Stereospecific synthesis and combinatorial chemistry L.O. To be able to describe examples of stereospecific synthesis as used in the production of drugs. To find out how combinatorial chemistry techniques are used in the pharmaceutical industry

Stereospecific synthesis Racemic mixtures – addition of H- or CN- to carbonyl compounds. This process is used in the laboratory synthesis of lactic acid (2-hydroxypropanoic acid) from ethanal. Stereospecific compounds – Formation of lactic acid in our muscles. The lactic acid prodced here is only the + isomer. This is because the reaction is catalysed by enzymes (natural catalysts made up of proteins) which are stereospecific (the active site causes this – lock and key hypothesis).

OPTICAL ISOMERS (enantiomers) = 4 different groups bonded to a central C atom such that one isomer is the non-superimposable mirror image of the other W mirror W Chiral (or asymmetric) carbon C C Y Y X X Z Z Hands!

Chirality and drug synthesis Most drugs act on proteins. These are either in enzymes or sensitive receptors on the surface of cells. These receptors respond to chemicals released from nerve endings and hormones. A particular way drugs can work is by targetting the active site of a specific enzyme. E.g. Sulfonamide drugs and penicillin act by killing dangerous bacteria by targeting enzymes. The key issue is to make sure the drug targets the bacterial enzyme active site specifically and does not affect any enzymes in the human the bacteria has infected. In our bodies, most molecules interact very selectively with the active sites in the protein structures of enzymes. The molecules are chiral but our bodies only work with 1 of the isomers.

Chiral compounds in the news…... Most drugs are therefore chiral BUT the 2 optical isomers will act on the body in different ways. Ideally one isomer is effective and one has no effect. But………. Thalidomide: One optical isomer helps morning sickness. The other one causes birth defects. Thalidomide occurs as a racemic mixture! Chrial separation was ESSENTIAL but did not occur.

Thalidomide activity p241 Chiral compounds in the news…... L-Dopa: Parkinson’s disease treatment (Dopamine) http://www.chm.bris.ac.uk/motm/thalidomide/start.html Ritalin http://www.thalidomide.org.uk/home.aspx Thalidomide activity p241

Combinatorial chemistry Technique used by large pharmaceutical companies to synthesise a large number of compounds quickly. Combinatorial chemistry allows chemists to carry out many reactions using computer-controlled equipment, producing milligrams of each product. In combinatorial chemistry reagents are mixed and conditions controlled automatically. Once made, each can be quickly tested for its effectiveness as a drug before being made conventionally on a larger scale if successful.

Combinatorial chemistry 96-well plate allows 96 reactions to be carried out at any one time. For example, esters can be synthesised using 8 different carboxylic acids and 12 different alcohols.

Combinatorial chemistry

Combinatorial chemistry Visit the following website to find out more about combinatorial chemistry and prepare a 1-page or 3-slide summary of this vital pharmaceutical technique. http://www.rsc.org/education/teachers/learnnet/alchemy/index2.htm