Red blood cells in patients afflicted with sickle-cell anemia show a reduced
capacity for holding oxygen. The adventitious discovery that the lipid lower-
ing agent clofibrate ( 10 ) possessed some antisickling activity led to further
investigation of related compounds. It was found that this unexpected activity
of these agents resulted from their bringing about an increased oxygen-
carrying capacity of normal blood cells. One of the compounds from this
work,efaproxiral( 15 ), is now used to deliver oxygen to hypoxic tumor
tissues to improve the efficacy of radiation therapy. Oxygen, whose presence
is crucial to the generation of cell-killing radicals, is often in short supply in
solid tumors. Reaction of the arylacetic acid ( 11 ) with thionyl chloride leads
to the corresponding acyl chloride. Condensation of that intermediate with
3,5-dimethylaniline leads to the anilide 14. Treatment of that product with
acetone and chloroform in the presence of strong aqueous base adds the
dimethyl acyl function to the phenol group. Thus, 15 is obtained.^3 This
unusual reaction can be visualized by assuming intitial formation of a
hemiacetal between the phenol and acetone (a); displacement of the hydroxyl
by the anion from chloroform would lead to the intermediate (b); simple
hydrolysis would then convert that group to a carboxylic acid.
O Cl
HO 2 C
H 3 C CH 3
10OHCOR11 ; R = OH
12 ; R = ClH 2 N CH 3CH 3
13 OHCH 3CH 3HNO14
(CH 3 ) 2 CO
CHCl 3CH 3CH 3HNO O
HO 2 C
H 3 C CH 3 15OH O- CHCl 2
Cl O
HCl
a b
Overthe past few years, it has been established that severalapparently quite
unrelated drug classes owe their activity to effects on a shared biochemical
system. The blood lipid lowering effect of the fibrates, such as, 10 ,andthe
hypoglycemic action of the recently introduced hypoglycemic thiazolidine-
diones both trace back to action on subtypes of the peroxisome proliferator-
activated receptors (PPAR), which regulates lipid and glucose metabolism.
Research targeted at PPAR has led to several novel hypoglycemic agents,
which are unrelated structurally to drugs previous used to treat diabetes.
- ARYLCARBONYL DERIVATIVES 45