Synthesis of 1-substituted ellipticines by a new route to pyrido[4,3-b]carbazoles

Bisagni, Émile; Ducrocq, Claire; Lhoste, Jean‐Marc; Rivalle, C.; Civier, A.

doi:10.1039/p19790001706

Cited by 37 publications

(16 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This stock solution was diluted to working concentrations immediately before use. Drug 1-substitution was effected by reaction of l-chloro, 5,1 1-dimethyl, 9-methoxy ellipticine [16] with diaminopropane as previously described [3,17]. A stock solution (1mM) of the compound was prepared in methanol since it is very insoluble in water.…”

Section: Materials and Methods Enzymementioning

confidence: 99%

Sequence-selective binding of an ellipticine derivative to DNA

et al. 1990

Self Cite

View full text Add to dashboard Cite

The DNA sequence specificity of an ellipticine derivative bearing an aminoalkyl side chain has been determined by a variety of footprinting methods. The drug exhibits sequence selective binding and discriminates against runs of adenines or thymines. Binding is shown to occur at various sequences with a preference for GC rich regions of DNA. A large enhancement of DNAase I and of hydroxyl radical cleavage in regions rich in A's or T's is observed together with hyperreactivity of adenines towards diethylpyrocarbonate in the presence of drug. This indicates the occurrence of drug-induced changes in critical conformational features of DNA. The total absence of hyperreactivity of guanine residues towards diethylpyrocarbonate appears to be related to the sequence selectivity of drug binding. No alteration of the dimethyl sulphate and methylene blue-induced cleavage of DNA is observed. Irradiation of ellipticine derivative-DNA complexes with UV light followed by alkali treatment leads to selective photocleavage at guanine residues, consistent with the deduced degree of selectivity of the binding reaction.

show abstract

Section: Materials and Methods Enzymementioning

confidence: 99%

Sequence-selective binding of an ellipticine derivative to DNA

et al. 1990

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

View full text Add to dashboard Cite

In connection with our interest in the synthesis and study of the biological properties of ellipticine analogues as anticancer agents, some 7H-pyrido[2,3-c]carbazoles (7H-PyC) and their corresponding tetrahydro derivatives (7H-THPyC) were synthesized. A common multistep pathway characterized by conventional reactions involving carbazole Fischer and Conrad-Limpach quinoline syntheses yielded the tetracyclic compounds. With the aim to improve the cytotoxic activity of the new 7H-PyC derivatives, we provided them with one or two diethylaminoethyl side chains. The new THPyCs, PyCs, and smaller pyrroloquinoline (PQ) derivatives were tested for their in vitro cytotoxic properties against several human tumor cell lines. Most of the compounds tested showed considerable cytotoxic activity, particularly compound 24, which, with two basic alkylamino chains, has IC(50) values in the sub-micromolar range, about one order of magnitude lower than those of the reference compound, ellipticine. Chemosensitivity tests on cisplatin-, mitoxantrone-, and multidrug-resistant (MDR) phenotypes indicated that compound 24 shows no cross-resistance; this suggests that, besides not being a potential MDR substrate, it might act as a mixed inhibitor of topoisomerases I and II. Flow cytometric and caspase-3 activation analyses revealed that 24 induces a caspase-3-dependent apoptotic cell-death mechanism. Linear dichroism and unwinding experiments suggested that the most active compounds act as DNA intercalators. For compound 24, an inhibitory concentration-dependent effect on topoisomerases II and I was demonstrated. Herein we discuss interesting structure-activity relationships with respect to molecular size and planarity, as well as the substitution and position of one side chain on the PyC nucleus, in comparison with corresponding smaller PQs.

show abstract

“…9-Methoxy-1-chloro-5,11-dimethyl-6H-pyrido [4,3-b]carbazole was prepared according to a previously published procedure in 7% yield (31). This compound was treated with 10-fold excess of boiling 3,3Ј-diamino-N-methyldipropylamine under nitrogen until the starting compound disappeared on TLC (1.5-2 h).…”

Section: Methodsmentioning

confidence: 99%

“…An ellipticine derivative, 9-methoxy-1-chloro-5,11-dimethyl-6H-pyrido [4,3-b]carbazole (31), was condensed with 3,3Ј-diamino-Nmethyldipropylamine, and the product of this reaction, Ell, was used for the preparation of all Ell-hormone conjugates. Although CCKBR recognizes peptide sequences as short as the C-terminal tetrapeptide, our previous experience (27) showed that tetrapeptide conjugates were poorly soluble.…”

Section: Synthesis Of Drug-peptide Conjugatesmentioning

confidence: 99%