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Terpyridine complexes are known for their broad biological activities, of which their anticancer potency is the most extensively studied. Strikingly, free ligand activity has rarely been described in the literature. In this study, a lipophilic derivative of terpyridine 4'-(1-decyl-2,3-triazol-4-yl)phenyl-2,2':6',2″-terpyridine (L) and its complexes were investigated to determine their mechanism of anticancer activity. Our results show that a free ligand expresses the same level of activity on a panel of cancer cells with a low toxicity towards normal fibroblasts as complexes with Cd, Zn or Cu. Breast cancer (MCF-7 cell line) was the most vulnerable for the tested compounds with the IC 50 values in the nanomolar range (IC 50  = 40 nM for L.) The addition of Cu(II) ions increased its activity even further, thus suggesting that ligand exchange and ROS production are the main components of its activity. A cell cycle analysis indicated its inhibition at the G0/G1 phase and the subsequent apoptosis as the cell death mode. A detailed analysis of the protein level that was involved in the aforementioned processes confirmed previous results. Furthermore, the reactive oxygen species generation and DNA intercalation confirmed its cleaving activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

((3RS,5SR)- and ((3RS,5RS)-2-(2-methoxybenzyl)-3-(1,10-phenanthrolin-2-yl)isoxazolidin-5-yl)methanol have been synthesized, according to 1,3-dipolar cycloaddition methodology, as DNA intercalating agents and evaluated for their anticancer activity against human cervical carcinoma HeLa and head and neck squamous cells carcinoma cell lines. The synthesized compounds exhibited good cytotoxic activity with IC 50 better than cisplatin, used as the main and effective treatment for HNSCC, and a 24.3-72.0-fold selectivity respect to the 184B5 non-cancerous immortalized breast epithelial cell lines. Unwinding assay, circular dichroism data, and Uv-vis melting experiments confirmed that these compounds act as DNA intercalators with a binding constant in the order of 10 4  M -1 . Docking studies showed that both compounds can interact as intercalating agent with both poly-d(AT) 2 and poly-d(GC) 2 , preferring an entrance by the minor groove of the poly-d(AT) 2 ., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A series of new pyrazolo[3,4-d]pyrimidine possessing 4-(1H-benzimidazol-2-yl)-phenylamine moiety at C4 position and primary as well as secondary amines at C6 position has been designed and synthesized. Their antitumor activities were evaluated against a panel of 60 human cancer cell lines at National Cancer Institute (NCI). Six compounds displayed potent and broad spectrum anticancer activities at 10 μM. Compounds 8, 12, 14 and 17 proved to be the most active and efficacious candidate in this series, with mean GI 50 values of 1.30 μM, 1.43 μM, 2.38 μM and 2.18 μM, respectively against several cancer cell lines. Further biological evaluation of these compounds suggested that these compounds induce apoptosis and inhibit human topoisomerase (Topo) IIα as a possible intracellular target. UV-visible and fluorescence studies of these compounds revealed strong interaction with ct-DNA and bovine serum albumin (BSA)., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A series of thirty two novel pyrrolo[2,3-b]pyridine analogues synthesized, characterized ((1)H NMR, (13)C NMR and MS) and cytotoxic evaluation of these molecules carried out over a panel of three human cancer cell lines including A549 (lung cancer), HeLa (cervical cancer) and MDA MB-231 (breast cancer), using sulforhodamine B assay method. Few molecules such as 5c, 5d, 5e, 5h, 5k, 5m, 5n, 5q, 5r, 7f, 7j, 7g and 7k exhibited maximum growth inhibitory action against the tested cancer cell lines at lower micro molar concentration. Noticeably, compounds exhibited good growth inhibition in all three cancer cell lines in the range of 0.12 μM-9.84 μM. Further study exposed that one of the active compound 5d could efficiently intercalate into calf thymus DNA to form 5d-DNA complex which might block DNA replication to influence their antiproliferative activity. The molecular interactions of all the synthesized analogs were also supported by molecular docking simulations. We believe that further optimization of these compounds will lead to potential anticancer agents., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Two new dicopper(II) complexes bridged by N-(2-hydroxy-5-methylphenyl)-N'-[3-(dimethyl-amino)propyl]oxamide (H3hmpoxd), and end-capped with 4,4'-dimethyl-2,2'-bipyridine (Me2bpy) and 2,2'-bipyridine (bpy), were synthesized and structurally characterized, namely [Cu2(hmpoxd)(CH3OH)(Me2bpy)](ClO4) (1) and [Cu2(hmpoxd)(bpy)](ClO4)∙CH3OH (2). The single-crystal X-ray diffraction analysis reveals that the endo- and exo-copper (II) ions bridged by the cis-hmpoxd(3-) ligand are located in square-planar and square-pyramidal geometries, respectively, for 1, and square-planar environments in 2. The DNA/protein-binding natures are studied theoretically and experimentally, indicating that both the two complexes can interact with the DNA in the mode of intercalation, and effectively quench the intrinsic fluorescence of protein BSA via the favored binding sites Trp213 for 1 and Trp134 for 2. In vitro anticancer activities showed that the two complexes are active against the selected tumor cell lines, and the anticancer activities are consistent with their DNA/BSA-binding affinities following the order of 1 > 2. The synergistic hydrophobicity of the bridging and terminal ligands in these complexes on DNA/BSA-binding events and in vitro anticancer activities is preliminarily discussed., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The synthesis of 5-amino substituted benzimidazo[1,2-a]quinolines prepared by microwave assisted amination from halogeno substituted precursor was described. The majority of compounds were active at micromolar concentrations against colon, lung and breast carcinoma cell lines in vitro. The N,N-dimethylaminopropyl 9 and piperazinyl substituted derivative 19 showed the most pronounced activity towards all of the three tested tumor cell lines, which could be correlated to the presence of another N heteroatom and its potential interactions with biological targets. The DNA binding studies, consisting of UV/Visible absorbency, melting temperature studies, and fluorescence and circular dichroism titrations, revealed that compounds 9, 19 and 20 bind to DNA as strong intercalators. The cellular distribution analysis, based on compounds' intrinsic fluorescence, showed that compound 20 does not enter the cell, while compounds 9 and 19 do, which is in agreement with their cytotoxic effects. Compound 9 efficiently targets the nucleus whereas 19, which also showed DNA intercalating properties in vitro, was mostly localised in the cytoplasm suggesting that the antitumor mechanism of action is DNA-independent., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Three novel aryloxazole compounds 1-3 were synthesized and characterized. The crystal structures of compounds 2 and 3 show that N atom locates at β-position and O atom at α-position in naphthalene cycle. The DNA binding constants for compounds 1-3 are 4.44 × 10(3), 5.31 × 10(3) and 2.64 × 10(3) M(-1), respectively. The viscosity measurements indicate that these compounds intercalate between the DNA base pairs. Upon irradiation, compounds 1-3 can effectively cleave pBR322 DNA. The cytotoxicity of the compounds against BEL-7402, A549, MG-63 and SKBR-3 were assayed by MTT method. The apoptosis and cell cycle arrest were investigated towards A549 cells. The antioxidant activities of the compounds against hydroxyl radicals were also explored., (Crown Copyright © 2014. Published by Elsevier Masson SAS. All rights reserved.)

The interaction of small molecules with DNA plays an essential role in many biological processes. As DNA is often the target for majority of anticancer and antibiotic drugs, study about the interaction of drug and DNA has a key role in pharmacology. Moreover, understanding the interactions of small molecules with DNA is of prime significance in the rational design of more powerful and selective anticancer agents. Two of the most important and promising targets in cancer chemotherapy include DNA alkylating agents and DNA intercalators. For these last the DNA recognition is a critical step in their anti-tumor action and the intercalation is not only one kind of the interactions in DNA recognition but also a pivotal step of several clinically used anti-tumor drugs such as anthracyclines, acridines and anthraquinones. To push clinical cancer therapy, the discovery of new DNA intercalators has been considered a practical approach and a number of intercalators have been recently reported. The intercalative binding properties of such molecules can also be harnessed as diagnostic probes for DNA structure in addition to DNA-directed therapeutics. Moreover, the problem of intercalation site formation in the undistorted B-DNA of different length and sequence is matter of tremendous importance in molecular modeling studies and, nowadays, three models of DNA intercalation targets have been proposed that account for the binding features of intercalators. Finally, despite DNA being an important target for several drugs, most of the docking programs are validated only for proteins and their ligands. Therefore, a default protocol to identify DNA binding modes which uses a modified canonical DNA as receptor is needed., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

A series of 3,6-bis(3-alkylguanidino) acridines was prepared and the interaction of these novel compounds with calf thymus DNA was investigated with UV-vis, fluorescence and circular dichroism spectroscopy, in addition to DNA melting techniques. The binding constants K were estimated to range from 1.25 to 5.26 × 10(5) M(-1), and the percentage of hypochromism was found to be 17-42% (from spectral titration). UV-vis, fluorescence and circular dichroism measurements indicated that the compounds act as effective DNA-intercalating agents. Electrophoretic separation proved that ligands 6a-e relaxed topoisomerase I at a concentration of 60 μM, although only those with longer alkyl chains were able to penetrate cell membranes and suppress cell proliferation effectively. The biological activity of novel compounds was assessed using different techniques (cell cycle distribution, phosphatidylserine externalization, caspase-3 activation, changes in mitochondrial membrane potential) and demonstrated mostly transient cytostatic action of the ethyl 6c and pentyl 6d derivatives. The hexyl derivative 6e proved to be the most cytotoxic. Different patterns of cell penetration were also observed for individual derivatives. Principles of molecular dynamics were applied to explore DNA-ligand interactions at the molecular level., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The third generation of isoxazole polycyclic aromatic hydrocarbons, acting as DNA-intercalator agents and possessing the binding constants in the range 10(4)-10(5) M(-1), in order to easily diffuse targeting remotely implanted tumors, has been synthesized in good yields according to the 1,3-dipolar cycloaddition methodology. The structure of the obtained cycloadducts has been determined by NOE experiments and supported by computational studies at PM3 level. All the obtained compounds have been tested for their in vitro cytotoxic activity and the most potent of them, (3RS,5SR)-2-benzyl-N,N-dimethyl-3-(pyren-1-yl)isoxazolidine-5-carboxamide (7d), showed an IC(50) of 4 μM upon the human lung cancer (A-549) cells. Moreover, compound 7d showed binding constant for the intercalation with calf thymus DNA, poly-d(AT)(2) and poly-d(GC)(2) of 1.7 × 10(5) M(-1), 1.6 × 10(5) M(-1) and 0.3 × 10(5) M(-1), respectively. Biological and docking studies showed that, in vitro, these compounds complex by intercalation between base pairs, approaching the DNA from its minor groove with a preference for the AT nucleobases pairs., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A series of novel 1,9-disubstituted β-carbolines was designed, synthesized and evaluated as cytotoxic and DNA intercalating agents. Compounds 7b, 7c, 8b and 8c exhibited the most potent cytotoxic activities with IC(50) values of lower than 20 μM against ten human tumor cell lines. The results indicated that (1) the 3-chlorobenzyl and 3-phenylpropyl substituents in position-9 of β-carboline nucleus were the suitable pharmacophoric group giving rise to significant antitumor agents; (2) the length of the alkylamino side chain moiety affected their cytotoxic potencies, and three CH(2) units were more favorable. In addition, these compounds were found to exhibit remarkable DNA intercalating effects., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Divalent Co, Ni and Cu hydrazone complexes containing [N'-(phenyl(pyridine-2-yl)methylidene) benzohydrazide] ligand were synthesised and characterised. Interactions of these complexes with DNA revealed an intercalative mode of binding between them. Further, all the hydrazone chelates showed moderate ability to cleave pUC19 DNA. Synchronous fluorescence spectra proved that the interaction of metal complexes with bovine serum albumin (BSA) resulted in a conformational change of the latter. Assay on the cytotoxicity of the above complexes against HeLa tumor cells and NIH 3T3 normal cells revealed that the complexes are toxic only against tumor cells but not to normal cells. In all the biological assays, the complex with copper ion as the metal center showed enhanced activities than the other two., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

A new ligand and two ruthenium(II) complexes [Ru(bpy)(2)(DNPIP)](ClO(4))(2)1 and [Ru(bpy)(2)(DAPIP)](ClO(4))(2)2 were synthesized and characterized. The DNA-binding constants for complexes 1 and 2 were determined to be 2.24 (±0.30) × 10(5) M(-1) (s = 1.29) and 6.34 (±0.32) × 10(4) M(-1) (s = 2.84). The photocleavage of pBR322 DNA by Ru(II) complexes was investigated. The cytotoxicity of complexes 1 and 2 were assessed against three tumor cell lines. The apoptosis and cellular uptake were studied. The retardation assay of pGL 3 plasmid DNA was explored. The cell cycle arrest was analysized by flow cytometry. The antioxidant activities of the ligand and complexes were also investigated., (Crown Copyright © 2011. Published by Elsevier Masson SAS. All rights reserved.)

From the anti-tumor active N-tryptophanyl-β-carboline-3-carboxylic acid benzyl ester and β-carboline-3-carbonyltryptophan benzyl ester, a pharmacophore, Trp-Trp-OBzl, was drawn. Based on the DOCK scores amino acid residue was inserted into the C-terminus of Trp-Trp-OBzl and twenty Trp-Trp-AA-OBzls (AA = amino acid residues) were provided as DNA intercalators. On the in vitro and in vivo models seventeen Trp-Trp-AA-OBzls were anti-tumor active, and twelve Trp-Trp-AA-OBzls were more active than cytarabine. In acute toxicity assay Trp-Trp-AA-OBzls did not damage the immunologic function and had an LD(50) of more than 500 mg/kg. The relationships of structure and activity were analyzed with 3D QSAR. The action mechanism studies revealed that the in vivo anti-tumor action of Trp-Trp-AA-OBzls was the result of DNA intercalation., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

In the present paper, we have described the synthesis and biological activity of the novel derivatives of imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes (7-21, 24-26, 28-29). A preponderance of these compounds exerted strong cytostatic effects on the panel of seven human tumour cell lines in a dose-dependent manner. In particular, imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes including 2-imidazolinyl derivatives showed the most potent antitumour activity. Similarly, triaza-benzo[c]fluorenes 18 and 20 induced strong growth inhibition of tested tumour cell lines, and showed low cytotoxicity in normal human fibroblasts. DNA interaction studies of these compounds demonstrated that N-methylated 16 and 2-imidazolinyl 28 triaza-benzo[c]fluorenes bind to DNA in an intercalative mode., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The reaction between 2-thiobarbituric acid (H(2)TBA), which was treated with an equimolar amount of potassium hydroxide, in a water with triphenytin chloride in methanol, results in the formation of the {[Ph(3)Sn(O-HTBA)]}(n) (1) complex. Crystals of the hydrated 1 with formula {[Ph(3)Sn(O-HTBA)]·0.7(H(2)O)}(n) were growth from methanol/acetonitrile solution, of the white precipitation, filtered off, from the reaction. The crystal structure of complex 1 has been determined by X-ray diffraction at 120 K. Complex 1 is polymeric. The geometry around the tin(IV) ions is trigonal bi-pyramidal with coordination to three C atoms from phenyl groups and one O atom from a de-protonated HTBA ligand. Complex 1 and the already known [(n-Bu)(3)Sn(O-HTBA)·H(2)O] (2) were evaluated for their in vitro cytotoxic activity (cell viability) against human cancer cell lines: HeLa (cervical), OAW-42 (ovarian), MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), A549 (lung), Caki-1 (renal) and additionally, the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) and normal immortalized human mammary gland epithelial cell line MTSV17 with a Trypan Blue assay. Moreover complex 1 was evaluated for its in vitro cell growth proliferation activity against leiomyosarcoma cells (LMS), MCF-7 and MRC-5 cells with a Thiazolyl Blue Tetrazolium Bromide (MTT) assay. The type of cell death caused by complexes 1 and 2 was also evaluated by use of flow cytometry assay. The results showed that these compounds mediate a strong cytotoxic response to normal and cancer cell lines tested through apoptosis and induce cell cycle arrest in S phase of the cell cycle, suggesting DNA intercalation (direct or indirect) with the complexes. Finally, the influence of these complexes 1 and 2 upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Novel amidino-substituted conformationally restricted derivatives of pentamidine were synthesized and their antiproliferative activity against several human cancer cell lines determined. It was found that introduction of furandicarboxamide core moiety (9, 10) increases antiproliferative activity as well as selectivity against certain tumor cell lines in comparison with amidino-substituted furan-mono-carboxamide (5, 6). Unlike the furan series where iso-propyl substituted amidine (10) exhibits more potent overall antiproliferative activity and selectivity toward certain cell lines, the same was found for unsubstituted amidines in pyridine series. Amongst all tested compounds the compound 10 is the only one that possesses antiproliferative activity against SW 620 cell line (4 μM). Spectroscopic studies of the interactions of prepared diamidines with double-stranded DNA and RNA polynucleotides show that all compounds preferentially bind into the minor groove of DNA, while most of them intercalate into RNA. The structure-dependant biological activity and the lack of DNA/RNA selective binding suggest that the mechanism of action of the here-presented compounds is controlled not only by the interactions with cellular nucleic acids, but also with other more specific protein targets., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

A novel series of 4-(4-phenyl-[1,2,3]-triazol-1-yl)-1,8-naphthalimide derivatives had been synthesized easily by employing "click reaction". For anti-tumor activity in vitro, all the compounds were found to be more toxic against MCF-7 than Hela and 7721 cells. 4a, 4b and 4e Showed improved cytotoxic activity against MCF-7 cells over Amonafide, in particular compound 4a, with an IC(50) could amount to 10(-7) M. The UV-vis spectra and Circular Dichroism titration indicated that the compounds behaved as effective DNA-intercalating agents. The investigation of their photo-damaging ability illuminated that these compounds could damage DNA effectively into form II and even form III., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

In this study, we used a solution of FeCl(3) in THF to facilitate the Mannich-type reaction of aldehyde, amine and phosphite compounds to form corresponding alpha-aminophosphonates in a one-pot, three-component reaction. Selected alpha-aminophosphonates were entered into a biological assay test and were studied by docking methods, using Autodock 3.0. The results showed that the reactions were carried out mildly and eco-friendly to form alpha-aminophosphonates in high yields. Some were found to have cytotoxic activity on the cell lines RAJI, JURKAT and MCF-7. An indole derived bis(alpha-aminophosphonates) showed maximum cytotoxic effect comparable to doxorubicin. Although the FDE (Final Docking Energy) for the most cytotoxic compound was of the most negative value, there is no correlation between FDE and cytotoxicity.

Sixteen novel N-(3-carboxyl-9-benzyl-beta-carboline-1-yl)ethylamino acids (6a-p) were synthesized as intercalating lead compounds. In the in vitro cytotoxic assay their IC(50) values against five human carcinoma cell lines ranged from 10.95 microM to about 400 microM. On S180 mouse model eight of them exhibited anti-tumor action, four of them showed the same anti-tumor potency as that of cytarabine. The preliminary toxicity evaluation revealed that the LD(50) values of 6a-p should be more than 500 mg/kg. With CT DNA as model system an intercalating mechanism was explored. Using 3D QSAR analysis the relationship of the in vivo anti-tumor activity and the structure was quantitatively described. By docking 6a-p onto d(CGATCG)(2) oligonucleotides the intercalation was demonstrated.

Novel imidazo[1,2-a]naphthyridinic systems 6a-15a and 6b-15b were obtained from Friedländer's reaction in imidazo[1,2-a]pyridine series. Most of the compounds were evaluated for their antitumor activity in the NCIs in vitro human tumor cell line screening panel. Among them, pentacyclic derivatives 13b and 14a exhibited in vitro activity comparable to anticancer agent such as amsacrine. Their mechanism of cytotoxicity action was unrelated to poisoning or inhibiting abilities against topo1. On the contrary, we highlighted a direct intercalation of the drugs into DNA by electrophoresis on agarose gel.

A series of antiviral compounds consisting of an intercalating acridine derived part, a spacer region and a reactive EDTA-derived conjugate was synthesized in an easy sequence starting from 1,omega-alkyldiamines. As shown in model screenings, in the presence of ascorbic acid the Fe-complexes of these compounds reduced the phage-titer of MS2-phages by several logarithmic decades.

Five new 9-anilinothiazolo[5,4-b]quinoline derivatives (compounds 5, 7, 9, 10, 11) have been prepared. Some of the compounds were prepared by coupling properly substituted anilines to the novel compound 9-chloro-2-(methylthio)thiazolo[5,4-b]quinoline. Of these, compound 7 (9-anilino-2-[[2-(N,N-diethylamino)ethyl]amino]thiazolo[5,4-b]quinoline) showed the best cytotoxic activity in several cell lines. All compounds demonstrated DNA binding in nanomolar range. Compound 7 inhibited the (14)C-thymidine incorporation into DNA. Results indicate that these derivatives deserve more considerations as potential antitumoral drugs.

Continuing our studies on combilexines, compounds consisting of a DNA intercalator linked to a minor groove ligand, new results are presented. The synthesis of a series of new propylamine oligopyrrole carboxamides closely related to netropsin and distamycin A, linked to a heterocyclic or anthraquinone system is reported. The cytotoxic activity in vitro, the DNA binding characteristics and the inhibition of the topoisomerase I of the compounds were studied in order to explain the biological mechanism of action of these new potential combilexines. Some of the synthesised compounds showed cytotoxic activity against human tumour cell lines, as well as DNA binding and topoisomerase I inhibiting properties.

A series of dendritic polyamines-(imide-DNA-intercalators) conjugates with different connectivity in their basic chain were synthesised and evaluated as antitumour compounds. Although their antiproliferative activity against HT-29 was not significant, conjugates 13 and 16 showed a promising profile as inhibitors of Lck.

Combilexines, compounds in which a DNA intercalator is linked to a minor groove binding component, interact with the DNA in a sequence specific manner to yield in most cases compounds with anticancer activity. A series of new compounds closely related to netropsin in which the two components were linked by an amide group was synthesised as potential combilexines. As some of these compounds showed cytotoxic activity in vitro, an attempt was made to rationalise their mechanism of action. The DNA binding characteristics of the carboxamides were evaluated by thermal denaturation experiments and by ethidium bromide displacement assay. Their ability to inhibit the topoisomerase I was also determined. It was concluded that the new compounds were only weak DNA ligands although able in some cases to inhibit topoisomerase I.

A series of bis([(9-oxo-9,10-dihydroacridine-4-carbonyl)amino]alkyl) alkylamines have been prepared and their antiproliferative properties have been tested against HT-29 cell lines. Compounds 6b and 6d showed an interesting cytotoxic profile and were subjected to further cytotoxic evaluation, DNA binding properties and molecular modelling studies. The evaluation of the cytotoxic activity of compounds 6b and 6d against pairs of cisplatin-sensitive and -resistant ovarian tumour cells shows that both compounds may be endowed with interesting antitumour properties because they are able to circumvent cisplatin resistance in A2780cisR, CH1cisR and Pam 212-ras tumour cells. On the other hand, DNA binding data indicate that compounds 6b and 6d are able to intercalate stronger than acridine within the double helix. Both compounds displace ethidium bromide with an efficiency ten times higher than acridine from several linear double-stranded DNAs and induce 43 degrees unwinding in supercoiled pBR322 DNA while acridine unwinds pBR322 DNA by only 24 degrees. Altogether these data indicate that the significant conformational changes induced by compounds 6b and 6d in the double helix are due to a bis-intercalative DNA binding mode. We propose that binding to DNA through bisintercalation might be at least in part responsible for the remarkable cytotoxic properties of these acridine derivatives. The complex of 6b with d(GCGCGC)(2) in the four possible orientations that the ligand can adopt when binding to the DNA hexamer have been modelled and subjected to molecular dynamics simulations with the aim of evaluating the binding preferences of this bisintercalating agent into the DNA molecule. The predictions suggest that 6b binds to d(GCGCGC)(2) with a parallel orientation of the chromophores relative to each other and with a preference for binding through the minor groove of the hexamer. The possible relevance of these findings to the process of bisintercalation and the antitumour profile of these compounds is discussed in this paper.

The synthesis of pyrrolo[2,3-e]indole derivatives with the structural characteristics of DNA bis- and mono-intercalators are described. A dihydro benzoindol analogue was also synthesised to elucidate the major structural requirements for cytotoxic activity. A biological evaluation of the test compounds was carried out in six different tumoral cell lines. The factors that affect the cytotoxic activity appear to be the substituents on the phenyl group, the presence of an amide group capable of strong interactions such as hydrogen bonding and solubility.