Studies on biliary excretion in the rabbit II. The relationship between the chemical structure of certain natural or synthetic pentacyclic triterpenes and their icterogenic activity. Part 1: The substituents on carbon atoms 3, 17, 22 and 24

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Abstract
Considerable interest has been aroused by the use of the pentacyclic triterpene acid, incterogenin, in studies associated with bilirubin excretion and the genesis of icterus of the intrahepatic chole-stasis type. This compound, which produces within a few hours after administration to sheep and rabbits a very marked decline in bile flow and the amount of bilirubin excreted hourly without any histological damage to the liver parenchyma visible in the ordinary light microscope, has proved to be very useful in the study of the South African ovine photosensitization disease known as "geeldikkop" ("yellow thick head"). In connexion with research on this disease, a study of the relationship between the chemical structure of the pentacyclic triterpenes and their icterogenic activity is in progress. The first part of this work dealing with certain structural variations in triterpenes of the oleanane and 24-noroleanane (hedragane) series is reported in this paper. Assays are recorded of sixteen of these compounds and some of their derivatives for such activity, using a modification of the rabbit test described in the first paper of this series (Heikel, Knight, Rimington, Ritchie and Williams 1960). Four new icterogenic agents are discussed, namely 22[BETA]-angeloyloxyoleanolic acid, 22[BETA]-angeloyloxyhedragolic acid, 22[BETA]-angeloyl-oxy-24-hydroxyoleanolic acid and 22[BETA]-angeloyloxy-24-oxo-oleanonic acid. The first two mentioned compounds are extremely active, their potency far surpassing that of icterogenin. Icterogenic activity of these acids appears, so far, to be based upon the presence of a [BETA]-equatorially orientated hydroxyl group at C(3) or a hydroxyl at C(24) and a 22[BETA]-angeloyl side-chain on the triterpene molecule. Stereoisomer specificity is shown in respect of ictero-genicity by these compounds since the epimers of two of these substances carrying a-axially orientated hy-droxyls at C(3) have been shown to have no such effect on bile flow or bilirubin excretion. Removal of the angelic acid side-chain, substitution of the hydroxyl groups or replacement of these with a ketone function, is followed by loss of activity.
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