triacylglycerols (or triglycerides) because they are triesters of glycerol with three long-chain
carboxylic acids. Hydrolysis of a fat or oil in an aqueous alkaline solution (saponification)
produces glycerol and three fatty acids. There are more than 100 naturally occurring
fatty acids. Polyunsaturated fatty acids, such as linoleic or linolenic acid, contain more
than one double bond; saturated fatty acids contain no double bonds. The primary bio-
logical function of triacylglycerols in animals is to function as an energy storage depot;
when triacylglycerols are metabolized they yield more than twice as many calories as
does an equal mass of a protein or carbohydrate.
Lipid biochemistry will receive increasing attention in medicinal chemistry because of
the epidemic of obesity occurring in developed countries with its associated co-morbidities
such as diabetes and accelerated atherosclerosis, leading to strokes and heart attacks.
There is compelling evidence that too much saturated fat in the diet can lead to the
development of heart disease, and perhaps cancer as well. Moreover, there is also accu-
mulating evidence that “trans” fats can likewise lead to an increased risk of cardiovascular
disease. Polyunsaturated oils tend to react by auto-oxidation, causing them to become
rancid and have a short shelf life; accordingly, partial hydrogenation is performed to
convert the oil into an appealing semi-solid with a prolonged shelf life. Regrettably, a
problem with partial hydrogenation is that the catalyst isomerizes some of the unreacted
double bonds from the natural cisconfiguration to the unnatural trans configuration.
8.1.4.2 Lipids: Phospholipids
Phospholipids are diesters of phosphoric acid (H 3 PO 4 ), just as fats and oils are esters of
carboxylic acids. There are two main types of phospholipids:phosphoglyceridesand
sphingolipids.Phosphoglycerides, organized into a lipid bilayer, comprise the major
lipid component of cell membranes. Since this bilayer is the principal barrier to the pas-
sage of molecules into and out of a cell, phosphoglyceride structure is of interest in
medicinal chemistry and drug design. Phosphoglycerides contain a glycerol backbone
linked by ester bonds to two fatty acids and one phosphoric acid. The two most impor-
tant phosphoglycerides are the lecithins and the cephalins.
Sphingolipids are the second major group of phospholipids. Rather than a glycerol
backbone, these lipids have sphingosine (a substituted dihydroxyamine) for their back-
bone structure. One particular sphingolipid,sphingomyelin, is a major lipid constituent
of neuronal axons within the brain and nervous tissue. The sphingolipids, together with
proteins and polysaccharides, constitute myelin, the lipid-based coating of neurons within
the brain. Since the need to develop drugs for demyelinating diseases, such as multiple
sclerosis, is a continuing drug design target, interest in sphingolipids is of relevance to
medicinal chemistry. General structures of some key lipids are given in figure 8.3.
8.1.4.3 Lipids: Prostaglandins and Eicosanoids
Prostaglandins are C20 carboxylic acids, derived from arachidonic acid, that contain a
5-membered ring, at least one double bond and several oxygen-containing functional
groups. The 1982 Nobel Prize in medicine was awarded to Bergström, Samuelson, and
Vane for their pioneering work in prostaglandin chemistry. Prostaglandins are found in
almost all animal tissues, and exert an extraordinary range of biological effects, resulting
472 MEDICINAL CHEMISTRY