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To structurally relate anticancer drug tamoxifen used in the treatment of breast cancer, a sequence of compounds is designed and synthesized as potential drug candidates. McMurry coupling reaction is used as the key synthetic step in the preparation of these analogues and the ratios of E/Z-isomers are determined on the basis of NMR and HPLC experiments. The new compounds are found to be cytotoxic in the micromolar range with 60 human tumor cell lines at one dose and five dose concentration levels. Detailed studies on the most active compounds 11-13 show these compounds are capable to inhibit the growth of cancer cells. Finally, with the aim to correlate the antiproliferative activity with an intracellular target(s), the effect on relaxation activity of DNA topoisomerase-II is assayed. The relevance of interaction of most active compounds with topoisomerase-II is demonstrated which is also supported by docking studies., 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.)

Human DNA topoisomerases represent one of the key targets of modern chemotherapy. An emerging group of catalytic inhibitors of human DNA topoisomerase IIα comprises a new paradigm directed to circumvent the known limitations of topoisomerase II poisons such as cardiotoxicity and induction of secondary tumors. In our previous studies, 4,6-substituted-1,3,5-triazin-2(1H)-ones were discovered as catalytic inhibitors of topo IIα. Here, we report the results of our efforts to optimize several properties of the initial chemical series that did not exhibit cytotoxicity on cancer cell lines. Using an optimized synthetic route, a focused chemical library was designed aimed at further functionalizing substituents at the position 4 of the 1,3,5-triazin-2(1H)-one scaffold to enable additional interactions with the topo IIα ATP binding site. After virtual screening, selected 36 analogues were synthesized and experimentally evaluated for human topo IIα inhibition. The optimized series displayed improved inhibition of topo IIα over the initial series and the catalytic mode of inhibition was confirmed for the selected active compounds. The optimized series also showed cytotoxicity against HepG2 and MCF-7 cell lines and did not induce double-strand breaks, thus displaying a mechanism of action that differs from the topo II poisons on the cellular level. The new series represents a new step in the development of the 4,6-substituted-1,3,5-triazin-2(1H)-one class towards novel efficient anticancer therapies utilizing the catalytic topo IIα inhibition paradigm., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A novel series of bis(hydroxymethyl)indolizino[8,7-b]indole hybrids composed of β-carboline (topoisomerase I/II inhibition) and bis(hydroxymethyl)pyrrole (DNA cross-linking) are synthesized for antitumor evaluation. Of tumor cell lines tested, small cell lung cancer (SCLC) cell lines are the most sensitive to the newly synthesized compounds. These hybrids induce cell cycle arrest at the G2/M phase, trigger tumor cell apoptotic death, and display diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Intriguingly, the substituent at N 11 (H or Me) plays a critical role in modulating Topo II inhibition and DNA cross-linking activities. N 11 -Me derivatives predispose to induce DNA crosslinks, whereas N 11 -H derivatives potently inhibit Topo II. Computational analysis implicates that N 11 -Me restrict the torsion angles of the two adjacent OH on pyrrole resulting in a favorable of DNA cross-linking. Among these hybrids, compound 17a with N 11 -H is more effective than cisplatin and etoposide, but as potent as irinotecan, against the growth of SCLC H526 cells in xenograft model., (Published by Elsevier Masson SAS.)

Novel series of conformationally constrained 2,4-chloro- and hydroxy-substituted diphenyl benzofuro[3,2-b]pyridines were rationally designed and synthesized. Their biological activities were evaluated for topoisomerase I and II inhibitory activity, and antiproliferative activity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with phenol moiety at 4-position of central pyridine exhibited significant dual topoisomerase I and II inhibitory activities, and strong antiproliferative activity in low micromolar range. Structure activity relationship study suggested that phenol moiety at 4-position of the central pyridine regardless of chlorophenyl moiety at 2-position of the central pyridine has an important role in dual topoisomerase inhibitory activity as well as antiproliferative activity. For investigation of mode of action for compound 14 which displayed the most strong dual topoisomerase I and II inhibitory activity and antiproliferative activity against HCT15 cell, we performed cleavable complex assay, band depletion assay, comet assay, and competitive EtBr displacement assay. Compound 14 functioned as non-intercalative catalytic topo I and II dual inhibitor. In addition, compound 14 induced apoptosis in HCT15 cells through increase of Bax, decrease of Bcl-2 and increase of PARP cleavage., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The quinoline motif fused with other heterocyclic systems plays an important role in the field of anticancer drug development. An extensive series of tetracyclic quinolino[3,4-b]quinoxalines N-5 or C-6 substituted with basic side chain and a limited number of tricyclic pyridazino[4,3-c]quinolines N-6 substituted were designed, synthesized and evaluated for topoisomerase IIα (Topo IIα) inhibitory activity, ability to bind and stabilize G-quadruplex structures and cytotoxic properties against two human cancer cell lines (HeLa and MCF-7). Almost all of the tested agents showed a high activity as Topo IIα inhibitors and G-quadruplex stabilizers. Among all the derivatives studied, the quinolino[3,4-b]quinoxalines 11 and 23, N-5 and C-6 substituted respectively, stand out as the most promising compounds. Derivative 11 resulted a selective binder to selected G-quadruplex sequences, while derivative 23 displayed the most interesting Topo IIα inhibitory activity (IC50 = 5.14 μM); both showed high cytotoxic activity (IC50 HeLa = 2.04 μM and 2.32 μM, respectively)., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The synthesis and biological evaluation of a new library of 4-(1,2-diarylbut-1-en-1-yl)isobutyranilides is described. The new compounds were found to be cytotoxic in the micromolar range in two human tumor cell lines, MCF-7 (mammary gland adenocarcinoma) and HeLa (cervix adenocarcinoma) and two human ovarian cancer cell lines (A2780 and OVCAR5). Detailed studies on the most active compound 6g show that it was able to induce apoptosis and suggest topoisomerase II as a possible intracellular target. The relevance of the interaction of the most active compound with topoisomerase II is demonstrated and supported by docking studies., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A series of 9-benzylamino acridine derivatives were synthesized as an extension of our discovery of acridine antitumor agents. Most of these acridine compounds displayed good antiproliferative activity with IC50 values in low micromole range and structure-activity relationships were studied. Topo I- and II- mediated relaxation studies suggested that all of our compounds displayed strong Topo II inhibitory activity at 100 μM, while only four exhibited moderate Topo I inhibitory activity. The typical compound 8p could penetrate A549 cancer cells efficiently. Compound 8p could intercalate within the double-stranded DNA structure and induce DNA damage. Moreover, compound 8p could induce A549 cells apoptosis through caspase-dependent intrinsic pathway and arrest A549 cells at the G2/M phase., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R(3) group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

According to the structure-activity relationship, drug combination principle and bioisosterism, a series of the novel esterification and amination 4'-demethylepipodophyllotoxin derivates were rationally designed in order to discover the potential antitumor prodrug. And then these compounds were tested by the drug-topoisomerase II docking models for virtual screening. Thus, twelve target compounds were screened out and synthesized. Most of compounds exhibited promising in vitro anti-tumor activity, particularly 4-N-tris(hydroxymethyl)metylaminomethane-4-deoxy-4'-demethylepipodophyllotoxin (Compound 1). The anti-tumor activity of Compound 1 against the tumor cell lines BGC-823 (i.e., the IC50 value of 5.35 ± 0.77 μM), HeLa (i.e., the IC50 value of 160.48 ± 14.50 μM), and A549 (i.e., the IC50 value of 13.95 ± 5.41 μM) was significantly improved by 706%, 31% and 900% than that of etoposide (i.e., the IC50 values of 43.74 ± 5.13, 209.90 ± 13.42, and 139.54 ± 7.05 μM), respectively. Moreover, the IC50 value of Compound 1 against the normal human cell line HK-2 (i.e., 16.3 ± 3.77 μM) was 78% lower than that of etoposide (i.e., 9.17 ± 1.58 μM). Compound 1 could diminish the relaxation reaction topoisomerase II DNA decatenation at a concentration of 10 μM and induce BGC-823 apoptosis by breaking DNA double-strand and activating ATM/ATR signaling pathways., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Five highly oxygenated friedelan derivatives (3a, 3b, 4, 5a and 5b) were synthesized. The structures of these compounds were established on the basis of spectral (IR, 1D and 2D NMR, MS etc.) and chemical data. The molecules, including the parent compounds were screened for three-dimensional (3D) molecular docking on the crystal structure of topoisomerase IIα (1 bgw for topoisomerase IIα, PDB). Compounds 3a and 5a showed a dose dependent inhibition of catalytic activity of human topoisomerase IIα., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

In order to develop potential anti-cancer agents that act on topoisomerase II and DNA, we have synthesized 12 new xanthone derivatives. In the cytotoxicity test, compounds 17 and 31 exhibited 2- to 7-fold stronger inhibitory activity than adriamycin against most cancer cell lines tested. Halohydrin group-tethered compounds 19, 21 and 27 showed comparable topoisomerase II inhibitory activity to etoposide at 100 microM concentration. In the DNA cross-linking test, compounds 20, 30 and 31 produced DNA cross-linked adducts and compound 30 was the strongest DNA cross-linker. Based on the combined pharmacological results, we suspected that the strong anti-cancer activity of compounds 16, 17, 20, 30 and 31 originated from the DNA mono-alkylation or cross-linking properties of the compounds., (2010 Elsevier Masson SAS. All rights reserved.)