Structure-activity relationship in a series of newly synthesized 1-amino-substituted ellipticine derivatives

Abstract

The synthesis of a series of 1-amino-substituted pyrido[4,3-b]carbazole derivatives, based on the substitution of corresponding 1-chloroellipticines, is reported. The cytotoxic properties on tumor cells grown in vitro, the in vivo acute toxicity of the most potent in vitro cytotoxic compounds, and the antitumor properties toward the L1210 leukemia system are described. No correlation between the apparent association constant to DNA and the in vitro cytotoxicity or the in vito antitumor efficiency could be observed in this series. 9-Hydroxylated derivatives were more cytotoxic in vitro than the corresponding 9-methoxylated compounds. However, their antitumor efficiencies on the in vivo experimental systems do not confirm the advantage of demethylation. The presence of a [(dialkylamino)alkyl]amino side chain at the 1 position of ellipticines increases the antitumor potency: 1-[[3-(diethylamino)propyl]amino]-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (5) is a very potent antitumor compound (% ILS of 134 on the L1210 leukemia system).

Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors

“…Several indole derivatives (like C 5 , C 6 , C 7 , C 16 , and C 20 ) were shown to be potent inhibitors of HIV-1 RNA production in cells chronically infected with the virus. Furthermore, because these compounds were also effective in preventing viral RNA splicing in cells transfected with the p⌬PSP plasmid, it is unlikely that the drug interferes with other processes involved in viral RNA synthesis, such as reverse transcription and͞or integration of the proviral DNA, as suggested (33). Because HIV-1, like other human viruses, uses alternative splicing to produce the large number of proteins required for its multiplication, inhibition of splicing appears a likely explanation for the inhibition of viral production by chronically infected cells.…”

“…In agreement with this, drug treatment of HeLa cells transfected with the p⌬PSP plasmid altered the splicing pattern of viral RNA in a dose-dependent manner. Such alterations of regulated splicing may well be a key step accounting for the remarkable antiviral activities exhibited by indole derivatives in cell culture systems (33).…”

DNA Binding Ellipticine Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationships

“…1-Methoxy-9-methyl-3-nitro-9H-carbazole (15). NaH (0.39 g, 2.75 mmol) and CH 3 I (0.546 g, 3.85 mmol) were added to a solution of methoxynitrocarbazole 14 (0.300 g, 1.24 mmol) in 10 mL DMF, and the mixture was held at reflux for 7 h. At the end (TLC), the mixture was poured into ice/H 2 O and extracted with CHCl 3 , and the organic phase was dried on Na 2 SO 4 3-(1-Methoxy-9-methyl-9H-carbazol-3-ylamino)but-2-enoic acid ethyl ester (19). www.chemmedchem.org placed with fresh medium containing the compound to be studied at the appropriate concentration.…”

“…It has been shown that the presence of a dialkylaminoalkylamino side chain at position 1 of ellipticine significantly increases the antitumor properties of the DNA-base-intercalating heterocycle system ( Figure 1). [18][19][20][21] A new series of 6H-pyridoA C H T U N G T R E N N U N G [4,3-b]carbazole derivatives, characterized by a basic N-dialkylaminoalkylcarboxamido side chain grafted onto an olivacine moiety, has recently been characterized. Some of these compounds display remarkable activity against various experimental tumors.…”

Synthesis of tetra- and pentacyclic carbazole-fused imides as potential antitumor agents

“…2 Examples include compounds like retelliptine, 3 pazelliptine, new tetra-and pentacyclic compounds with a carbazole-2,3-dicarboximide core structure and their in-vitro tumor cell-growth inhibitory activity. …”