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A series of N -substituted-4-thiocarbamoyl-5-pyrazolone derivatives (HL1-HL4) is presented as chelating agents for complexation with Fe(III), Ni(II) and Cu(II) metal ions. The synthesized pyrazolone ligands and their newly metal complexes are characterized by different spectral and analytical methods such as UV–Vis, IR, 1H NMR, 13C NMR, ESR, MS, magnetic measurement, and TGA. The spectral data reveal that ligands coordinated to metal ions in a bidentate pattern via O & N atoms of the OH group at C(5) and thiocarbamoyl (–CSNHR) at C(4) of the pyrazolone ring. Also, the analytical data suggest the stoichiometries 2:3 (M:L) for both Cu(II) & Ni(II) complexes and 1:3 for Fe(III) complexes. Besides, the normal magnetic moments values for Fe(III) complexes confirm high spin octahedral structure while the diamagnetic nature of all Ni(II) complexes is consistent with square planar geometry. However, the subnormal magnetic values for Cu(II) complexes suggest the proposal of their binuclear structures. The ESR spectra of the Cu(II) complexes support the distorted square planar geometry with a considerably strong intradimeric spin-exchange interaction. Moreover, the anticancer, antibacterial and antifungal activities are screened. Among the synthesized compounds, HL4 ligand exhibits a significant broad spectrum of action against Gram-positive (S. aureus), Gram-negative bacteria (P. vulgaris), and antifungal potency against A. fumigatus & C. albicans in comparison with gentamicin and ketoconazole drug. Such potency of HL4 could be related to the insertion of the p -chloro in the phenyl group attached to the pharmacophoric thiocarbamoyl group at C(4). Furthermore, IC 50 values of two Cu(II) complexes derived from HL2 and HL3 display nearly twofold or threefold more cytotoxicity impact against three cell lines (MCF-7, HCT116 and HepG-2) compared with cis -platin as positive control. [ABSTRACT FROM AUTHOR]

A series of thiophene incorporating pyrazolone moieties 5a–f and 6a–c were synthesized via diazo coupling of diazonium salt of 3-substituted-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophenes 1a–c with 3-methyl-1H-pyrazol-5(4H)-one, 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one or 3-amino-1H-pyrazol-5(4H)-one, respectively. Newly synthesized dyes were applied to polyester fabric as disperse dyes in which their color measurements and fastness properties were evaluated. These dyes showed generally red to blue shifted color with high extinction coefficient in comparison with aniline-based azo dyes. The antitumor activity of the synthesized dyes was evaluated. The results showed clearly that most of them exhibited good activity and compounds 5c and 5d exhibited moderate activity.

Graphical abstract Highlights • New thiophene and thienopyrimidine derivatives have been synthesized. • Six thienopyrimidine derivatives showed noticeable high anticancer activity. • These derivatives showed good DNA binding affinity. • They also showed good ihibitory activity against three enzymes targeted in cancer therapy. • This study provides promising leads for further development of antitumor agents. Abstract New thiophene (2 – 13) and thienopyrimidine (15 – 27) derivatives have been synthesized. Twenty three compounds were screened against five cell lines namely; hepatocellular carcinoma (liver) HepG-2, epidermoid carcinoma (larynx) Hep-2, mammary gland (breast) MCF-7, human prostate cancer PC-3 and epithelioid cervix carcinoma HeLa. The results revealed that compounds 15 , 16 , 17 , 24 and 25 showed the highest antitumor activity against all tested cell lines compared to Doxorubicin. In order to explain the expected mode of action of the observed anticancer activity, compounds 15 , 16 , 17 , 24 and 25 were selected to screen their DNA binding affinity and enzyme inhibitory activity against DNA polymerase, thymidylate synthase and tyrosine kinase. The results revealed that the tested compounds showed good DNA binding affinity as well as good inhibitory activity against the three enzymes which might explain the observed anticancer activity of the target compounds. [ABSTRACT FROM AUTHOR]

The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives based on our lead NCI 748494/1 , possessing different N-linkers to aromatic and heterocyclic rings. In addition, a molecular hybrid series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-mercaptopurine (6-MP) was synthesized in order to explore its “double-drug” antitumor effect. The synthesized compounds were evaluated for their in vitro antitumor activity against three c-Met addicted cancer cell lines (A549, HT-29 and MKN-45). Most compounds showed moderate to excellent antitumor activity. Compound 3d showed potent inhibitory activity more than reference Foretinib, BMS-777607 and NCI 748494/1 with IC 50 values in the range 0.01–0.31 µM against the cancer cell lines. The calculated IC 50 of 3d against c-Met kinase was found to be 2.71 µM, which is more potent than NCI 748494/1 (IC 50  = 31.70 µM). Docking studies were performed to identify the binding mode of 3d with c-Met kinase domain in comparison to moderate and weak derivatives. The present study clearly demonstrates that 1,2,4-triazine ring exhibits promising antitumor activity and the double-drug optimization strategy led to identifying 3d as a potent c-Met kinase inhibitor suitable for further development. [ABSTRACT FROM AUTHOR]

To contribute to the development of an efficient method for the conversion of antibacterial fluoroquinolones to antitumor fluoroquinolones, a series of C3/C3 bis-fluoroquinolone fused heterocycles cross-linked with a [1,2,4]-triazolo[3,4-b] [1,3,4]-thiadiazole core as a common bioisostere of two carboxylic acid groups was designed and synthesized as their hydrochloride salts. Structures were characterized by elemental analysis and spectral data and their in vitro antitumor activity against L1210, CHO and HL60 cell lines was screened by determination of their IC50 values in the methylthiazole trazolium (MTT) assay. Two compounds were highly potent against the HL60 cell line and represent promising lead compounds for future development.

Background: The medicinal plants Vincetoxicum arnottianum (VSM), Berberis orthobotrys (BORM), Onosma hispida (OHRM and OHAM) and Caccinia macranthera (CMM) are used traditionally in Pakistan and around the world for the treatment of various diseases including cancer, dermal infections, uterine tumor, wounds etc. The present study focuses on the investigation of the selected Pakistani plants for their potential as anticancer agents on human bone and breast cancer cell lines in comparison with non-tumorigenic control cells. Methods: The antitumor evaluation was carried out on human bone (MG-63, Saos-2) and breast cancer cell lines (MCF-7, BT-20) in contrast to non-tumorigenic control cells (POB, MCF-12A) via cell viability measurements, cell cycle analysis, Annexin V/PI staining, microscopy based methods as well as migration/invasion determination, metabolic live cell monitoring and western blotting. Results: After the first initial screening of the plant extracts, two extracts (BORM, VSM) revealed the highest potential with regard to its antitumor activity. Both extracts caused a significant reduction of cell viability in the breast and bone cancer cells in a concentration dependent manner. The effect of VSM is achieved primarily by inducing a G2/M arrest in the cell cycle and the stabilization of the actin stress fibers leading to reduced cell motility. By contrast BORM's cytotoxic properties were caused through the lysosomal-mediated cell death pathway indicated by an upregulation of Bcl-2 expression. Conclusions: The antitumor evaluation of certain medicinal plants presented in this study identified the methanolic root extract of Berberis orthobotrys and the methanolic extract of Vincetoxicum arnottianum as promising sources for exhibiting the antitumor activity. Therefore, the indigenous use of the herbal remedies for the treatment of cancer and cancer-related diseases has a scientific basis. Moreover, the present study provides a base for phytochemical investigation of the plant extracts. [ABSTRACT FROM AUTHOR]

The jolkinolides are a series of naturally occurring ent-abietane diterpenes with potent antitumor activity, which have been isolated from the genus Euphorbia. We describe the first method for the total synthesis of 3,19-dihydroxyjolkinolide and its derivatives. The strategy for the synthesis of 3,19-dihydroxyjolkinolide A has 12 steps with an overall yield of 4.3%. The synthesized compounds were evaluated for their antitumor activity in nine kinds of tumor cell lines. [ABSTRACT FROM AUTHOR]

A series of thiophene incorporating pyrazolone moieties 5a – f and 6a – c were synthesized via diazo coupling of diazonium salt of 3-substituted-2-amino-4,5,6,7-tetrahydrobenzo[ b ]thiophenes 1a – c with 3-methyl-1 H -pyrazol-5(4 H )-one, 3-methyl-1-phenyl-1 H -pyrazol-5(4 H )-one or 3-amino-1 H -pyrazol-5(4 H )-one, respectively. Newly synthesized dyes were applied to polyester fabric as disperse dyes in which their color measurements and fastness properties were evaluated. These dyes showed generally red to blue shifted color with high extinction coefficient in comparison with aniline-based azo dyes. The antitumor activity of the synthesized dyes was evaluated. The results showed clearly that most of them exhibited good activity and compounds 5c and 5d exhibited moderate activity. [ABSTRACT FROM AUTHOR]

A series of disubstituted xanthones was obtained by cationic modification of xanthone’s C2 and C7 with amine groups of different p K a values. Modified structures by using moieties with high p K a values had good antitumor activity according to the MTT assay, AO/EB staining and flow cytometry assay, especially bis-dimethylamine derivative ( 5a ). Further study indicated that compound 5a had good binding activity to telomeric G-quadruplex DNA, as detected by using spectroscopy methods, melting profiles, polymerase chain reaction stop assay and molecular modeling study. The results suggested that the antitumor activity of 5a might be associated with its stabilization of G-quadruplex DNA, which could be developed as new G-quadruplex DNA stabilizer and potent antitumor agents. [ABSTRACT FROM AUTHOR]

CRBN protein is an E3 ubiquitin ligase which plays an important role in the ubiquitin-proteasome system of eukaryotic cells. Small molecules can modulate CRBN and induce multiple target proteins to bind with CRBN, which contributes to ubiquitination and degradation of target proteins. Modulating the CRBN protein through small molecules provides a novel idea for treatment of tumors and immune system disease. Due to most of CRBN modulators containing glutarimide skeleton, we aimed to discover novel potent CRBN modulators. In this study, Lipinski's rule and Veber rule, pharmacophore based virtual screening, docking based virtual screening and ADMET screening methods were performed to discover potential CRBN modulators. The antitumor activity of 11 candidates were evaluated by MTS assay. AN7535 showed potent antitumor activity with IC 50 = 0.72 μM against HL-60 and IC 50 = 1.438 μM against SMMC-7721. AO6355 showed potent antitumor activity with IC 50 = 7.469 μM against SMMC-7721. MD simulations and binding free energy calculations suggested that AN7535 and AO6355 could stabilize the CRBN protein and have favorable binding affinity with CRBN protein. Luciferase complementation assay suggested AN7535 could bind to CRBN with IC 50 = 215.9 μM. [Display omitted] • The multilayer virtual screening methods were used to discover novel CRBN modulators. • AN7535 and AO6355 exhibited strong inhibitory effect on HL-60 or SMMC-7721 cell lines. • Luciferase complementation assay was performed to investigate the binding of candidate compounds and CRBN. [ABSTRACT FROM AUTHOR]

A series of hybrid anaplastic lymphoma kinase (ALK) inhibitors (Y1 ∼ Y30) were designed by assembling aminoindazole of Entrectinib onto 2-position of 2,4-diarylaminopyrimidine (DAAP) fragment to serve as ATP dual-mimic agents. Under structure-based optimization, all conjugates were detected moderate to excellent cytotoxicity potency, among which the pyrrolidine analog Y28 exerted optimal antiproliferative effects on ALK-addicted cell lines with IC 50 values below 20 nM. As a highly potent ALK inhibitor (ALKWT, IC 50 = 1.6 nM), Y28 was also capable of suppressing ALK-resistant mutations including ALKL1196M (0.71 nM) and ALKG1202R (1.3 nM). Intriguingly, Y28 turned out to effectively inhibit colony formation and restrain cell migration of H2228 cells in a dose dependent manner. In addition, flow cytometric analysis indicated that Y28 could induce cell apoptosis and achieve cell cycle arrest in G2 phase. Notably, oral administration of Y28 at 50 mg/kg regressed tumor in the H2228 xenograft model with tumor growth inhibition value of 70.46%. Finally, the binding models of Y28 with ALKWT & ALKG1202R within the active site well established its mode of action and accounted for the superior activities as a promising antitumor candidate. [Display omitted] • A series of ATP dual-mimic conjugates were designed as ALK inhibitors. • Structural evolution furnished the most powerful ALK inhibitor Y28. • Y28 presented encouraging antiproliferative effects with apoptosis-inducing action. • Y28 achieved a remarkable G2 phase arrest in H2228 cells. • Y28 suppressed tumor growth and restrained tumor cell migration. [ABSTRACT FROM AUTHOR]

A series of novel 2,4-diarylaminopyrimidine analogues (G-1 ∼ G-8 and I-1 ∼ I-24) were rationally designed by incorporating 2-alkyl-3-acyl-1 H- indol fragment to interact with the hydrophobic region of the intractable ALKG1202R mutant. Wherein, compound I-24 bearing a 2-methyl-3-dimethylformamido-1 H -indol moiety was identified as the most promising ALK inhibitor with IC 50 values below 4 nM against ALKWT, ALKL1196M and ALKG1202R, accompanied by concrete down-regulation of phospho-ALK and its relative downstream signaling. Subsequently, I-24 displayed significant anti-proliferative activity in the nanomolar range towards ALK-positive cell lines including a panel of Ba/F3 cells harboring mutational ALK. Dramatically, the involvement of I-24 decreased colony formation and migration tendency on H2228 cells. Meanwhile, flow cytometry analysis indicated that I-24 could induce cell apoptosis and achieve cell cycle arrest in G1 phase. Notably, oral administration of I-24 at 50 mg/kg regressed tumor in the H2228 xenograft model with tumor growth inhibition value of 93.5%. Collectively, I-24 with favorable PK profile was supposed to further investigation as potent ALK inhibitor to circumvent clinical drug resistance. [Display omitted] • 3-acyl-indol-based 2,4-diarylaminopyrimidine analogues were designed and synthesized. • I-24 was identified as a potent ALK inhibitor with anti-mutation effects. • I-24 down-regulated the phosphorylation of ALK and its downstream proteins. • I-24 exhibited good liver microsomal stability with rational PK profiles. • I-24 significantly suppressed the tumor growth in H2228 xenograft mouse model. [ABSTRACT FROM AUTHOR]

Berberine hydrochloride (BH) is an isoquinolin alkaloid with promising anticancer efficacies. Nevertheless, further development and application of this compound had been hampered by its poor aqueous solubility, low gastrointestinal absorption, and rapid metabolism in the body. In this study, a solid lipid nanoparticle (SLN)-based system was developed for efficient incorporation and persistent release of BH. The drug-loading SLNs (BH-loaded SLNs) were stable, with a mean particle size of 81.42 ± 8.48 nm and zeta potential of −28.67 ± 0.71 mV. BH-loaded SLNs showed desirable drug entrapment efficiency and drug-loaded, and the release of BH from SLNs was significantly slower than free BH. Importantly, our in vitro study indicated that BH-loaded SLNs more significantly inhibited cell proliferation on MCF-7, HepG 2, and A549 cancer cells. Meanwhile, clone formation, cellular uptake, cell cycle arrest, and cell apoptosis studies also demonstrated that BH-loaded SLNs enhanced the antitumor efficacies of BH on MCF-7 cancer cells. Taken together, our results suggest that this SLN formulation may serve as a novel, simple, and efficient system for the delivery of BH. [ABSTRACT FROM AUTHOR]

In this work, a xanthone derivative was obtained by cationic modification of the free hydroxyl group of xanthone with dimethylamine group of high pKa value. The interactions of xanthones with DNA were investigated by spectroscopic methods, electrophoretic migration assay and polymerase chain reaction test. Results indicate that xanthones can intercalate into the DNA base pairs by the hydrophobic plane and the xanthone with dimethylamine side chain may also bind the DNA phosphate framework by the basic amine alkyl chain, thus showing a better DNA binding ability than the xanthone. Furthermore, inhibition on tumor cells (ECA109, SGC7901, GLC-82) proliferation of xanthones were evaluated by MTT method. Analysis results show that the xanthone with dimethylamine side chain exhibits more effective inhibition activity against three cancer cells than the xanthone. The effects on the inhibition of tumor cells in vitro agree with the studies of DNA binding. It means that the amine alkyl chain would play an important role in its antitumor activity and DNA binding property. [ABSTRACT FROM AUTHOR]

Abstract: A series of new anilides (2a–c, 4–7, 17a–c, 18) and quinolones (3a–b, 8a–b, 9a–b, 10–15, 19) with nitrogen-bearing substituents from benzo[b]thiophene and thieno[2,3-c]thiophene series are prepared. Benzo[b]thieno[2,3-c]- and thieno[3′,2′:4,5]thieno[2,3-c]quinolones (3a–b, 8a–b) are synthesized by the reaction of photochemical dehydrohalogenation from corresponding anilides. Anilides and quinolones were tested for the antiproliferative activity. Fused quinolones bearing protonated aminium group, quaternary ammonium group, N-methylated and protonated aminium group, amino and protonated amino group (8a, 9b, 10–12) showed very prominent anticancer activity, whereby the hydrochloride salt of N′,N′-dimethylaminopropyl-substituted quinolone (14) was the most active one, having the IC50 concentration at submicromolar range in accordance with previous QSAR predictions. On the other hand, flexible anilides were among the less active. Chemometric analysis of investigated compounds was performed. 3D-derived QSAR analysis identified solubility, metabolitic stability and the possibility of the compound to be ionized at pH 4–8 as molecular properties that are positively correlated with anticancer activity of investigated compounds, while molecular flexibility, polarizability and sum of hydrophobic surface areas were found to be negatively correlated. Anilides 2a–b, 4–7 and quinolones 3a–b, 8a–b, 9b and 10–14 were evaluated for DNA binding propensities and topoisomerases I/II inhibition as part of their mechanism of action. Among the anilides, only compound 7 presented some DNA binding propensity whereas the quinolones 8b, 9b and 10–14 intercalate in the DNA base pairs, compounds 8b, 9b and 14 being the most efficient ones. The strongest DNA intercalators, compounds 8b, 9b and 14, were clearly distinguished from the other compounds according to their molecular descriptors by the PCA and PLS analysis. [Copyright &y& Elsevier]

The incidence of malignant tumor with high mortality is increasing yearly. CRBN E3 ubiquitin ligase was proved to be an antitumor target. It was found that thalidomide and its analogs could bind to CRBN E3 ubiquitin ligase and modulate CRBN. CRBN modulators could promote the binding of CRBN to specific target proteins or block the binding of CRBN to some endogenous proteins. In this way, CRBN modulators suppress various tumor cells by modulating the interactions between CRBN and various antitumor target proteins. However, almost all CRBN modulators reported include glutarimide scaffold. Therefore, the aim of this study is to developed novel CRBN modulators. Virtual screening methods and bioassay methods, including structural similarity search, molecular docking, substructure search, antitumor evaluation and apoptosis assay were used to search novel potential CRBN modulators in Specs database. Finally, 15 compounds exhibited strong inhibition activity against A549 cells. Among these active compounds, The IC 50 value against A549 of AG6033 was 0.853 ± 0.030 μM. Apoptosis assay demonstrated that AG6033 could promote apoptosis of A549 cells. Further mechanism studies suggested that AG6033 caused remarkable decrease of GSPT1 and IKZF1, the substrates of CRBN, and AG6033 induced cytotoxic effects was CRBN-dependent. [Display omitted] • Several virtual screening methods were used to discover novel CRBN modulators. • 15 compounds showed strong antitumor activity. • Compound AG6033 can cause degradation of GSPT1 and IKZF1. [ABSTRACT FROM AUTHOR]

Carboxylic acid imides 1- 26 have been synthesized and screened for their antibacterial against gram-positive and gram-negative organisms and their antitumor activity against 60 tumor cell lines taken from nine different organs. Compounds 12, 14, and 16 were the most active and broad-spectrum antibacterial member in this study. Compound 9 showed the most cytotoxicity with a significant inhibition for renal cancer cells. 2D-QSAR study provides details on the fine relationship linking structure and activity and offers clues for structural modifications that can improve the activity. Docking study of the compounds 12, 14, and 16 into the active site of the topoisomerase II DNA gyrase enzymes revealed a similar binding mode to bound inhibitor Clorobiocin. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: To contribute to the development of an efficient method for the conversion of antibacterial fluoroquinolones to antitumor fluoroquinolones, a series of C3/C3 bis-fluoroquinolone fused heterocycles cross-linked with a [1,2,4]-triazolo[3,4-b] [1,3,4]-thiadiazole core as a common bioisostere of two carboxylic acid groups was designed and synthesized as their hydrochloride salts. Structures were characterized by elemental analysis and spectral data and their in vitro antitumor activity against L1210, CHO and HL60 cell lines was screened by determination of their IC50 values in the methylthiazole trazolium (MTT) assay. Two compounds were highly potent against the HL60 cell line and represent promising lead compounds for future development. [Copyright &y& Elsevier]

Abstract: 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 &y& Elsevier]

A series of novel stilbene-sydnone derivatives were synthesized by the following sequence of reactions: starting from methyl anthranilate via glycine- and nitrosoglycine derivatives the corresponding 3-(o-carbomethoxyphenyl)-4-H/Me/Ph-sydnones were prepared and transformed to 3-(o-formylphenyl)-4-H/Me/Ph-sydnones, starting materials for Wittig reaction with various phosphonium salts to stilbenylsydnone derivatives. Final products were evaluated for their cytotoxic properties on five cancer cell lines, whereby the cis-4-methyl-3-[2-[2-(4-methylphenyl)ethenyl]phenyl]sydnone 5 and cis-4-phenyl-3-[2-[2-(4-chlorophenyl)ethenyl]- phenyl]sydnone 10 showed the most pronounced activity. [ABSTRACT FROM AUTHOR]

Abstract: A synthesis and biological evaluation of new benzimidazole derivatives, related to 2,3-disubstituted acrylonitriles, benzimidazo[1,2-a]quinoline-6-carbonitriles and heteroaromatic fluorenes was described. The molecular and crystal structures of three compounds 4, 16 and 17 reveal that non-fused fluoro derivative, 4, deviates from planarity by 13.11(2)°, while fused methyl, 16, and fluoro, 17, derivatives are planar within 4° exhibiting a planar aromatic surface capable to intercalate into double-stranded DNA. Compound 4 exists as E-isomer. The crystal structures confirmed that hydrogen bonding patterns are characterized dominantly by the weak C–H⋯N(F) bonds, except in the case of 4 where the presence of ethanol molecule of crystallization resulted in the N–H⋯O and O–H⋯N hydrogen bonds formation. In the crystal structures of 16 and 17 cyano group participates in hydrogen bonding formation, while in 4 this is not the case. All compounds, except 16 and 14 exerted pronounced antiproliferative activity on five tumor cell lines, whereby 2-benzimidazolyl-3-N-methylpyrolyl-acrylonitrile 13 and its fused analogue 23 exerted the highest activity on all cell lines (IC50 =0.8–30μM) and showed a special selectivity toward HeLa cells. There is no major difference in the biological activity between non-fused and fused analogues. Similarly, all compounds showed significant interaction with ct-DNA, supporting the fact that their antitumor activity could partially be the consequence of DNA-binding. The cyano moiety is important for the activity, but not the selectivity of tested compounds. [Copyright &y& Elsevier]

Abstract: A series of amidino-substituted benzimidazoles, related to furyl-phenyl- and thienyl-phenyl-acrylates, naphthofurans and naphthothiophenes were prepared, their antitumor evaluation and interactions with ct-DNA have been investigated. All tested compounds show differential and strong antitumor activity without apparent difference depending on their structures. Interestingly, the MCF-7 tumor cell line is highly sensitive to all compounds. Compounds 6–9 showed noticeable selectivity in regard to normal fibroblasts (WI 38). Compounds 4–9 interact with ct-DNA by more binding modes, whose mutual distribution is dependent on the compound/DNA ratio. The “acyclic”4–6 and “cyclic” compound 7 interact mostly within the minor groove of DNA, although partial intercalation of 6 and 7 cannot be excluded. The “cyclic” compounds 8 and 9 intercalate between DNA base pairs at high excess of DNA over compounds. [Copyright &y& Elsevier]

Abstract: A 3-(dibenzothien-4-yl)indole and a phenylbenzothienoindole or a 3-(dibenzofur-4-yl)indole and a phenylbenzofuroindole were prepared by a metal-assisted C–N intramolecular cyclization of the methyl esters of N-Boc-(E) or (Z)-β-dibenzothien-4-yl or β-dibenzofur-4-yl dehydrophenylalanines. The latter were obtained by Suzuki cross-coupling of the methyl esters of N-Boc-(E) or (Z)-β-bromodehydrophenylalanines with dibenzothien-4-yl or dibenzofur-4-yl boronic acids, in high yields. The intramolecular cyclization from E or Z pure Suzuki-coupling products gave the corresponding heteroaryl and heteroannulated indoles, in different ratios, by either direct cyclization or cyclization after isomerisation. Three of the cyclized compounds, the two heteroarylindoles and the phenylbenzothienoindole, were evaluated for their capacity to inhibit the in vitro growth of three human tumor cell lines, MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and SF-268 (CNS cancer). The methyl 3-(dibenzothien-4-yl)indole-2-carboxylate was the most potent compound with GI50 values ranging from 11 to 17μM. [Copyright &y& Elsevier]

Abstract: The paper describes synthesis of several novel thiosemicarbazone derivatives. Furthermore, crystal and molecular structure of 4-diethylamino-salicylaldehyde 4-phenylthiosemicarbazone revealed planarity of conjugated aromatic system, which suggested the possibility of DNA binding by intercalation, especially for here studied naphthalene derivatives. However, here presented DNA binding studies excluded this mode of action. Physicochemical and structural properties of novel derivatives were compared with previously studied analogues, taken as reference compounds, revealing distinctive differences. In addition, novel thiosemicarbazone derivatives (1, 2 and 5–8) clearly display stronger antiproliferative activity on five tumor cell lines than the reference compounds 3 and 4, which supports their further investigation as potential antitumor agents. [Copyright &y& Elsevier]