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

Abstract

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.

Novel Nitrobenzazolo[3,2-a]quinolinium Salts Induce Cell Death through a Mechanism Involving DNA Damage, Cell Cycle Changes, and Mitochondrial Permeabilization

“…In terms of the mode of action similarities where also observed between ellipticine and the NBQs. Ellipticine’s cytotoxic involves mutagenic effects and DNA damage including intercalation, adduct formation and inhibition of topoisomerase II [38,39]. The representative NBQ’s studied here show the ability to induce cell cycle arrest and DNA fragmentation, with stronger effects being observed in cells exposed to NBQ 38, which caused arrest at G 0 /G 1 similarly to what has been reported for ellipticine [40,41].…”

Cell Cycle Arrest and Induction of Apoptosis in Colon Adenocarcinoma Cells by a DNA Intercalative Quinoline Derivative, 4-Morpholinopyrimido [4′,5′:4,5] Selenolo (2,3-b) Quinoline

“…Since ellipticine has been reported to intercalate with DNA and induce apoptosis in cancer cells, [15][16][17][18] various structural analogs have been developed through structure-based design strategy. [19,20] Such analogs include various planar, aromatic, and heterocyclic molecules with comparable biological activities. Quinolines and their derivatives are among such interesting class of molecules possessing a broad spectrum of biological activities such as antimalarial, antimicrobial, [21] and anticancer activity.…”

The synthesis of 7,8,9,10-tetrafluoroellipticine

“…[1][2][3] Notably, ring-A substitution can have a major impact on the biological activity of ellipticine (1a). [4][5][6][7][8][9][10][11] The prototypical example is 9-hydroxyellipticine (1b), which has a high affinity for DNA, high activity against L1210 mice leukemia, and low toxicity at a therapeutic dose. 12 Of special interest is 9-fluoroellipticine (1c), which inhibits aryl hydrocarbon hydroxylase without inducing mutagenicity.…”