – e.g. morphine hydrochloride

Question 6

what are the Classes of Alkaloids?

Answer 6

Quinoline: eg quinine

Indole: e.g. strychnine, physostigmine, ergot alkaloids (including LSD), vinca alkaloids

Tropane: e.g. cocaine, atropine

Isoquinoline: e.g. morphine, codeine

Bisbenzylisoquinoline: e.g. tubocurarine

Pyridine: e.g. nicotine

Miscellaneous: e.g. caffeine, ephedrine, colchicine

Question 7

give examples of uses of Quinoline Alkaloids

Answer 7

Quinine: An antimalarial from which newer drugs (e.g. chloroquine, mefloquine) have been developed. Also acts as an anti-arrhythmic, so avoid in heart disease. Used in ‘tonic water’

Quinidine: closely related to quinine - a more potent anti-arrhythmic

Derivatives of quinine are used as antimalarials

Chloroquine - Sometimes used in amebiasis, rheumatoid arthritis and lupus

Mefloquine (or Lariam®) - side effects can include depression and anxiety

Question 8

what motifs do Quinoline Alkaloids have?

Answer 8

they all contain a “quinoline” group

Question 9

what motifs do Indole Alkaloids have?

Answer 9

These structures contain an indole

Question 10

what motifs do Tropane Alkaloids have?

Answer 10

These structures contain tropane

Question 11

where do Isoquinoline Alkaloids come from?

Alkaloid examples?

toxicity?

Answer 11

Papaver somniferum (Papaveraceae)

Opium, the dried latex from the unripe capsule (fruit)

Seeds used in cooking and for oil

Analgesic (pain killer)

Alkaloid examples: morphine, codeine, Thebaine

Toxicity: depends - seeds and oil safe, alkaloids not!

Question 12

what motifs do Isoquinoline Alkaloids have?

Answer 12

Alkaloids in this class contain isoquinoline, or derivatives of isoquinoline (such as benzoisoquinoline)

Question 13

what are different Isoquinoline Alkaloids used for?

Answer 13

Papaverine: a smooth muscle relaxant, used for male impotence

Morphine: a strong pain-killer – can be acetylated to diamorphine (heroin) using acetic anhydride

Thebaine: toxic, can be converted to codeine, also used as a source of Bentley compounds, such as etorphine, used as veterinary sedative and for euthanasia

Codeine: also an analgesic, and used for coughs and to treat diarrhoea

Question 14

What is meant by “biosynthetic precursor”?

Answer 14

In cells, biological molecules are built up in from smaller precursors. Small molecules are gradually elaborated into larger and more complex structures. A biosynthetic precursor is a molecule which goes on to become another important biological molecule. You can often see parts of the structure of the biosynthetic precursor in the final product.

Question 15

The majority of opioid alkaloids used as therapeutics (or their precursors) are still extracted from plants (or other natural sources). Suggest reasons for this.

Answer 15

Opioid alkaloids have very complex structures which are difficult to make synthetically, so it is easier to extract them from natural sources. In addition, plants produce very large quantities of opioid alkaloids, so it is easy to extract a large quantity of the desired products.

Question 16

Alkaloids have basic nitrogen atoms. How might this aid the extraction of material from natural materials?

Answer 16

As the nitrogen atom is basic, it can be protonated and deprotonated easily – so it makes it easy to extract from other material, as depending on whether it is protonated or not, they can be extracted into water or organic solvents selectively.

Question 17

Outbreaks of ergotism have been documented in historical sources, but the descriptions of the symptoms in these records can often differ. Suggest reasons for this.

Answer 17

Ergotism arises from eating grain contaminated with fungi which produces a large number of different alkaloids. It is likely that different alkaloids in this group have different effects, so the overall clinical presentation of the resultant disease (and hence the description) will differ if people have consumed larger quantities of one alkaloid in the mixture over another. These differences can arise from different strains of fungi or different environmental conditions influencing the alkaloids produced.

Question 18

Papervarine is often administered as the hydrochloride salt. The structure of papervarine is shown below.

Convert the molecule to the hydrochloride salt form.

Answer 18

Question 19

TTX has been reported to be found in some types of shellfish as well as in pufferfish. What does this suggest about the biosynthesis of TTX?

Answer 19

This could suggest a couple of things, but they are both related to the same point – that there is a similarity between the shellfish and the pufferfish.

This could be an intrinsic biological similarity – that they share a biosynthetic pathway.

It could also be an environmental similarity – for example, they could both derive the toxin in the same way from an external source (such as a shared food stuff).

Question 20

a) . By injection, the fatal dose of TTX in mice has been reported to be around 8 µg per kg. Can you estimate how much TTX would be fatal to a person if were administered by injection?
b) . When we’ve been carrying out these calculations, we’ve had to make some assumptions about the data. What are some of the limitations of the data we’ve used to form our conclusions?

Answer 20

8 µg per kg x 75 kg = 600 µg

600 µg ÷ 1000 = 0.6 mg

There are a few here.

• You might consider if the data for mice would be equivalent to the data in humans?
• Do mice respond to TTX in the same way a person would?
• We estimated an average weight for a person too.
• Would all people respond to a toxin in the same way?