Synthesis and biological evaluation of new pyrrolopyrazinone compounds as potential antitumor agents

A series of pyrrolo[1,2-a]pyrazinone compounds(5a-9f) were synthesized,and their cytotoxic activity against SKOV-3,A549.HeLa cells in vitro were evaluated by the MTT method.Some of the compounds showed potential antitumor activity against three tumor cell lines.Among them,compounds 9c and 9d showed the most potent cytotoxic activity.The preliminary mechanism of action was discussed.     

The thermal degradation characteristics of selected organoplatinum antitumor agents

The thermal decomposition characteristics of representatives of three classes of organoplatinum compounds have been examined by thermogravimetry. Substituted salicylato(1,2-diaminocyclohexane)platinum(II) compounds undergo thermal decomposition by sequential loss of first the salicylato ligand and then the amine ligand to afford a residue corresponding to the platinum content of the compound. The thermal decomposition of N-arylsalicylaldimino(1,2-diaminocyclohexane)platinum(II) nitrate is more complex, but is also characterized by two major weight losses. Thermal decomposition ofbis-(2-thiophenecarboxylato)platinum(II) is characterized by ligand fragmentation to generate a residual mass corresponding to the platinum content of the compound.     

Synthesis and characterization of rhenium complexes of 1,2,3-trihydroxybenzene as potential antitumor agents

Oxorhenium(V) complexes composed of β-emitting ¹⁸⁶Re and ¹⁸⁸Re isotopes are of current interest in radiopharmaceutical medicine. Rhenium complexes of 1,2,3-trihydroxybenzene were prepared by reactions of a Re(V) precursor (tetrabutylammonium tetrachlorooxorhenate) with twofold molar excess of the ligand in acetonitrile. The structural formulae of the complexes and their consequent reaction products, as well as those of the final reaction products bis(1,2,3-trihydroxybenzene)-dioxorhenium(VII) and 1,2,3-trihydroxybenzene-chloro-dioxorhenium(VII), synthesized in two different reactions differing in the amount of triethylamine added to the reaction mixture, were estimated by means of physicochemical and spectroscopic methods. ESI-MS spectra in negative mode were also obtained. The reactions during the course of complex formation and consequent decomposition were primarily followed by ESI-MS, and time-dependent ESI-MS signals were recorded and compared to those obtained by UV/Vis absorption spectroscopy.     

Redox-active cobalt complexes as promising antitumor agents

Cobalt(iii) complexes with tetradentate aliphatic Schiff"s bases containing also compounds of the vitamin PP series or their analogs as axial ligands were synthesized as potential antitumor agents. The behavior of these redox-active complexes in chemical processes that presumably govern their biological action was studied. These processes include aquation and subsequent decomposition, electrode and homogeneous redox reactions, and catalytic activity in autooxidation of biosubstrates, especially at the stages of generation and consumption of reactive oxygen species (ROS). The antitumor action of these complexes in vivo was studied. Changes in the organisms of laboratory animals characteristic of processes involving ROS were followed at the cellular and molecular levels. The tumor-selective action of the complexes is due to specific features of microenvironment of tumor cells. Some of them exhibit a strong antimetastatic effect, which exceeds that for a number of drugs used in clinical practice. A complex with nicotinamide was recommended for preclinical studies. The scope of application of the redox-active transition metal complexes in oncology is discussed.     

Thermal degradation behavior of some ruthenium complexes with fluoroquinolone derivatives as potential antitumor agents

Three new complexes with ligands belong to the fluoroquinolone class having the general formula [RuL₂Cl₂]Cl nH₂O ((1) L: norfloxacin (nf), n = 4; (2) L: ciprofloxacin (cp), n = 3; (3) L: enrofloxacin (enro), n = 5) were synthesized and characterized by chemical analysis UV–Vis and IR spectroscopy. In all complexes fluoroquinolone derivative acts as bidentate chelate ligand. The thermal behavior steps were investigated in synthetic air flow. The thermal transformations are complex processes according to TG and DTG curves including dehydration, quinolone derivative degradation, as well as RuCl₃ conversion in RuO₂.     

Novel heparan sulfate mimetic compounds as antitumor agents

Heparan sulfate glycosaminoglycans (HSGAGs) are involved in tumor cell growth, adhesion, invasion, and migration, due to their interactions with various proteins. In this study, novel HSGAG-mimetic compounds (KI compounds) were designed and synthesized. As a result of cell-based assays, KI-105 was found to exert potent inhibitory activities against migration and invasion of human fibrosarcoma HT1080 cells. The present results indicate that a novel invasion/migration inhibitor, KI-105, can increase the adherence of HT1080 cells. It was conceivable that this cellular effect was caused by an increase in the amount of cell-surface HSGAGs and focal adhesions. Although further investigations are needed to decipher the molecular mechanism of KI-105, it is suggested that heparanase and Cdc42 are involved in its biological effects.     

Rhodium-105 complexes as potential radiotherapeutic agents

Rhodium-105 complexes have been investigated for their suitability as the basis of potential bifunctional chelating agents for therapeutic radiopharmaceuticals. Rhodium-105 is a reactor-produced therapeutic radionuclide that is available in high specific activity. The chemistry and biology of several six-coordinate Rh(III) complexes of the general form [RhCl2L]+, where L is a tetradentate ligand containing at least three thioethers donor atoms, is discussed. The backbone chain length of the acyclic or macrocyclic ligand determines the geometry about the Rh(III) centre (cis vs. trans), with the larger ligands preferentially forming trans-dichloro complexes. The stability of all of the 105Rh complexes is very high (>5 days) and the biological clearance properties of the complexes are consistent with their relative lipophilicities.     

Triphenyltin chloride complexes containing bidentate organodiimines as effective antitumor agents

Three triphenyltin chloride complexes, [(Ph₃SnCl)₂?·?(bpy)_1.5] (1), [(Ph₃SnCl)₂.tbpe] (2), and [(Ph₃SnCl)₂?·?bpe] (3), were synthesized by reaction of triphenyltin chloride with 4,4′-bipyridine (bpy), trans-1,2-bis(4-pyridyl)ethylene (tbpe), and 1,2-bis(4-pyridyl)ethane (bpe) in water/acetonitrile. Both 2 and 3 are binuclear; each consists of two Ph₃SnCl molecules bridged by the bidentate ligand. Complex 1 consists of two crystallographically independent and chemically different coordination complexes, mononuclear and binuclear in equal proportion. The structures of these complexes were investigated by single-crystal X-ray analysis, elemental analyses, NMR spectroscopy as well as electronic absorption and emission spectroscopy. The three complexes exhibit in vitro antitumor activity against human breast cancer cell line, MCF7.     

Synthesis of fused 1,2,4-triazines as potential antimicrobial and antitumor agents

5-Benzylidene-3-(p-chlorophenyl)-2-aminothiocarbonyl-1,2,4-triazine (2) was prepared via condensation of oxazolinone (1) with thiosemicarbazide. Fused 1,2,4-triazine derivatives (3, 4 and 9) were synthesized from the reaction of compound 2 with ω-bromomethyl aryl ketones, ethyl chloroacetate, and acetic anhydride. Treatment of 4 with acetic anhydride and aromatic aldehydes yielded the corresponding acetyl, diacetyl derivatives (6 and 7) and 7-benzylidene-5-(p-chlorophenyl)-4-thioxo-3-arylidene-1,2,4-triazino [2,1-a]-1,2,4-triazine-1,8-diones (8). The electron impact mass spectra of both the above series of compounds have also been recorded and their fragmentation pattern is discussed. All synthesized fused 1,2,4-triazine derivatives were primary in vitro screened for their antimicrobial and antitumor activity.

     

Sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic compounds

The utility of a series of sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic substrates is described. Sulfated α-, β- and γ-cyclodextrin with degrees of substitution of 12, 13 and 14, respectively, a sulfated β-cyclodextrin with a degree of substitution of 9 and a sulfobutyl ether β-cyclodextrin with a degree of substitution of 6.3 are examined. Results with 33 water-soluble cationic organic salts are reported. Chiral differentiation with the sulfated cyclodextrins is compared to prior results obtained with anionic carboxymethylated and phosphated cyclodextrins. The highly sulfated cyclodextrins are often more effective at causing enantiomeric differentiation in ¹H NMR spectra than the sulfobutyl ether, carboxymethylated and phosphated cyclodextrins, and are recommended as the first choice of a chiral solvating agent for the analysis of chiral cationic organic salts in aqueous solution.     

Synthesis,characterization and DNA-binding properties of Ru(II) complexes coordinated by ofloxacin as potential antitumor agents

Three Ru complexes coordinated by oxfloxacin, [Ru(L)₂(OFX)]Cl·2H₂O (L = bpy, 1; dmbpy, 2; phen, 3; and OFX = ofloxacin), were synthesized and characterized. These complexes can inhibit the growth of cervical cancer HeLa cells efficiently. Furthermore, these three complexes exhibited excellent binding affinities with DNA, as confirmed by spectroscopy methods and viscosity experiments. Therefore, the synthesized Ru(II) complexes have excellent DNA-binding abilities with potential applications in cancer chemotherapy.     

Synthesis and biological evaluation of novel acenaphthene derivatives as potential antitumor agents

Twelve novel acenaphthene derivatives have been synthesized. The structures of all compounds were confirmed by 1H-NMR, MS and elemental analysis. Their antitumor activities were evaluated in six human solid tumor cell lines, namely non-small cell lung cancer (H460), human colon adenocarcinoma (SW480), human breast cancer cell (MDA-MB-468 and SKRB-3), human melanoma cell (A375) and human pancreatic cancer (BxPC-3). Among them, compound 3c shows the best antitumor activity against SKRB-3 cell line, as high as the positive control adriamycin.     

Preparation of fused 1,3-oxazine-2,4-diones as potential antitumor agents

A series of indole, thiophene and pyrrole-fused 1,3-oxazine-2,4-diones, 2-methyl-1,3-oxazin-4-ones and 2-dimethylamino-1,3-oxazin-4-ones were synthesized and evaluated as antitumor agents.     

Benzimidazo[1,2-c]quinazoline dimers as potential antitumor agents

The 6-substituted benzimidazo[1,2-c]quinazoline 1 is a lead structure from our DNA intercalator program and is cytotoxic to the human colon cancer tumor line HT-29 with an inhibitory concentration 50, IC₅₀ of 4.00 μM. In order to try and improve the limited cytotoxicity of this class of compound we prepared a series consisting of two benzimidazo[1,2-c]quinazoline moieties linked by a polyalkylamino bridge, of different length and substitution. The compound with the -NH-(CH₂)₃-N(CH₃)-(CH₂)₃-NH-bridge had an inhibitory concentration 50, IC₅₀ of 0.5 μM. When tested in vivo, however, no clear anti-tumor activity was produced in the human breast cancer tumor line MX-1 or the human melanoma tumor line LOX, human tumor xenografts models.     

Carbohydrate-appended 2,2'-dipicolylamine metal complexes as potential imaging agents

Three discrete carbohydrate-appended 2,2'-dipicolylamine ligands were complexed to the {M(CO)(3)}(+) (M = (99m)Tc/Re) core: 2-(bis(2-pyridinylmethyl)amino)ethyl-beta-d-glucopyranoside (L(1)()), 2-(bis(2-pyridinylmethyl)amino)ethyl-beta-D-xylopyranoside (L(2)()), and 2-(bis(2-pyridinylmethyl)amino)ethyl-alpha-d-mannopyranoside (L(3)). An ethylene spacer is used to separate the carbohydrate moiety and the dipicolylamine (DPA) function in all three ligands. The Re complexes [Re(L(1-3))(CO)(3)]Br were characterized by (1)H and (13)C 1D/2D NMR spectroscopies, which confirmed the pendant nature of the carbohydrate moieties in solution. NMR measurements also established the long-range asymmetric effect of the carbohydrate functions on the chelating portion of the ligand. One analogue, [Re(L(1))(CO)(3)]Cl, was characterized in the solid state by X-ray crystallography. Further characterization was provided by IR spectroscopy, elemental analysis, conductivity, and mass spectrometry. Radiolabeling of L(1)-L(3) with [(99m)Tc(H(2)O)(3)(CO)(3)](+) afforded high yield compounds of identical character to the Re analogues. The radiolabeled compounds were found to be stable toward ligand exchange in the presence of a large excess of either cysteine or histidine over a 24-h period.     

Synthesis and biological evaluation of some novel thiadiazole-benzofuran hybrids as potential antitumor agents

Two series of novel 1,3,4-thiadiazole-benzofuran and 1,3,4-thiadiazole-furochromene derivatives were synthesized through heterocyclization of alkyl 2-(1-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)ethylidene)hydrazine-1-carbodithioate 3a–f and 2-(1-(5-methoxy-8-methyl-2,6-dioxo-2,6-dihydropyrano[3,2-g]chromen-3-yl)ethylidene)hydrazinecarbothioamide 9a,b with various hydrazonoyl halides, respectively. The structure of the newly synthesized products was elucidated through elemental analysis, spectral data and alternative routes whenever possible. Ten new compounds were evaluated for their anticancer activity against the human breast carcinoma (MCF-7) cell lines in comparison with reference doxorubicin using MTT assay. The results showed that some new compounds have promising anticancer activity.     

A Theoretical design of new inorganic ring systems as potential antitumor agents

Quantum calculations of electronic structures and ring stabilities along the (NCMe)_3?x(NPMe₂)_x and (NCNMe₂)_3?x(NPMe₂)_x predict that the aziridinyl mixed terms (x = 1 and 2) of these two families may be anticancer agents even more efficient than (NCAz)₃(TEM) and (NPAz₂)₃(MYKO 63).     

Synthesis of 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives as potential antitumor agents

Iron deprivation has been previously proven to be a promising strategy in treating tumor cells. A series of cis,cis-1,3,5-triaminocyclohexane N-pyridyl derivatives as iron-depleting antitumor agents were prepared. Cytotoxic activity of these derivatives was evaluated in the HeLa cancer cell line. Among the tested derivatives, N-ethyl-N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (17) exhibited potent cytotoxicity against this cancer cell line. On the basis of the structure of 17, a bifunctional iron chelator 24 was designed and prepared. Bifunctional agent 24 possessing a maleimide linker that is functional for conjugation to thiolated monoclonal antibodies is a promising lead compound for development of antitumor conjugates for antibody-targeted therapies.     

Tridentate bipyrazole compounds with a side-arm as a new class of antitumor agents

Eight tridentate bipyrazole derivatives with different side arms have been prepared in one step and with good yields. The products were screened for their cytotoxic activity against three tumor cell lines—human breast cancer cell line MDA-MB231, human prostate cancer cell line PC3, and human colorectal cell line LoVo, by use of colorimetric MTT assay. Structure–activity relationships reflected the effect of substituted drugs. Among this series, two compounds had remarkable in-vitro antiproliferative activity against the LoVo cell line with IC50 values ranging from 2.6 to 2.7 μg ml^?1. All the compounds had suitable drug-like characteristics according to Lipinski’s rule.     

Synthesis, characterization and antitumor activity study of some cyclometalated organoplatinum(II) complexes containing aromatic N-donor ligands

A general approach has been designed to synthesize some mononuclear and binuclear cyclometalated platinum(II) complexes, containing aromatic N-donor ligands with the presence of one Cl⁻trans to carbon. In this way, cyclometalated platinum(II) complex [Pt(C^N)Cl(dmso)], 1, C^N = N(1),C(2′)-chelated, deprotonated 2-phenylpyridine and dmso = dimethylsulfoxide, was used as a precursor to react with imidazole derivatives (1-methylimidazole, 2a, imidazole, 2b,), monodentate pyridine derivatives (4-methylpyridine, 2c, pyridine, 2d,) and bidentate pyridine derivative (4,4′-bipyridine, 3 and 4,). Synthesized complexes were fully characterized by using multinuclear NMR spectroscopy (¹H, ¹³C{¹H} and ¹⁹⁵Pt), correlation NMR spectroscopy (¹H-¹H COSY, ¹³C{¹H}-¹H Heteronuclear Multiple Quantum Correlation, HMQC, Heteronuclear Multiple Bond Correlation, HMBC, ¹⁵N-¹H HETCOR), elemental analysis, X-ray crystallography and ESI-Mass spectrometry. Antitumor effects of mononuclear cyclometalated platinum(II) complexes 2a, 2c, 2d and 3 were determined on Jurkat, K562, and Raji cell lines and results showed reasonable cytotoxicities.