Synthesis and Antiproliferative Evaluation of 7-Aminosubstituted Pyrroloiminoquinone Derivatives Vale rie Be ne teau, a Alain PierreÂ, b Bruno Pfeier, c Pierre Renard c and Thierry Besson a, * a Laboratoire de Ge Ânie Prote Âique et Cellulaire, UPRES 2001, Po Ãle Sciences et Technologie, Universite  de La Rochelle, Avenue Marillac, 17042 La Rochelle cedex 1, France b Institut de Recherche Servier, 11 Rue des Moulineaux, 92150 Surennes, France c A.D.I.R. et Cie, 1 Rue Carle He Âbert, 92415 Courbevoie cedex, France Received 19 June 2000; revised 25 July 2000; accepted 4 August 2000 AbstractÐCoupling of ®ve amines on the 7-methoxy-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline core was achieved and aorded, in particular, an opened analogue of the natural alkaloid wakayin. Evaluation of cytotoxic activity of compounds 2, 10±13 on L1210 cells aorded IC 50 in the range 0.25±5.3 mM. # 2000 Elsevier Science Ltd. All rights reserved. Introduction Since the discovery of discorhabdin C in 1986 until isolation and characterization of veuitamine in 1997, more than 40 pyrroloiminoquinone alkaloids have been isolated from sponges and ascidians. 1 For these marine organisms devoid of skeleton and immune system, ®xed or not very mobile, secondary metabolites would have a basic role in communication, defense or attack towards other organisms. Pyrroloiminoquinones have recently received increasing attention as a source of new and useful anticancer drugs. In particular wakayin 1, isolated from Ascidian Clavelina species, shows biological activities such as inhibition of topoisomerase I. 2 Until now, only two approaches to structures analogous to wakayin were reported with no biological activity described. 3 As part of our work on heterocyclic compounds with potential pharmacological value, 4 we planned to synthesize pyr- roloiminoquinone 2 which is structurally very close to the natural alkaloid, by the retrosynthetic pathway shown in Scheme 1, from tryptamine and 7-methoxy- 3,4-dihydro-1H-pyrrolo[4,3,2-de]quinolin-8-one 3. Chemistry The strategy used for building the tricyclic system 3 was inspired by the work of Joule and Alvarez. 5 6,7-Dime- thoxy-4-methylquinoline 4 was formed by reaction between 3,4-dimethoxyaniline and methylvinylketone in re¯uxing acetic acid with iron(III) chloride. Nitration of 4 (concentrated nitric acid, 50  C) led to the 5- nitro compound 5 in a good yield (78%). According to Vismara's method, oxidation of the methyl group to aldehyde was achieved in DMSO with tri¯uoroacetic acid, iodine, tert-butyliodide and iron(II) chloride. The aldehyde function was then protected as a dimethylacetal to give 7 in 87% yield. The pyridine ring and the nitro group were simultaneously reduced by an excess of sodium borohydride in methanol with nickel chloride to aord diamine 8 in a very good yield (95%). Cyclization of the pyrrole ring occurred by heating compound 8 at 80  C in aqueous HCl and THF in a 62% yield (Scheme 2). Aminoindole 9 was treated by ceric ammonium nitrate (CAN) in aqueous acetonitrile to generate the quinone structure. Substitution of the C-7 methoxy group by the amine was achieved in situ, without isolating the very unstable intermediate 3. The product of coupling was then transformed into its tri¯uoroacetate salt (Scheme 3). In this way, tryptamine was condensed on the pyrroloiminoqui- none core to aord compound 2. Because some studies 6 have proved the utility of DNA-intercalating heterocyclic 0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(00)00450-9 Bioorganic & Medicinal Chemistry Letters 10 (2000) 2231±2234 *Corresponding author. Fax: +33-5-46-45-82-65(or 47). E-mail: tbes- son@univ- lr.fr