Irinotecan, structure

In a similar way (and as described for the aromatic isocyanides), aliphatic a, 3-un-saturated isocyanides can also be used, leading to similar structures with a cyclo-hexano instead of a benzo moiety [84]. Based on the approach using aromatic isocyanides, a small library of about 20 camptothecin derivatives has been prepared, of which irinotecan and topotecan have entered the clinical treatment of cancer [85]. For the synthesis of the camptothecin derivatives, 3-206 was alkylated with the appropriate propargylic bromides 3-207 to give 3-208, which were irradiated in benzene at 70 °C, together with the respective isocyanide 3-209 and hexamethylditin... 

Figure 1 Chemical structures of some amphipathic weak bases that have been loaded and stabilized in liposomes using trialkylammonium salts of polyanionic trapping agents in our lab. (A) Doxorubicin, (B) epirubicin, (C) vinorelbine, (D) vincristine, (E) vinblastine, (E) topotecan, (G) irinotecan, (H) swainsonine, (I) 2-diethylami-noethyl-ellipticinium, (J) 6-(3-aminopropyl)ellipticine, and (K) LAQ824.

This chapter reviews recent progress in irinotecan pharmacogenetics, including novel functional genetic variations and the haplotype structures of UGTlAs, with particular focus on the cumulative data showing the clinical relevance of UGTIAI... 

Wadkins, R.M., et al. 2004. Discovery of novel selective inhibitors of human intestinal carboxy-lesterase for the amelioration of irinotecan-induced diarrhea Synthesis, quantitative structure-activity relationship analysis, and biological activity. Mol Pharmacol 65 1336. 

Irinotecan (1) is a derivative of the pentacyclic quinoline alkaloid camptothecin (2) the latter was first isolated from the heartwood of the tree species Camptotheca acuminata (Nyssacea) by Wall et al. in 1966.1 Two years later A. T. McPhail and G. A. Sim determined the structure of 2 by X-ray analysis.2... 

The results of this effort were a detailed pattern of structure-activity relationships (Figure 16.2), and the production of two compounds, topotecan 3[8] and irinotecan 4[9], which were approved for clinical use in 1996, the main indications being ovarian and small-cell lung cancer for the former and metastatic colorectal cancer for the latter. Irinotecan is a water-soluble prodrug of the active compound SN-38 (5) Figure 16.3). Several reviews of this phase of research have been published [10-12]. 

Exatecan is a novel synthetic camptothecin derivative with a unique hexacyclic structure. It does not require metabolic activation, whereas irinotecan does. In vitro experiments in various cell lines have suggested that exatecan may be 6 and 28 times more active than SN-38 (7-ethyl-lO-hydroxycamptothecin, the active metabolite of irinotecan) and topotecan respectively. Furthermore, it has a 2-10 times higher therapeutic index than irinotecan and topotecan. In addition, exatecan may even be active in P-glycoprotein-mediated multidrug-resistant tumor cells. Its dose-limiting adverse effects are neutropenia and liver dysfunction. The recommended dosages of exatecan for phase II trials are 0.5 mg/m /day or 0.3 mg/ m /day as a 30-minute infusion on 5 consecutive days for minimally pretreated and heavily pretreated patients respectively (14,15). 

Both irinotecan and topotecan contain lactone structures, which can be hydrolysed non-enzymatically into the openring form. Under acidic conditions, the equilibrium between the biologically active lactone form and the less active carboxylated form is generally shifted to the lactone form, whereas at physiological or higher values of pH, the lactone form is unstable, because hydrolysis to the... 

In contrast to the structurally related topotecan, irinotecan is a prodrug, which has to be converted to its active form, SN-38 (4,30). Cleavage of the side-chain, a bulky piperidino moiety, at the CIO position is rapidly catalysed by carboxylesterases after intravenous administration. SN-38 (7-ethyl-lO-hydroxy-camptothecin) is 1000 times more potent than the parent compound. There is an equilibrium between the active lactone and the inactive carboxylated forms in a pH- and protein-dependent manner for both irinotecan and SN-38 (31,32). 

The acute form of diarrhea is short-lived and can be effectively prevented or rapidly suppressed by concomitant atropine. The cholinergic symptoms are accompanied by abdominal cramps (36%), sweating (57%), salivation (11%), visual disturbances (15%), lacrimation (12%), and piloerection (3%). The recommended dose of atropine is 0.25 mg intravenously for prevention or 0.25-1.0 mg for acute treatment of patients with early cholinergic symptoms. As cholinergic symptoms have not been observed with other camptothecin derivatives, it can be speculated that these adverse effects are restricted to irinotecan, whose piperidino group bears some structural similarity to the potent nicotine receptor stimulant dimethylphenylpiperazinium (106). 

A few years after the introduction of Taxol in 1996, further phytogenic anticancer drugs were launched to treat advanced cancers. Topotecan, marketed by Smith Kline Beecham under the trade name of Hycamtin, was approved by the FDA to treat ovarian cancers that have resisted other chemotherapy drugs. Furthermore, irinotecan was introduced by Pharmacia Upjohn under the trade name of Camptosar for the treatment of metastatic cancer of the colon or rectum. Both compounds are derivatives of camptothecin which was isolated from the Chinese tree Camptotheca acuminata, well known in Chinese Traditional Medicine for anticancer treatment [65]. Isolation of the bioactive principle camptothecin and its structure elucidation had already been performed in 1966... 

Figure 8.7 Chemical structures of camptothecin, irinotecan, and topotecan.

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