Synthesis, biological activity and comparative analysis of DNA binding affinities and human DNA topoisomerase I inhibitory activities of novel 12-alkoxy-benzo[c]phenanthridinium salts

New antitumor 12-alkoxy-benzo[c]phenanthridinium derivatives were obtained in high yields through multistep syntheses. Analysis of DNA binding and human DNA topoisomerase I inhibitory activities demonstrates that new compounds, combining 2, 6, and 12 substitutions, interact strongly with DNA and exhibit important topoisomerase I inhibition. The cytotoxicities against solid tumor cell lines are also determined and compared with those for fagaronine and ethoxidine.     

New insight for fluoroquinophenoxazine derivatives as possibly new potent topoisomerase I inhibitor

Fluoroquinolones, represented by ciproxacin and norfloxacin, are well-known clinical antimicrobial agents, and their phenyl ring expanded quinophenoxazines are reported as possible antitumor active compounds. These quinophenoxazines are known to inhibit DNA topoisomerase II essential for cell replication cycle. But there were no reports for topoisomerase I inhibition study for these compounds. In this report, we have prepared a few quinophenoxazine analogues and tested their topoisomerases I and II inhibitory activities and cytotoxicity. From the result, we found that quinophenoxazine analogues possessed strong topoisomerase I inhibitory capacity as well as topoisomerase II inhibition. Among the compounds prepared, A-62176 analogues showed strong topoisomerases I and II inhibitory activities. Interestingly, compound 8 missing the 3-aminopyrrolidine moiety at C2 position has similar potent inhibitory capacity against topoisomerases I and II at higher concentrations (20 and 10 microM, respectively). But compound 8 inhibited topoisomerase I function more selectively at lower concentration, 2 microM. Our observation might strongly implicate that fluoroquinophenoxazines can be developed as efficient topoisomerase I inhibitor with the elaborate modification.     

Novel naphthalimide–amino acid conjugates with flexible leucine moiety as side chain: Design,synthesis and potential antitumor activity

A series of novel naphthalimide derivatives with flexible leucine side chains were designed and synthesized. Their antitumor activities were evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8 and A375 cancer cell lines in vitro. The preliminary results showed that most of the derivatives had moderate antitumor activities with the IC₅₀ values of 10^?6–10^?5 M. More importantly, compounds 8a–c exhibited exclusive antitumor activities against MCF-7 cell line. The interaction between compound 8b and BSA was also investigated. DNA binding experiments showed that these derivatives behaved as DNA intercalating agents. This work provided a novel class of naphthalimide-based lead compounds with exclusive antitumor activities against MCF-7 cell line for further optimization.     

Novel angular furoquinolinones bearing flexible chain as antitumor agent: design, synthesis, cytotoxic evaluation, and DNA-binding studies

A series of novel N-substituted angular furoquinolinone derivatives were synthesized and evaluated for their antitumor activities against QGY, K562, HeLa, P388, and A549 cell lines in vitro. The derivatives bearing basic amino side chain showed an improved antitumor activity. Compound 5h N-(2-dimethylamino-ethyl)-2-(4,8,9-trimethyl-2-oxo-2H-furo[2,3-h]quinolin-1-yl)-acetamide exhibited the highest activities against P388 and A549 cell lines, which are evidenced by the IC(50) values that are four to five fold lower than that for unsubstituted parent compound. DNA-binding experiments suggested that these derivatives bind to DNA through intercalation.     

Novel heterocyclic family of phenyl naphthothiazole carboxamides derived from naphthalimides: synthesis, antitumor evaluation, and DNA photocleavage

A new heterocyclic family of (2-(dimethylamino)ethyl)-2-substituted phenylnaphtho[2,1-d]thiazole-5-carboxamides modified from naphthalimides was designed, synthesized, and quantitatively evaluated as antitumor agents and photonucleases. All these compounds were found to be more cytotoxic against P388 than against A549. B(3) (m-NO(2)) was found to be the strongest inhibitor for P388 with IC(50) of 1.49 microM, while B(2) was the most cytotoxic compound against A549 with IC(50) of 12 microM. B(4) (p-CH(3)), the most efficient DNA photocleaver, showed detectable DNA cleavage at 0.5 microM and total cleavage from form I to 100% form II at 50 microM. The photocleaving mechanism was changed with the modification to be via superoxide anion and radical.     

Synthesis and antitumor evaluation of a novel series of triaminotriazine derivatives

A series of triaminotriazine derivatives (compounds 5a-f, 6a-x, and 7a-g) was designed, synthesized, and evaluated for their inhibition activities to colorectal cancer (CRC) cell lines (HCT-116 and HT-29). Most of the synthesized compounds demonstrated moderate anti-proliferatory effects on both HCT-116 and HT-29 cell lines at the concentration of 10 microM. The inhibitory activities against HCT-116 and HT-29 cell lines were discussed to develop the structure-activity relationships of this new series. Compounds 6l and 6o exhibited prominent inhibition activities toward HCT-116, with IC50s of 0.76 and 0.92 microM, respectively. The in vivo antitumor studies and pharmacokinetics of compound 6l showed that it might be a promising new hit for further development of antitumor agents.     

Semi-synthesis, topoisomerase I and kinases inhibitory properties, and antiproliferative activities of new rebeccamycin derivatives

In the course of structure-activity relationship studies, new rebeccamycin derivatives substituted in 3,9-positions on the indolocarbazole framework, and a 2',3'-anhydro derivative were prepared by semi-synthesis from rebeccamycin. The antiproliferative activities against nine tumor cell lines were determined and the effect on the cell cycle of murine leukemia L1210 cells was examined. Their DNA binding properties and inhibitory properties toward topoisomerase I and three kinases PKCzeta, CDK1/cyclin B, CDK5/p25 and a phosphatase cdc25A were evaluated. The 3,9-dihydroxy derivative is the most efficient compound of this series toward CDK1/cyclin B and CDK5/p25. It is also characterized as a DNA binding topoisomerase I poison. Its broad spectrum of molecular activities likely accounts for its cytotoxic potential. This compound which displays a tumor cell line-selectivity may represent a new lead for subsequent drug design in this series of glycosylated indolocarbazoles.     

Synthesis, antitumor evaluation and DNA photocleaving activity of novel methylthiazonaphthalimides with aminoalkyl side chains

A series of methylthiazonaphthalimides was synthesized and quantitatively evaluated as efficient DNA intercalators, antitumor agents and DNA photocleavers. A(1) showed both efficient antitumor activities against cell lines of A549 and P388 with IC50 of 82.8 and 31 nM, respectively. A(3) was the strongest antitumor agent against A549 with the IC50 of 20.8 nM. A(2), the most efficient DNA intercalator, was found to be the strongest DNA photocleaver via superoxide anion. An explanation was given for the disaccord between antitumor and DNA photocleaving activities.     

2,6-Dithienyl-4-furyl pyridines: Synthesis,topoisomerase I and II inhibition,cytotoxicity, structure–activity relationship,and docking study

For the development of novel antitumor agents, 2,6-dithienyl-4-furyl pyridine derivatives were prepared and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against several human cancer cell lines. Among the 21 prepared compounds, compound 24 exhibited strong topoisomerase I inhibitory activity. In addition, a docking study with topoisomerase I and compound 24 was performed.     

Synthesis and biological evaluation of histone deacetylase and DNA topoisomerase II-Targeted inhibitors

HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated. Among the synthesized hybrid compounds, compound 16b showed the potent HDAC inhibitory activity at a low nanomolar level and exhibited antiproliferative activity toward cancer cell lines including MCF-7 (breast), HCT-116 (colon), and DU-145 (prostate) cancer cells at a low micromolar level. Moreover, compound 16a showed HDAC6-selectivity 20-fold over HDAC1.     

Synthesis and antitumor activity of novel 10-substituted camptothecin analogues

In an attempt to improve the antitumor activity and decrease the cytotoxicity of camptothecin, 18 new 10-substituted camptothecin derivatives were prepared. The cytotoxicity in vitro on cancer cell lines and antitumor activity in vivo, and inhibitory properties of topoisomerase I of these derivatives were evaluated. Most of these derivatives possessed lower cytotoxicities than CPT, and the compounds 13, 21, 22, 23, and 24 showed similar topoisomerase I inhibitory activity to CPT. Analogues 13 exhibited the best antitumor activity in vivo among all derivatives we prepared.     

Analogues of antifungal tjipanazoles from rebeccamycin

Analogues of antifungal tjipanazoles were obtained by semi-synthesis from rebeccamycin, an antitumor antibiotic isolated from cultures of Saccharothrix aerocolonigenes. The antiproliferative activities of the new compounds were evaluated in vitro against nine tumor cell lines. The effect on the cell cycle of murine leukemia L1210 cells was examined and the antimicrobial activities against two Gram positive bacteria, a Gram negative bacterium and a yeast were determined. The inhibitory properties toward four kinases and toward topoisomerase I were evaluated. The most cytotoxic compound in the series was a dinitro derivative characterized as a potent topoisomerase I inhibitor.     

Syntheses of novel antitumor dihydroxanthone derivatives with inhibitory activity against DNA topoisomerase II.

A series of methoxycarbonyl group modified nidulalin A analogs were synthesized to improve stability against esterases. The amide derivatives showed cytotoxic activity along with inhibitory activity against DNA topoisomerase II. Among the analogs, amide 9a exhibited antitumor activity in Colon 26 murine tumor model.     

Inhibitory activities against topoisomerase I and II by polyhydroxybenzoyl amide derivatives and their structure-activity relationship

o-, m-, p-Phenylenediamines having 2,3,4-trihydroxy, 3,4 dihydroxy, and 4-hydroxybenzoyl moieties were prepared and their inhibitory activities were measured against topoisomerase I and II. More hydroxy groups on two aromatic rings increased the activities. Bis(trihydroxybenzoyl)-o-phenylenediamide showed IC(50)=0.90 and 0.09 microM against topoisomerase I and II, respectively. Compounds with hydroxy groups protected by acetyl moiety still had the activities. Less hydroxy groups decreased their activities. Benzothiazole derivatives also indicated the activities.     

Synthesis, topoisomerase I inhibition and antitumor cytotoxicity of 2,2':6',2"-, 2,2':6',3"- and 2,2':6',4"-terpyridine derivatives

For the development of new anticancer agents, 2,2':6',2"-, 2,2':6',3"- and 2,2':6',4"-terpyridine derivatives were designed and evaluated for their topoisomerase I inhibitory activity and antitumor cytotoxicity. Structure-activity relationship studies indicated that 2,2':6',2"-terpyridine derivatives were highly cytotoxic toward several human tumor cell lines, whereas 2,2':6',3"- and 2,2':6',4"-terpyridine derivatives were potent topoisomerase I inhibitors.     

2,4,6-Trisubstituted pyridines: Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship

Designed and synthesized were a series of pyridines substituted at 2, 4, and 6 positions with various 5- or 6-memberd heteroaromatics as antitumor agents. They were evaluated their topoisomerase I and II inhibitory activities along with cytotoxicities against several human cancer cell lines. Among the prepared compounds, 10-20 showed significant topoisomerase I or II inhibitory activities, and 21-26 showed considerable cytotoxicities against several human cancer cell lines. Structure-activity relationship study indicates that 4'-pyridine at 6-position of central pyridine plays a key role in biological activity.     

Preparation of yuanhuacine and relative daphne diterpene esters from Daphne genkwa and structure-activity relationship of potent inhibitory activity against DNA topoisomerase I

Two new daphne diterpene esters Yuanhuajine (2) and Yuanhuagine (4), together with three known daphne diterpene esters yuanhuacine (1), yuanhuadine (3), and yuanhuapine (5), were isolated and identified from Daphne genkwa, a traditional Chinese medicine. Their structures were elucidated by a combination of UV, IR, MS and NMR ((1)H NMR, (13)C NMR, HSQC, and HMBC) spectra. In order to explore the structure-activity relationship, three compounds 6, 7, and 8 were prepared as three derivatives of 1. Inhibitory activities against DNA topoisomerase I (topo I) were assessed for the compounds 1-8. These compounds, except for 8, exhibited potent inhibitory activities against DNA topo I at IC(50) levels of 11.1-53.4 microM and they are new type of topo I inhibitors bearing different structures compared with the known topo I inhibitors. The agarose-gel electrophoresis experiments showed that the orthoester group of daphne diterpene esters was necessary for the inhibitory activity against DNA topo I, and the inhibition against DNA topo I is probably one of the anti-tumor mechanisms of daphne diterpene esters.     

Understanding topoisomerase I and II in terms of QSAR

A variety of antitumor agents currently used in chemotherapy or evaluated in clinical trials are known to inhibit DNA topoisomerase I or II. We have developed sixteen quantitative structure-activity relationships (QSAR) for different sets of compounds that are camptothecin analogs, 1,4-naphthoquinones, unsaturated acids, benzimidazoles, quinolones, and miscellaneous fused heterocycles to understand chemical-biological interactions governing their inhibitory activities toward topoisomerase I and II.     

Synthesis of new camptothecin analogs with improved antitumor activities

Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.     

Anthracycline antibiotics and their derivatives,inhibitors of topoisomerase I

The relationship between the structure of new semisynthetic derivatives of doxorubicin, daunorubicin, and carminomycin and their ability to inhibit topoisomerase I were studied. The new derivatives inhibit the activity of topoisomerase I at low concentrations, induce the death of K-562 leukemia cells in culture, and produce an antitumor effect in experimental animals bearing P388 leukemia.