Syntheses, characterization and antitumor activities of transition metal complexes with isoflavone

Five new complexes were synthesized by the reaction of 4′-methoxy-5,7-dihydroxy-isoflavone ligand (a) with transition metal ions zinc (Zn²⁺) (complex b), manganese (Mn²⁺) (complex c), copper (Cu²⁺) (complex d), cobalt (Co²⁺) (complex e) and nickel (Ni²⁺) (complex f). The composition of the complexes has been characterized by elemental analysis, IR, mass spectrometry (MS) and ¹H NMR spectrometric techniques. Their antitumor properties were evaluated against five human cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. The results indicated that the complexes possess higher growth inhibitory effects than free isoflavone and corresponding metal ions. Complex c and f showed greater antitumor activity and selectivity than other described complexes, even more effective than the positive control cisplatin against the selected cell lines. In addition, DNA flow cytometric analysis demonstrated that complexes display a significant G₂/M phase arrest, which then progressed to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI).     

Transition metal complexes of phenanthrenequinone thiosemicarbazone as potential anticancer agents: synthesis,structure, spectroscopy,electrochemistry and in vitro anticancer activity against human breast cancer cell-line,T47D

The thiosemicarbazone derivative of 9,10-phenanthrenequinone, 1, and its metal complexes were synthesized. The X-ray crystal structure for 1 confirms the presence of the E tautomeric arrangement in this compound. Its copper complex shows 1:1 stoichiometry while nickel and cobalt compounds show 1:2 stoichiometry. The X-ray crystal structure of the nickel complex indicates two tridentate ligands coordinating in the thiolato form yielding an octahedral geometry for the 'mer' isomer. The copper complex exhibits maximum antiproliferative activity against human breast cancer cell-line, T47D probably due to inhibition of steroid binding to the cognitive receptor or by preventing dimerization of the estrogen receptor.     

Design,synthesis and biological activities of sorafenib derivatives as antitumor agents

A series of novel sorafenib derivatives, 9a–w, was designed and synthesized in high yields using various substituted anilines, and their antiproliferative activities against HCT116, PC-3 and MDA-MB-231 cell lines were also evaluated and described. All compounds exhibited potent antiproliferative activity against HCT116 and PC-3 cells with IC₅₀ = 2.8–52.0 and 2.2–45.6 μM; compounds 9p and 9q demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines, the cytotoxicity of compound 9r is more potent than that of sorafenib. Compounds (9g, 9p, 9q and 9r) were chosen for further evaluation of the anti-angiogenesis activity, and showed the inhibition of sprout formation from aortic ring ex vivo. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR and HRMS.     

Design,synthesis and biological activities of Nilotinib derivates as antitumor agents

A novel class of Nilotinib derivatives, B1–B20, were synthesized in high yields using various substituted anilines. All the title compounds were evaluated for their inhibitory activities against Bcr–Abl and antiproliferative effects on human leukemia cell (K562). The pharmacological results indicated that some compounds exhibited promising anticancer activity. In particular, compound B14 containing tertiary amine side chain exhibited Bcr–Abl inhibitory activity similar to that of Nilotinib. It was suggested that the introduction of the tertiary amine moiety could improve Bcr–Abl inhibitory activity and antitumor effects.     

Novel thiosemicarbazone derivatives as potential antitumor agents: Synthesis, physicochemical and structural properties, DNA interactions and antiproliferative activity

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.     

Design, synthesis and biological activities of thiourea containing sorafenib analogs as antitumor agents

A novel series of diaryl thiourea containing sorafenib derivatives 9a-t was designed and synthesized. The structures of all the newly synthesized compounds were determined by (1)H NMR, (13)C NMR and HRMS. Their antiproliferative activities against HCT116 and MDA-MB-231 cell lines, and their inhibitory activities against the phosphorylation of VEGFR were evaluated and described. Some of the compounds showed significant activities against both cell lines and VEGFR. Compounds 9g, 9m, 9o and 9p demonstrated competitive antiproliferative activities to sorafenib, the reference standard, while compounds 9d, 9m, and 9p showed significant inhibitory activities against the phosphorylation of VEGFR.     

Synthesis,characterization and antitumor studies of transition metal complexes of o-hydroxydithiobenzoate

o-Hydroxydithiobenzoate (o-HOdtb) forms complexes, [Ni(o-HOdtb)(o-HOdtbS)], [Cu(o-Odtb)], [Co(o-HOdtb)(3)], [Fe(2)(o-Odtb)(3)], [Bu(n)(4)N][V(o-Odtb)(3)] and [Bu(n)(4)N][Zn(o-HOdtb)(3)] which were characterized by analyses and physicochemical studies. The bonding sites of o-HOdtb and the geometry of the complexes were determined by magnetic susceptibility, IR, ESR, NMR, M?ssbauer and electronic spectral data. The structure of [Bu(n)(4)N][Zn(o-HOdtb)(3)] and H(2)C(o-HOdtb)(2) were assigned by single crystal X-ray diffraction studies. The monomeric complex [Bu(n)(4)N][Zn(o-HOdtb)(3)] crystallizes in Pna2(1) space group. The M?ssbauer spectra of [Fe(2)(o-Odtb)(3)] at 298 and 80K suggest the presence of high spin iron(III) with an S=5/2 state. All the metal complexes were observed to inhibit the growth of tumor in vitro, whereas, ligand did not. In vivo administration of these complexes resulted in prolongation of survival of tumor-bearing mice. Tumor bearing mice administered with metal complexes showed reversal of tumor growth associated induction of apoptosis in lymphocytes. The paper discusses the possible mechanisms and therapeutic implication of the ligand and its metal complexes in tumor regression and tumor growth associated immunosuppression.     

Selenium-containing naphthalimides as anticancer agents: design, synthesis and bioactivity

Selenium analogues (4b-4h, and 4j) of two known sulfur compounds were synthesized and tested their anticancer activities. The selenium compound 4b had comparable activity with its sulfur analogue 4a, while DNA-binding study showed these two compounds had similar interaction with ct-DNA, the K(b) was 8.23 and 2.36, respectively. The primary results showed that most compounds had moderate anticancer activities with IC(50) values between 10(-6) and 10(-5) M. Another selenium analogue 4j showed the highest activity with the IC(50) values around 5.3 μM against K562 and MCF-7 cell lines. More importantly, the organochalcogen compounds exhibited stronger anticancer activities against K562 cell line than the other cell lines tested.     

Synthesis and characterization of copper(II) complexes of 4-alkyl/aryl-1,2-naphthoquinones thiosemicarbazones derivatives as potent DNA cleaving agents

Copper (II) complexes of some alkyl/aryl-1,2 naphthoquinones thiosemicarbazone have been prepared and characterized. The crystal structure determined for one of the free ligands viz. 4-Pyrrolidine-1-yl-[1, 2] naphthaquinone thiosemicarbazone (5) indicates it to crystallize in the “E’ conformation which is supported by the NMR data. The ligands and copper complexes were evaluated for their DNA cleaving activities in case of circular double stranded plasmid DNA pBR322 under aerobic conditions. Amongst the ligands, compound 8 shows almost quantitative conversion to the linearized DNA in presence of H₂O₂ oxidant. All copper conjugates show more pronounced interaction with DNA while compounds 3 and 7 are able to yield linearized DNA in presence of the oxidant.     

Organometallic-based antibacterial and antifungal compounds: transition metal complexes of 1,1'-diacetylferrocene-derived thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone

Organometallic-based, 1,1'-diacetylferrocene-derived antibacterial and antifungal thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone have been prepared by condensing equimolar amount of 1,1'-diacetylferrocene with thiocarbohydrazide, carbohydrazide thiosemicarbazide and semicarbazide, respectively. These were used as ligands for the preparation of their cobalt (II), copper (II), nickel (II) and zinc (II) metal complexes. All the synthesized ligands and their complexes were characterized by IR, NMR, elemental analyses, molar conductances, magnetic moments and electronic spectral data. These synthesized compounds were screened for their antibacterial activity against Escherichia coli, Bacillus subtillis, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi, and for antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata using the agar-well diffusion method. All the compounds showed good antibacterial and antifungal activity which increased on coordination with the metal ions thus, introducing a novel class of organometallic-based antibacterial and antifungal agents.     

Design,synthesis and anticancer activity of novel nopinone-based thiosemicarbazone derivatives

A series of new nopinone-based thiosemicarbazone derivatives were designed and synthesized as potent anticancer agents. All these compounds were identified by ¹H NMR, ¹³C NMR, HR-MS spectra analyses. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against three human cancer cell lines (MDA-MB-231, SMMC-7721 and Hela). Among them, compound 4i exhibited most potent antitumor activity against three cancer cell lines with the IC₅₀ values of 2.79 ± 0.38, 2.64 ± 0.17 and 3.64 ± 0.13 μM, respectively. Furthermore, the cell cycle analysis indicated that compound 4i caused cell cycle arrest of MDA-MB-231 cells at G2/M phase. The Annexin V-FITC/7-AAD dual staining assay also revealed that compound 4i induced the early apoptosis of MDA-MB-231 cells.     

Design,synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents

The naturally occurring coumarins and resveratrol, attract great attention due to their wide range of biological properties, including anticancer, antileukemic, antibacterial and anti-inflammatory activities; moreover, their cancer chemopreventive property have been recently emphasized. A novel class of hybrid compounds, obtained by introducing a substituted trans-vinylbenzene moiety on a coumarin backbone, was synthesized and evaluated for the antitumor profile. A number of derivatives showed a good antiproliferative activity, in some cases higher to that of the reference compound resveratrol. The most promising compounds in this series were 14 and 17, endowed with excellent antiproliferative and proapoptotic activities. The present study suggests that the 7-methoxycoumarin nucleus, together with the 3,5-disubstitution pattern of the trans-vinylbenzene moiety, are likely promising structural features to obtain excellent antitumor compounds endowed with a apoptosis-inducing capability.     

Benzothiazole thiourea derivatives as anticancer agents: Design,synthesis, and biological screening

In a systematic effort to identify a potent anticancer agent, we synthesized benzothiazole thiourea derivatives and examined their cytotoxic activity against five different human and animal cancer cell lines. Benzothiazolylthiocarbamides have been prepared in excellent yields by reaction of substituted 2-amino benzothiazoles with carbon disulfide and dimethyl sulfate followed by their ammonolysis. Cytotoxicity of the four compounds were screened for antitumor activity against human breast cancer cells (MCF-7), human cervix epithelial carcinoma (HeLa), human colon cancer cell line (HT-29), human leukemia cell line (K-562), and mouse neuroblastoma cell line (Neuro-2a) using cisplatin as a reference by MTT assay. Our results presented herein provide experimental evidence that benzothiazolylthiocarbamides induce apoptosis in cancer cell lines. According to flow cytometry results, treatment of HT-29 cells with 1-(6-ethoxy-1,3-benzothiazol- 2-yl)thiourea produced a large population of apoptotic cell (79.45%), which was 1.2-fold higher than that produced by cisplatin (65.28%) at the same concentration.     

Synthesis and characterization of the ligand based on benzoxazole and its transition metal complexes: DNA-binding and antitumor activity

A new ligand 2-((2-((benzo[d]oxazol-2-yl)methoxy)phenoxy)methyl)benzoxazole (L) and its four transition metal complexes M(NO₃)₂L (M = Cu, Co, Ni, Zn), have been synthesized and investigated. The single crystal structures of the complexes show that all of them have similar molecular structure and the ligand exhibits good coplanarity after coordination with the metal ions. Further investigation of DNA binding indicates that both the ligand L and the complexes can bond to DNA by intercalation mode, and the latter possesses much stronger binding affinity. Antitumor activity of these compounds tested on the four cancer cell lines, follows the order: Cu-L > Ni-L ≈ Co-L > Zn-L ? L, which are thought to be related with their DNA-binding affinity.     

Palladium(II) complexes of quinolinylaminophosphonates: synthesis, structural characterization, antitumor and antimicrobial activity

Three types of palladium(II) halide complexes of quinolinylaminophosphonates have been synthesized and studied. Diethyl and dibutyl [α-anilino-(quinolin-2-ylmethyl)]phosphonates (L1, L2) act as N,N-chelate ligands through the quinoline and aniline nitrogens giving complexes cis-[Pd(L1/L2)X₂] (X═Cl, Br) (1-4). Their 3-substituted analogues [α-anilino-(quinolin-3-ylmethyl)]phosphonates (L3, L4) form dihalidopalladium complexes trans-[Pd(L3/L4)₂X₂] (5-8), with trans N-bonded ligand molecules only through the quinoline nitrogen. Dialkyl [α-(quinolin-3-ylamino)-N-benzyl]phosphonates (L5, L6) give tetrahalidodipalladium complexes [Pd₂(L5/L6)₃X₄] (9-12), containing one bridging and two terminal ligand molecules. The bridging molecule is bonded to the both palladium atoms, one through the quinoline and the other through the aminoquinoline nitrogen, whereas terminal ligand molecules are coordinated each only to one palladium via the quinoline nitrogen. Each palladium ion is also bonded to two halide ions in a trans square-planar fashion. The new complexes were identified and characterized by elemental analyses and by IR, UV-visible, ¹H, ¹³C and ³¹P nuclear magnetic resonance and ESI-mass spectroscopic studies. The crystal structures of complexes 1-4 and 6 were determined by X-ray structure analysis. The antitumor activity of complexes in vitro was investigated on several human tumor cell lines and the highest activity with cell growth inhibitory effects in the low micromolar range was observed for dipalladium complexes 11 and 12 derived from dibutyl ester L6. The antimicrobial properties in vitro of ligands and their complexes were studied using a wide spectrum of bacterial and fungal strains. No specific activity was noted. Only ligands L3 and L4 and tetrahalidodipalladium complexes 9 and 11 show poor activities against some Gram positive bacteria.     

Lapachol and its congeners as anticancer agents: a review

Lapachol is a naturally occurring 1,4-naphthoquinone originally isolated by the Italian phytochemist E. Paterno from Tabebuia avellanedae (Bignoniaceae) in 1882 and subsequently found in several other genera belonging to the families of Leguminosae, Malvaceae, Plumbaginaceae, Lamiaceae, Arecaceae, Scrophulariaceae, Verbenaceae, Celastraceae, Avicenniaceae, Caesalpiniaceae, Rubiaceae, and Proteaceae. A wide range of pharmacological activities have been observed for lapachol and its semi-synthetic derivatives in the literature, such as antileishmanial, anticarcinomic, anti-inflammatory, antimalarial, antiseptic, antitumor, antiviral, bactericidal, fungicidal, insectifugal, pesticidal, schistosomicidal, termiticidal, and viricidal effects. The aim of this review is to discuss in detail the phytochemical properties and pharmacological effects of the title compound that have been reported thus far, highlighting its potential therapeutic benefits for the future.     

Novel fluorinated acridone derivatives. Part 1: synthesis and evaluation as potential anticancer agents

We report on the synthesis of a novel series of fluorinated acridones from 5-trifluoromethyl-1,3-cyclohexanedione. The cytotoxic activities of the compounds were studied in several cancer cells. Compounds 9a, 9c, 9e, 9f, and 9h exhibited significant anticancer activities in selected cell lines. Compound 9c is the most active showing GI₅₀ that ranged in values from 0.13 to 26 μM, covering a wide range of cancer cell lines.     

1,2,3-Triazole-nimesulide hybrid: Their design,synthesis and evaluation as potential anticancer agents

A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC₅₀ ～6–10 μM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60–70% at 10 μM) that was supported by the docking studies (PLP score 87–94) in silico.     

Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells

Fourteen new naphthalene-based thiosemicarbazone derivatives were designed as anticancer agents against LNCaP human prostate cancer cells and synthesized. MTT assay indicated that compounds 6, 8 and 11 exhibited inhibitory effect on LNCaP cells. Among these compounds, 4-(naphthalen-1-yl)-1-[1-(4-hydroxyphenyl)ethylidene)thiosemicarbazide (6), which caused more than 50% death on LNCaP cells, was chosen for flow cytometric analysis of apoptosis. Flow cytometric analysis pointed out that compound 6 also showed apoptotic effect on LNCaP cells. Compound 6 can be considered as a promising anticancer agent against LNCaP cells owing to its potent cytotoxic activity and apoptotic effect.