The title compounds were synthesized in 9-10 steps in order to compare their cytotoxic properties to that for 1-(3-dimethylaminopropyl)-amino-4,5-dimethyl- 8-hydroxy-5H-pyrido[4,3-b]indole. Whereas the latter is a potent cytotoxic agent, displaying significant antitumour activity, the corresponding 9-propyl (and 7,9-dimethyl) derivatives were found to be > 10-fold less cytotoxic.
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Synthesis and biological studies of 1-amino beta-carbolines.
Bioorg Med Chem Lett
December 2004
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK.
A selection of 1-amino-substituted beta-carbolines have been prepared by amination of 1-chloro-beta-carboline as simple mimics of manzamine A and chloroquine and their intercalating ability, anticancer and antimalarial activity were studied.
View Article and Find Full Text PDF1-Amino-substituted 8-hydroxy-4,5-dimethyl-5H-pyrido[4,3-b]indoles with propyl- or methyl substituents at the 9-, and 7,9-positions: synthesis and biological evaluation.
Anticancer Drug Des
June 1998
UMR 176 CNRS-Institut Curie, Orsay, France.
The title compounds were synthesized in 9-10 steps in order to compare their cytotoxic properties to that for 1-(3-dimethylaminopropyl)-amino-4,5-dimethyl- 8-hydroxy-5H-pyrido[4,3-b]indole. Whereas the latter is a potent cytotoxic agent, displaying significant antitumour activity, the corresponding 9-propyl (and 7,9-dimethyl) derivatives were found to be > 10-fold less cytotoxic.
View Article and Find Full Text PDFFurther SAR in the new antitumor 1-amino-substituted gamma-carbolines and 5H-benzo[e]pyrido[4,3-b]indoles series.
Anticancer Drug Des
June 1992
URA 1387 CNRS, Synthèse Organique, Institut Curie, Orsay, France.
Using previously described techniques, various new 1-amino-substituted 5H-pyrido[4,3-b]indoles (gamma-carbolines, gamma-C) and 5H-benzo[e]pyrido[4,3-b]indoles (BPI) have been synthesized and evaluated. For known compounds containing a 1-[(dimethylamino)propyl] group, 1a and 1b in the gamma-C series and 2 in the BPI series are the most active. Studies with newly synthesized derivatives show that: (i) in the gamma-C series, the 4-unsubstituted-8-hydroxy-compound was inactive, whereas the 4-unsubstituted-9-hydroxy-5H-benzo[e]pyrido[4,3-b]indole is active; (ii) the 4-ethyl-8-hydroxy-5H-pyrido[4,3-b]indole derivative retains antitumor properties, but the 1-amino-substituted 4-ethyl-9-hydroxy-5H-benzo[e]pyrido[4,3-b]indole analog is devoid of biological activity; (iii) in the 5H-benzo[e]pyrido[4,3-b]indole series, the displacement of a hydroxyl group from the 9- to 10-position leads to inactive compounds.
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Biochem Pharmacol
May 1989
Sanofi Recherche, Toulouse, France.
The interrelationship between affinity for DNA, cytotoxicity and induction of single-strand DNA breaks in cultured L1210 cells was studied for 21 compounds belonging to two series of tricyclic intercalators: 1-amino-substituted 4-methyl-5H-pyrido[4,3-b]indoles (gamma CARB) and 1-amino-substituted 4-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridines (PPP), which are simplified analogues of Ellipticine derivatives obtained by deletion of one cycle. Adriamycin, m-AMSA (4'-(9-acridinylamino) methanesulfon-m-anisidide), PZE (10-[diethylaminopropyl amino]-6-methyl-5H-pyrido[3',4':4,5]-pyrrolo[2,3-g] isoquinoline and RTE [( 1-(3-diethylaminopropylamino)-9-methoxy ellipticine, bimaleate) are used as reference compounds. The intercalation of these compounds into DNA was strongly suggested by three experimental observations: (i) the competitive inhibition of ethidium bromide intercalation, (ii) bathochromic and hypochromic effects on absorption spectra induced by DNA, and (iii) drug-induced increase of the DNA length, measured by viscosimetry.
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J Med Chem
February 1988
UA 533 CNRS, Laboratoire de Synthèse Organique, Institut Curie, Orsay, France.
A series of 1-amino-substituted 4-methyl-5H-pyrido[4,3-b]indoles that are structurally related to ellipticines by deletion of a ring have been synthesized in order to evaluate their DNA affinity, their in vitro cytotoxicity on L1210 cultured cells, and their in vivo antitumor activity. Among 24 derivatives that have been prepared and studied for the structure-activity relationship in this new class of antineoplastic agents, those that have a NH(CH2)3N(R)2 side chain (R = CH3 or C2H5) at their 1-position, a 4-methyl group, and an 8-OH substituent, either with a 5-NH or with a 5-NCH3 group, show the most potent cytotoxicities on L1210 cultured cells and in vivo antitumor properties in P388 and L1210 leukemia systems. In vivo antineoplastic activity of the most potent products was confirmed in P388 and L1210 leukemia systems.
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