[Inhibition of ecdysone biosynthesis by synthetic molecules].

Abstract

We studied the putative inhibitory activity of about 50 synthetic molecules on the biosynthesis of ecdysone. Most of these molecules had been synthesized according to the conceptual framework of suicide substrate type inhibitors. They potentially react either with well-known catalytic mechanisms (hydroxylations at C-22 and C-25) or with more hypothetic ones (introduction of the keto group at C-6 and the hydroxylation at C-14). The two hydroxylations which take place on the side chain at C-22 and C-25 in the last steps of the ecdysone biosynthetic pathway, and which are catalysed by cytochrome P-450 dependent monooxygenases, can be effectively affected. The essential chemical arrangement which produced a consequent inhibitory effect included an acteylenic or an allenic inhibitory function, near the hydroxylation to inhibit, with a hydroxyl group, preferably grafted in C-20. In order to increase the inhibitory effect, several characteristics gradually appeared: shortness of the side chain, hydroxyl group in position (R) at C-20 and at C-22, if necessary; in the proximal shortening side chain molecules, hydroxyl group at C-17 in position beta; lowering steric hindrance at C-20. It seemed that a molecule bearing a side chain in a relative position behind the midplan of the steroid nucleus induced a more important inhibitory effect. On the contrary, the form of the steroid nucleus itself (as in cholesterol, 7-dehydrocholesterol, 3-dehydrocholesterol, or in a molecule with a saturated B cycle) did not play a deciding part in the activity of the compound. Only the molecules with a typical ecdysteroid nucleus showed a poor inhibitory effect. Molecules acting as suicide substrate type inhibitors on the ecdysone biosynthesis should produce an irreversible inactivation of the enzyme and show a biosynthetic inhibition specifically linked to ecdysteroid. It was not the case of all the tested molecules. Some of them induced a very important inhibition without possessing the other characteristics of a suicide substrate type compound. Other derived chemicals, which were not synthesized according to the framework of the suicide substrate type molecules, showed all the characteristics of this type of molecules. In the course of this work, it has been possible to point out several molecules showing an important inhibitory effect on ecdysone biosynthesis.