Synthesis and cytotoxic activity of hydroxylated derivatives of olivacine in relation with their biotransformation.
The chemical synthesis of 9-hydroxyolivacine and 7-hydroxyolivacine based on a biomimetic approach is described. These two hydroxylated derivatives have been found as main in vitro metabolites of olivacine after incubation with rat hepatic microsomes. The pretreatment of animals with benzo[a]pyrene caused a large increase in both microsomal hydroxylations, whereas the pretreatment with phenobarbital caused a weak increase, with a preservation of 9-hydroxylation/7-hydroxylation ratio greater than 1 in both cases. The two hydroxyolivacines have been also found as principal in vivo metabolites of olivacine in rat bile as glucuronide and sulfate conjugates. The pretreatment of animals with benzo[a]pyrene reverses the 9-hydroxyolivacine/7-hydroxyolivacine ratio excretion in bile to a value that is less than 1. In both in vitro and in vivo experiments, the free metabolites were identified by HPLC and UV-visible, MS, and 1H NMR spectra. Hydroxylation at position 9 increases the in vitro cytotoxicity against leukemia L1210 cells (ID50 = 0.06 microM compared to 2.03 microM for olivacine) and an opposite effect is observed for hydroxylation at position 7 (ID50 = 12.8 microM). On the other hand, hydroxylation at position 9 has no effect on the in vivo antitumor activity against L1210. This might be related to the oxidative and conjugative metabolic pathways that play an important role in antitumor activity and deactivation of olivacine and its hydroxy metabolites.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002227:Carbazoles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D004611:Ellipticines; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002227:Carbazoles; D004611:Ellipticines; C011521:olivacine; C045586:9-hydroxyolivacine; C045585:7-hydroxyolivacine