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Section 1 Flashcards

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1
Q

What is the definition of medicinal chemistry?

A

A branch of chemistry focused on drug design, synthesis, and development.

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2
Q

When was the concept of active molecules discovered?

A

Early part of the second millennium.

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3
Q

Which preparations of plants to treat conditions are still used today?

A

Feverfew plant - anti-inflammatory and anti-hyperalgesic (Perthanolide)
Opium poppy - analgesic (morphine)
Ma Huang - cough, asthma (ephedrine)
Cinchona/fever tree - malaria, fever (quinine)
Incas plant - local anaesthetic, stimulant, euphoric (cocaine)
Foxglove - cardiac stimulant (Digoxin)

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4
Q

In what year was cocaine first isolated?

A

1860

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5
Q

What did Niemann note about cocaine when it was isolated in 1860?

A

That it “numbed the tongue”.

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6
Q

What was discovered about cocaine in 1880?

A

von Anrep recognised its use as a local anaesthetic after trials on animals on himself.

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7
Q

What 3 things was cocaine used as in the late 1800s?

A

Anaesthetic
Stimulants
Antidote to morphine addiction.

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8
Q

What were the 3 early synthetic Caine anesthetics?

A

Cocaine 1800s
Amylocaine 1903
Procaine 1905

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9
Q

What is semi-synthesis?

A

The chemical derivatisation of a natural product which relies on the ability to obtain the original precursor in a pure form by harvesting it from the plant that produces it.

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10
Q

What was the first key example of semi-synthesis?

A

Conversion of morphine to diacetylmorphine/diamorphine/heroin using combustion analysis with acetic anhydride.
By Alder Wright in 1874.

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11
Q

What are alkaloids?

A

A class of nitrogenous organic compounds of plant origin which display physiological action on human beings.

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12
Q

Name 4 alkaloids which were isolated in the 1800s.

A

Morphine - 1805
Colchicine - 1820
Cocaine - 1855
Ephedrine - 1885

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13
Q

What functional groups present on many active plant-based natural products are useful in extraction of the pure form?

A

Basic amine
Carboxylic acid.

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14
Q

How is ephedrine extracted from Ephedra sinica (Ma Huang)?

A
  1. Plant is dried and powdered.
  2. Partitioned between benzene (organic phase) and aqueous sodium carbonate solution (aqueous phase). Ephedrine is unionised in the basic environment so is highly organic solute which would partition into the benzene organic phase, seperate from the acidic or water-soluble components.
  3. Aqueous phase disposed of.
  4. Organic phase mixed with HCl (aquoeus acidic phase).
  5. Basic ephedrine molecule becomes ionised in acidic environment as amine becomes protonated. Ionised ephedrine partitions into aqueous phase.
  6. Organic phase disposed of.
  7. Aqueous phase mixed with chloroform (organic phase).
  8. Potassium carbonate added to neutralise HCl and convert aqueous component into alkaline environment, which converts ephedrine back to unionised freebase form (i.e., pure basic form of amine, not its salt).
  9. Unionised basic ephedrine partitions into organic phase (now organically soluble again).
  10. Organic phase separated and evaporated, leaving a solid form of ephedrine with minimal impurities.
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15
Q

After semi-synthesis of ephedrine, how can an even purer form with less impurities be achieved?

A

Convert into a salt (amine protonated), for example using oxalic acid, and and recrystallise the oxalate salt.

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16
Q

What were the steps towards aspirin identification and isolation?

A
  1. 1829 - Salicin isolated from active bark extract from the white willow tree.
  2. 1838 - Salicin glycoside hydrolysed and the products are oxidised to produce Salicylic acid.
  3. Ingestion of salicylic acid or salicin (prodrug of salicylic acid) resulted in extreme irritation and discomfort.
  4. 1853 - less irritant version produced.
  5. 1897 - aspirin isolated and produced.
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16
Q

What is the earliest example of semi-synthesis?

A

Production of aspirin (acetylsalicylic acid) from salicylic acid via acetylation using acetic anhydride.

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17
Q

What 4 advances technologies have allowed advances in knowledge of drug targets?

A

Improvements in spectroscopy
X-ray crystallography
In silico techniques
Imaging

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18
Q
A
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19
Q

How were substances described before the 1900s?

A

Methods of isolation
Appearance
Simple characterisations e.g., melting point

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20
Q

How were complex structures of substances solved in the past?

A

Use of:
Elemental analyses
Degradation studies
Functional group manipulations/

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21
Q

What does X-ray crystallography do?

A

Produces a 3D structure of a scaffold which allows complex structures to be fully elucidated more quickly and with greater confidence.

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22
Q

How does the structure of the anticancer agent Calichaemicin contribute to its mechanism of action?

A

Calichaemicin contains an unusual unsaturated section known as an enediyne (a single alkene and 2 alkynes within a cyclic structure).
1. Calichaemicin binds to minor groove of DNA.
2. The enediyne generates potent radical species.
3. Radicals extract hydrogen atoms from deoxyribose backbone of DNA, causing strand breakage.
4. Cellular apoptosis

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23
Q

How is Calichaemicin usually produced and why?

A

It is too toxic on its own so it is produced as an antibody-drug conjugate known as Gemtuzumab Ozogamicin.
The antibody targets CD33, a transmembrane protein present on leukemic blast cells.

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24
Q

What is total synthesis?

A

The complete chemical synthesis of a complex molecule from simple, commercially-available precursors.

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25
Q

What are 5 benefits of total synthesis compared to semi-synthesis?

A

Isolation can be time-consuming, expensive, and highly variable.
Large quantities of material (kgs) are required to produce mgs of pure isolated product.
Raw materials access can be restricted due to climatic or political factors.

Total synthesis provides reliable access to new and unnatural analogues,
Total synthesis is amenable to scale-up in order to manufacture large quantities of material.

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26
Q

From where is Galantamine derived?

A

The snowdrop plant aka Galanthus. However, it is commercially produced through total synthesis.

27
Q

How does Galantamine work?

A

Vascular dementia and Alzheimer’s - Binds to presynaptic nicotinic acetylcholine receptors to facilitate the release of presynaptic acetylcholine. Also has acteylcholine esterase inhibitory activity.

28
Q

How did total synthesis of ephedrine develop over time?

A

In 1929, racemic synthesis of ephedrine using benzaldehyde was used.
In 1934, an enantioselective synthesis , also using benzaldehyde, was developed to produce levo-ephedrine.

29
Q

What is the process of enantioselective synthesis of ephedrine?

A
  1. Benzaldehyde mixed with pyruvic acid in the presence of glucose and yeast (enables high levels of sterochemical control) to produce a keto-alcohol with correct stereochemistry.
  2. Reductive amination of keto-alcohol in presence of methylamine. Amine on methylamine reacts and condenses with ketone of keto-alcohol.
  3. Product is dehydrated to become an imine.
  4. Imine reduced with hydrogen over platinum catalyst. Hydrogen addition to imine double bond is controlled by hydroxyl group of keto-alcohol so that only one stereo-outcome is achieved.
  5. Natural levo-ephedrine produced in high and reproducible yields.
30
Q

Where is Eribulin, the anti-tumour drug, derived from?

A

From Halichondrin B, isolated from the marine sponge Halichodria okadai.

31
Q

How does Eribulin work?

A

Anti-tumour agent which targets tubulin and inhibits microtubule growth, causing formation of non-productive tubulin aggregates. This causes persistent mitotic arrest (i.e., inhibits mitosis) and induces apoptosis.

32
Q

Describe the discovery of Rifampicin.

A

Rifamycin B isolated from plant due to its activity against gram-positive bacteria, especially Mycobacterium tuberculosis.
Derivatives were investigated using semi-synthetic approaches to find improved potency. Rifampicin, which contained an N-amino-N-methylpiperazine side chain, was found to have high bactericidal action and higher oral bioavailability.

33
Q

What 3 theories were developed by Paul Ehrlich.

A

Side-chain theory
Receptor theory - specific chemical entities that could interact with drugs.
Magic bullet - substance which can target bacteria without impacting the patient’s own cells. (selective toxicity)

34
Q

How did John Langley develop the concept of receptors?

A
  1. Isolated Pilocarpine from Jaborandi plant.
  2. Injected pilocarpine into frog and observed decreased heart rate.
  3. Injected pilocarpine, followed by atropine, and observed an increase heart rate.
  4. Determined that Pilocarpine was an agonist where atropine was an antagonist (at muscarinic receptors).
35
Q

Detail the history of enzymes.

A
  1. 1878 - idea of enzymes introduced to describe a component involved in the fermentation of sugar to alcohol.
  2. 1894 - lock and key hypothesis.
  3. 1907 - first enzyme identified , Zymase - extracted from yeast and used to ferment sugar without the presence of living cells.
  4. 1937 - first enzyme crystallised, lysozyme.
  5. 1965 - first X-ray crystal structure of enzyme, lysosyme.
  6. 1969 - first synthesis of an enzyme - Ribonuclease using solid-phase peptide synthesis.
36
Q

What was the 1982 Nobel Medicine prize for?

A

Discoveries concerning prostaglandins and related biologically active substances.

37
Q

What was the 1988 Nobel Medicine prize for?

A

Discoveries of important principles for drug treatment:
Beta-blockers, propanolol
H2 antagonists, Cimetidine
Nucleic acid synthesis inhibition in cancer cells.

38
Q

What was the 2012 Nobel Medicine prize for?

A

Revealing the inner workings of an important family of G-protein coupled receptors, beta-adrenergic receptors.

39
Q

What was the 2015 Nobel Medicine prize for?

A

Discoveries concerning novel therapies against roundworm parasite infections and malaria.

40
Q

What was the goal of Project 523?

A

Identify antimalarial drugs which could be used on the battlefield of the Vietnam war.

41
Q

Detail how Youyou Tu isolated and identified Artemisinin.

A
  1. Screened 2000 extracts to find 680 which exhibited activity.
  2. Identified extracts from qinghao plant inhibited P. falciparum by 68% in mice.
  3. Realised results were not reproducible.
  4. Reviewed ancient Chinese literature and found the use of the plant. Realised that her preparatoin involved heating the plant, while ancient preparation did not so the active ingredient wouldn’t degrade.
  5. Changed preparation method to separation by acid extraction, leaving a neutral fraction which was found to inhibit P falciparum growth by 100% with no toxicity.
42
Q

Describe the structure of artemisinin.

A

A multi-cyclic structure containing 7 chiral centres.
Contains an unusual and unstable trioxane ring (3 oxygens in ring) which includes endoperoxide (2 oxygens of trioxane which aren’t in main ring).

43
Q

Describe the semi-synthesis of Artemisinin analogues such as Artemether and Arteether.

A
  1. Lactone carbonyl group of Artemisinin reduced using hydride reducing agent e.g., sodium borohydride
  2. Lactol produced known as dihydroartemisinin (i.e., artemisinin with 2 hydrogens across the carboynl pi bond)
  3. Hydrogen of fydroxy group can be substituted with various alcohols to generate different analogues.
44
Q

Describe the semi-synthesis of the Artemisinin analogue, sodium artesunate.

A
  1. Lactone carbonyl group of Artemisinin reduced using hydride reducing agent e.g., sodium borohydride
  2. Lactol produced known as dihydroartemisinin (i.e., artemisinin with 2 hydrogens across the carboynl pi bond)
  3. Condensation of dihydroartemisinin usnig succinic acid to produce sodium artesunate.
45
Q

Name one group which is necessary for activity and one group which isn’t in Artemisinin analogues.

A

Necessary - endoperoxide.
Unnecessary - lactone.

46
Q

Why is the endoperoxide necessary to artemisinin analogue activity?

A

During haemoglobin digestion in the infected RBC by malaria parasite, free heme is produced. Heme catalyses the cleavage of the endoperoxide structure, resulting in the alkylation of heme and essential proteins, leading to generation of reactive oxygen species (ROS). These ROS are toxic and kill the parasite.

47
Q

Why are artemisinins only effective during an active malaria infection?

A

Artemisinins are activated by heme cleaving the endoperoxide in its structure, then alkylates the heme to form toxic products. Heme is usually inaccessible, but becomes exposed when digested by the parasite in its food vacuole.

48
Q

Other than the endoperoxide, what is required for anti-malarial activityin artemisinins? How do we know this?

A

An alpha hydrogen on carbon 4.
Following activation by heme, this hydrogen shifts to carbon 1 (previously in endoperoxide) to form a C4-centered radical which can produce toxic species.
When this is replaced by a methyl group in the alpha position (regardless of what is in the beta position), the molecule is 100x less active than artemisinin.
When the alpha hydrogen is retained but a methyl is in the beta position, the molecule is 2x more active than artemisinin as the methyl stabilises the C4 radical.

49
Q

What is the active metabolite of the prodrug Artemisinin? How is it formed?

A

Dihydroartemisinin.
Artemisinin is metabolised in the liver by CYP enzymes.

50
Q

What is artemisinin combination therapy (ACT)?

A

Combination of:
A short-acting artemisinin based compounds such as Artemisinin, Artemether and sodium artesunate.
A longer-acting companion drug such as Mefloquine, Amodiaquine, Sulfadoxine, Piperaquine etc.

51
Q

Why is artemisinin combination therapy used?

A

Artemisinins provides quick and effective results but alone could lead to recrudescence and resistance, which is prevented by the longer acting companion drug.

52
Q

What is Ingenol?

A

A diterpine derived from E. pelpus sap which has recently been approved for treatment of actinic keratosis, a pre-cancerous skin condition caused by UV exposure.

53
Q

What is the 2-stage model of skin carcinogenesis for use in cancer research studies?

A
  1. Tumour initiator used to promote carcinogenesis
  2. Tumour promoter used for cancer progression.
54
Q

Name a tumour promoter used in cancer research studies.

A

Phorbol triacetate.

55
Q

What was the effect of E. pelpus sap on melanoma cell lines.

A

Dose-dependent effect between sap and melanoma cell growth.
Also, melanoma cell line (MM96L) differentiated from poly-dendritic phenotype to the bipolar phenotype usually displayed in skin cells.

56
Q

How does Ingenol work?

A

Influence signals through PKC/MEK/ERK pathway to invoke cell death through apoptosis.
Induce interleukin decoy receptors to reduce long-term cell viability.

57
Q

What was the issue discovered with Ingenol after use in the community?

A

Irritation and increased risk of skin cancer at the site of application.

58
Q

What is a diterpene?

A

A class of terpene (naturally occurring hydrocarbon-based compound from essential oils in fungus/plants) formed from 4 isoprene units.

59
Q

Name 2 pharmaceutical diterpenes.

A

Ingenol
Paclitaxel

60
Q

Identify two structural features that are common to cocaine, amylocaine and procaine

A

Benzoate and tertiary amine

61
Q

Describe esterification, the process made to produce procaine using para-aminobenzoic acid and N,N-diethylethanolamine (solvent).

A

Esters can be prepared via a condensation reaction between a carboxylic acid and an alcohol. This reaction may be catalyzed by an acid or a base.

62
Q

From what natural precursor is Paclitaxel derived>

A

Baccatin III

63
Q

What is the major natural penicillin from which numerous other penicillins are synthesised?

A

Penicillin G

64
Q

What does it mean if the pH of a solution is above or below the pKa of a compound?

A

If the pH of solution is greater than the pKa, the group is in the conjugate base form (deprotonated).

If the pH of solution is less than the pKa, the group is in the conjugate acid form (protonated).

65
Q

What is a diterpine?

A

Diterpenes are a class of chemical compounds composed of four isoprene units, often with the molecular formula C20H32

Chem (7 decks)

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