These are my notes from discussion section number 8 of Harvard’s Chemistry 101: Chemical Biology Towards Precision Medicine course, taught by Edward Harvey and Chris Gerry on October 27, 2015.

General Q&A

Q. What is click chemistry?

A. For more background, see [Kolb 2001, Hein 2008]. These sort of reactions were originally achieved through Cu or Ru catalysts, but these are toxic. Caroline Lubertozzi (sp?) developed a catalyst-free system using a cyclooctyne and an azide. Alkynes really want to be perfectly linear, so being part of the 8-membered ring introduces strain, which the reaction relieves, thus making it favorable without a catalyst. This is often called bioorthogonal labeling because these are groups you never see in biological systems.

Q. Besides the blood-brain barrier, what other barriers are difficult for small molecules to cross?

A. There are several important barriers, here is a list for orally delivered drugs:

  1. Stomach - acidic (pH = 1) environment
  2. Small intestine - permeability through gut wall
  3. Liver - metabolic enzymes in the liver sometimes will add hydrophilic groups to make it rapidly excreted
  4. Blood supply - must permeate capillary pores (90-150Å diameter)
  5. Cell membrane Upon reaching target tissue, the compound must permeate the cell membrane. Usually this is just passive diffusion through the phospholipid bilayer; there are a small minority of drugs that hijack active transporters.

Intravenous administration bypasses 1, 2, and to some extent 3. Drugs for extracellular proteins don’t need to worry about 5.

Challenges in neglected tropical diseases

The reading for today is [Burrows 2014], which discusses current challenges for chemical biology and diversity oriented synthesis in enabling drug discovery in neglected tropical diseases.

Leishmaniasis is a protozoal parasite that lives inside lysosomes in human macrophages. Current standard of care drugs such as miltefosine have considerable adverse effects, and many of them, such as meglumine antimoniate have to be given intravenously and contain antimony (Sb) which can accumulate to toxic levels in the patient’s tissues.