ChemInform Abstract: Regiospecific Inverse-Electron-Demand Diels-Alder Reaction of Simultaneously Electrogenerated Diene and Dienophile: An Expeditious Route to Polyfunctionalized 1,4-Benzoxazine Derivatives.

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Semisynthesis of RPR 121056A, a major metabolite of irinotecan (CPT-11)

The semisynthesis of RPR 121056A (4), a major metabolite of irinotecan (CPT-11, 2) is reported starting from SN-38 (3) and an appropriate side-chain precursor, and using a 2-step sequence. This semisynthesis is based on the 10-O-acylation of SN-38 with the conveniently protected carbamoylchloride derivative 10 followed by cleavage of the benzylic protecting groups by hydrogenolysis. Preliminary in vitro results show that RPR 121056A displays no cytotoxicity

Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients

Irinotecan [7-ethyl-10-14-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11)] is a promising water-soluble analogue of camptothecin [S. Sawada et al., Chem. and Pharm. Bull. (Tokyo), 39: 1446-1454, 1991]. We have reported previously the presence of an important polar metabolite, in addition to 7-ethyl-10-hydroxycamptothecin (SN-381 β-glucuronide, in samples of plasma taken from patients undergoing treatment with CPT-11 (L. P. Rivory and J. Robert, Cancer Chemother. Pharmacol. 36: 176-179, 1995; L. P. Rivory and J. Robert, J. Cromatogr., 661: 133-141, 1994). Plasma samples (0.5 ml) containing comparatively large amounts of this metabolite were extracted by solid-phase columns and subjected to high-performance liquid chromatography and mass spectrometry in parallel to fluorometric detection. The metabolite yielded [M+1] ions with a m/z of 619, representing the addition of 32 atomic mass units to CPT-11. Purified fractions were subjected to proton nuclear magnetic resonance, and the structure determined, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1- piperidino]carbonyloxycamptothecin (APC), was further validated following synthesis. Like CPT-11, APC was found to be only a weak inhibitor of the cell growth of KB cells in culture (IC, 2.1 versus 5.5 μg/ml for CPT- 11 and 0.01 μg/ml for SN-38, the active metabolite of CPT-11) and was a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). In contrast to CPT-11, APC was not hydrolyzed to SN-38 by human liver microsomes or purified human liver carboxylesterase. Furthermore, APC did not inhibit the hydrolysis of CPT-11 in these preparations. Interestingly, APC was only a weak inhibitor of acetylcholinesterase in comparison to CPT-11 and neostigmine. It appears likely, therefore, that APC does not contribute directly to the activity and toxicity profile of CPT-11 in vivo

RPR 119990, a Novel ␣-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic Acid Antagonist: Synthesis, Pharmacological Properties, and Activity in an Animal Model of Amyotrophic Lateral Sclerosis

ABSTRACT ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidaz