The molecule shown here is Methotrexate, a drug used to treat cancer. Determine the geometry of each of the labeled atoms (a through e). (5 points) 2. The fluid component of blood—minus the red and white blood cells—is an aqueous solution. Cell membranes include a hydrophobic layer that only hydrophobic substances can pass through. Pharmaceutical chemists (the people who design drugs) know that in order to be useful, a drug must be soluble in the bloodstream so that it can reach cells throughout the body, but in many cases it also must able be able to pass through cell membranes in order to get inside cells. Does the molecule shown here meet those two requirements? Explain, referring to specific features of the molecule’s structure. (2 points)

3. Another challenge for pharmaceutical chemists is to ensure that a drug can get into the body in the first place. If a drug is administered orally, it must be able to pass through the cells lining the stomach (where the pH is around 2) or through the cells lining the small intestine (where the pH is around 7) in order to actually enter the body and have a therapeutic effect. Explain why the molecule shown here can pass through cell membranes in the stomach but not in the small intestine. (3 points)

4. Fluorine, the most electronegative atom, is almost never found in naturally occurring biological molecules. However, pharmaceutical chemists often design drugs, such as the one shown here, that contain fluorine atoms in place of hydrogen atoms.

(a) Draw a water molecule as a bent “H—O—H” near the F atom. Add a dashed line to show the hydrogen bond that forms between the fluorinated drug molecule and the water molecule. Draw the dashed line carefully to show which atoms are connected by the hydrogen bond. (3 points)

(b) Explain why the molecule shown above is more soluble than the same molecule with an H atom in place of the F atom. (2 points)

5. Drug designers often start with a “lead compound” that exhibits a mild therapeutic effect. The designers chemically modify the molecule in multiple ways and then test each variant to see whether it works better than the original lead compound. The modifications often include the addition or removal of functional groups. To mimic this process, start with the molecule shown below and perform the chemical modifications listed below (Steps 1 – 4).

Step 1: Remove the entire carboxyl group and replace it with a hydrogen atom.
Step 2: Replace two of the hydrogen atoms in the hexagonal ring structure with hydroxyl groups (note that only one hydroxyl group can be attached to a given carbon atom).
Step 3: Locate the amino group that is not part of a ring structure and replace one of its hydrogen atoms with a CH3 group.
Step 4: Add a CH3 group to one of the hydroxyl groups to form an ether linkage.

(a) Paste in a drawing of the final molecular structure. (4 points)

(b) What is the net (overall) charge of the original molecule at neutral pH? What is the net charge of the fully modified molecule (the one you drew) at neutral pH? (2 points)

6. A common anesthetic is synthesized from these two molecules, by condensing the carboxyl group with the hydroxyl group.

(a) Draw the structure of the anesthetic. (2 points)

(b) Name the type of linkage formed as a result of the condensation reaction. (2 points)