CHEM10052-CHEMICAL MEDICINE

1. Answer all parts

(a) Anticancer drug A is provided for clinical use as precursors B and C.

(i) Briefly explain the mechanism of action of anticancer drug A. [3]

(ii) Explain how anticancer drug A can be modified for use as an imaging agent and why this would be useful. [3]

(iii) Explain why A is supplied as precursors B and C and draw a reaction scheme for its synthesis. [4]

(b) A ferric (Fe3+) hemoprotein has been shown to act as a highly selective MRI-active dopamine sensor. The figure below shows the structure of the active site of the protein before (D) and after (E) addition of dopamine.

(i) Explain how the hemoprotein affects the MRI signal. [4]

(ii) Explain why the MRI signal changes in the presence of dopamine. [3]

(iii) Describe the interactions contributing to the selectivity of the protein sensor for dopamine. [3]

2. Answer all parts.

(a) Consider the compounds A to D below.

(i) Identify the functional groups in compounds A to D that are ionised at physiological pH. Assign A-D to the following pKa values: 5.4, 5.2, 4.5, and 3.7. [4]

(ii) Rank compounds A to D in order of log Do/w at the pH of the stomach. Indicate the most and least lipophilic compounds. Explain your reasoning and predict which of the compounds A to D would be most readily absorbed in the stomach. [4]

(b) Consider the pharmaceutical compound E.

Explain why none of the nitrogen atoms in E are protonated at physiological pH. [3]

The sulfone group in E is proposed to form important binding interactions with the active site of the target enzyme. Describe the likely interaction and propose a series of synthetic analogues of E that would enable the strength of this interaction to be varied. Synthetic routes are not required. [3]

Suggest three synthetic analogues of E that would enable the relationship between lipophilicity and pharmaceutical activity to be systematically examined. Synthetic routes are not required. [2]

Suggest a non-synthetic strategy for tuning the aqueous solubility of a pharmaceutical preparation containing compound E. [2]

Suggest a synthetic analogue of E with a near identical three-dimensional structure, but drastically decreased aqueous solubility. [2]

3. Answer all parts.

(a) Consider the fluorinated drug A below.

For the C–C bond indicated in A, draw the structure of the most stable conformational isomer in a Newman projection. Justify your answer by drawing and labelling the key stereoelectronic and electrostatic interactions. [6]

(b) Suggest reagents and intermediates for the conversion of molecule B to the fluorinated oxetane C. Reaction mechanisms are not required. [6]

(c) Consider the statin drug D below.

(i) Outline how D lowers cholesterol levels. [4]

(ii) Suggest a pharmacological role for the fluorine atom in D. [1]

(d) Oxetane E is a stronger base than tetrahydrofuran F.

Describe how spectroscopic measurements using compound G could be used to rank the H-bond acceptor abilities of E and F. [3]

4. Answer all parts.

(a) Consider the molecules aniline, toluene and cyclohexylamine.

(i) Compute 14-bit fingerprints of the three molecules using 0, 1st and 2nd order bond paths with the aid of the hash function below. [3]

(ii) Compute Tanimoto coefficients for all pairings using the fingerprints derived in (a) (i). [3]

(b) Consider the set of compounds A-F below that have been classified as active or inactive towards a particular target.

(i) Suggest a 3-point pharmacophore model that may be used to discriminate active from inactive compounds and justify your answer. The model may be built using the following pharmacophore features: A (hydrogen-bond acceptor), H (aromatic/hydrophobic), D (hydrogen-bond donor), P (positive charge), N (negative charge). [3]

(ii) Discuss three pitfalls that may be encountered when applying the proposed pharmacophore model to screen a library to find new active compounds. [3]

(c) Compounds G-I are ligands for a protein binding site sketched below.

(i) Sketch two possible low energy binding modes for compound G and justify your reasoning. [4]

(ii) Propose an explanation for the trends in the dissociation constants measured for compounds G, H, I. [4]

5. Answer all parts.

(a) PROTACs are small molecules that bind simultaneously to a target protein and an E3 ligase such as MDM2 to stimulate the degradation of the target protein.

Name the bioorthogonal reaction used to couple components A and B in the presence of a copper(I) catalyst as shown and suggest suitable functional groups X and Y for this reaction. [2]

Draw a detailed mechanism for the reaction in (a)(i), clearly identifying each step in the catalytic cycle. [2]

Draw a diagram showing how component B binds to MDM2. Clearly indicate the amino acids mimicked by each part of B in the binding site. [2]

To couple the two components A and B inside a cell in the absence of a copper catalyst, trans-cyclooctene was used as the X group in component A. Draw the structure of the complementary Y group used in this intracellular reaction and write a curly arrow mechanism for the coupling of the two components. [3]

Suggest one advantage of coupling A and B inside a cell, rather than before delivery to a cell. Explain your answer. [1]

(b) Monoclonal antibodies (mAbs) linked to cytotoxic drugs give antibody-drug conjugates that can target cancerous cells within an organism.

(i) Using a dose-response curve, explain how the therapeutic window of a cytotoxic drug can be extended when it is conjugated to a mAb. [4]

(ii) Cytotoxic auristatin peptide derivatives have been linked to mAbs using a disulfide linker as shown in D. Explain why this linker can be cleaved inside a cancerous cell and show the expected product(s) of the cleavage reaction. [2]

(iii) Give the chemical structure of an alternative linker motif that could be used to release the cytotoxic auristatin payload under the acidic conditions found in a tumour environment. Your linker design must be compatible with coupling to the mAb at the same site as the disulfide. [4]

6. Answer all parts.

(a) Discuss the importance of plasma protein binding in drug discovery. [2]

(b) Use the information below to explain which of compounds A and B would be the better lead candidate for development as an oral medicine. Provide a detailed justification for your choice, which should also include calculations of properties pertinent to pharmacodynamic action, ligand binding and developability. [12]

(c) Highlight any potential safety concerns related to the candidate structures C and D in pharmaceutical applications. Suggest analogues to mitigate or eliminate toxicity and justify your answer. [6]