Biological Activity of Rosin Derivatives - Rosin-based Chemicals and Polymers - page 197

Scheme 6.20 Structure of glucose and maltose derivatives (80-82)
Elevated blood lipid levels are important risk factors in the development of
atherosclerosis. A new effective and well-tolerated antilipaemic drug is always a
valuable addition to the existing therapeutic agents [59]. Therapeutic approaches
to this disease have therefore focused on the minimisation of epidemiologically
defined risk factors, primarily on the reduction of serum cholesterol levels. It has
been found that tricyclic diterpenoids such as totarol, abietic acid, dihydroabietic
acid, dehydroabietic acid and their derivatives have serum cholesterol lowering
effects in cholesterol-fed rats. Various amides of tetrahydroabietic, dihydroabietic,
abietic and dehydroabietic acids were prepared through chloride intermediates and
were tested for hypocholesterolaemic activity in cholesterol-fed rats. Substituted
N -phenyl and N -benzyl abietamide derivatives, including dehydro-, dihydro-, and
tetrahydroabietamide derivatives ( 83 - 86 ) ( Scheme 6.21 ) were found to be cholesterol
lowering agents. Compounds ( 83 - 86 ) had a significant effect on reducing cholesterol
levels in the blood even when administered in a very minute amount and so were
potentially very valuable as anti-arteriosclerotic agents. The reduced elevated serum
cholesterol levels induced by dihydroabietic anilide reached 97% and the ID 50 value
of N -(4-methoxybenzyl)dihydroabietamide reached 0.005. Anilide derivatives of
rosin acids possess much higher ability to lower blood cholesterol levels than the
amides of fatty (laurinic) acid which are known to be phytosterols for a long time.
Structure-activity relationships revealed that the introduction of an aromatic ring into
the amine moiety of secondary amides markedly enhanced the activity of the parent
acids. The secondary amides bearing an aliphatic ring were slightly less active than
those having an aromatic ring, but those having an alkyl or allyl group were completely
inactive. Amide derivatives of tetrahydroabietic and dihydroabietic acids appear to
be more effective in reducing blood serum cholesterol than abietic or dehydroabietic
acid. N -Phenyl tetrahydro or N -phenyl diydroabietamide and N -benzyl tetrahydro
or N -benzyl dihydroabietamide are considered to be promising parent compounds
for potent hypocholesterolamic drugs [60].