Dinuclear palladium(II) complexes containing two monofunctional [Pd(en)(pyridine)Cl] units bridged by Se or S. Synthesis, characterization, cytotoxicity and kinetic studies of DNA-binding

Two novel dinuclear palladium(II) complexes, {[Pd(en)Cl]₂(bpse)}(NO₃)₂ (1) and {[Pd(en)Cl]₂ (bpsu)}(NO₃)₂ (2), (where en is ethylenediamine; bpse is bis(3-methyl-4-pyridyl) selenide; bpsu is bis(3-methyl-4-pyridyl) sulfide) have been synthesized. The complexes have been characterized by elemental analysis, IR, ¹H NMR, and ¹³C NMR. They have been assayed for antitumor activity in vitro against the mice leukemia L1210 and the human coloadenocarcinoma HCT8 cell lines. The results show that compound 1 has a lower I.D.₅₀ value against the two cancer cell lines as compared to compound 2; the compounds also shows a lower I.D.₅₀ value than cisplatin against the HCT8 cell line, but a higher I.D.₅₀ value than cisplatin against the L1210 cell line. Binding studies indicate that compound 1 possibly interacts with DNA by a nonintercalative mode. Kinetics of binding of the two compounds to DNA are firstly studied using ethidium bromide as a fluorescence probe with stopped-flow spectrophotometer under pseudo-first-order condition. The stronger binding of two steps in the process of the compounds interacting with DNA are observed, and the k_obs and E_a of binding of the two steps (where k_obs is the observed pseudo-first-order rate constant, E_a is the observed energy of activation) are obtained.     

Selective cytotoxicity of withaphysalins in myeloid leukemia cell lines versus peripheral blood mononuclear cells

Withaphysalins are C(28)-steroidal lactones structurally based on the ergostane skeleton that possess antiproliferative activity against tumor cell lines. In the present study, the antileukemic actvity of withaphysalin O (1), M (2), and N (3) isolated from Acnistus arborescens, against two leukemic cell lines, HL-60 and K562, was evaluated, and the cytotoxicity compared with the effects on peripheral blood mononuclear cells (PBMC). All tested compounds reduced the number of viable cells of the tumor cell lines after 24 h of exposure, except for compound 2 against the K562 cell line. The reduction was time-and concentration-dependent, and the IC(50) values ranged from 0.7 to 3.5 microM after 72 h of incubation. In addition to the growth inhibitory properties, the drugs decreased DNA synthesis after 24 h of drug exposure evaluated by the 5-bromo-2 -deoxyuridine incorporation method. None of the tested compounds reduced the number of PBMC (IC(50)>20 microM) after 72 h of incubation, in contrast to doxorubicin that decreased viable cells and increased non-viable cells even after 24 h of incubation. Morphological analysis of treated cells using hematoxylin/eosin staining indicated the presence of necrotic cells for all tested compounds in HL-60, confirmed by the use of acridine orange/ethidium bromide staining. In addition to necrotic cells, K562 cells showed morphological alterations consistent with apoptosis.     

Cytotoxicity and induction of apoptosis by 4-amino-3-acetylquinoline in murine leukemia cell line L1210

Nitrogen heterocyclic compounds are used in the pharmaceutical industry, in medicine and in agriculture for their biological activity. 4-Amino-3-acetylquinoline, a new synthetically prepared quinoline derivative, was the most effective compound in our primary cytotoxic screening. In this study, we evaluated cytotoxic/antiproliferative activity of quinoline using murine leukemia cell line L1210. Its ability to induce apoptosis was studied, too. Quinoline derivative acted cytotoxically on tumor cell line L1210, the IC(100) value were 50 microg/ml (for 24 h), 25 microg/ml (for 48 h) and 10 microg/ml (for 72 h). The IC(50) values was found to be less than 4 microg/ml, a limit put forward by the National Cancer Institute (NCI) for classification of he compound as a potential anticancer drug. The cytotoxic concentrations of 4-amino-3-acetyl quinoline induced morphological changes of L1210 cells and the apoptotic DNA fragmentation.     

DNA interaction and antitumor activity of a Pt(III) derivative of 2-mercaptopyridine

The complex [Pt2(Spy-)4Cl2], where Spy- is deprotonated 2-mercaptopyridine, was prepared and analyzed spectroscopically. A single signal in the 195Pt NMR spectrum indicates the equivalence of the two Pt(III) ions. The interaction of this complex with DNA was studied by circular dichroism and the modifications caused by the complex in plasmid pBR322 DNA were imaged by atomic force microscopy. Preliminary results showed higher activity against HeLa and U937 tumor lines for the Pt-2-mercaptopyridine complex in comparison with cisplatin. The values of LC50 were lower than those obtained for cisplatin. Promising perspectives for this compound are expected due to its similarity with the analogous Pt and 2-mercaptopyrimidine antitumor compound.     

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl₂] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl₂), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound, N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl₂)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl₂ compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl₂ was also more toxic to the ER positive breast cancer line, MCF-7, than to an ER negative line, MDA-MB231.     

cis-Dichloroplatinum(II) complexes tethered to 9-aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.

A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values between the CH-1 and CH-1cisR pair of cell lines for the 9-aminoacridine-4-carboxamide tethered platinum complexes indicates that repair of platinum-induced DNA damage may be a major determinant of the activity of these compounds.     

Antiproliferative activity and QSAR study of copper(II) mixed chelate [Cu(N-N)(acetylacetonato)]NO3 and [Cu(N-N)(glycinato)]NO3 complexes, (Casiopeínas)

Mixed chelate copper(II) complexes patented and mark title registered as Casiopeínas^® are antineoplastic agents with general formulas [Cu(N-N)(α-l-amino acidato)]NO₃ and [Cu(N-N)(O-O)]NO₃, where the N-N donor is an aromatic substituted diimine (1,10-phenanthroline (phen) or 2,2′-bipyridine (bpy)) and the O-O donor is acetylacetonate (acac) or salicylaldehydate (salal). In the present work, the series of complexes [Cu(N-N)(acac)]NO₃ and [Cu(N-N)(gly)]NO₃ with several substituents on the diimine ligand were selected to perform a quantitative structure-activity relationship (QSAR) study. Two main analysis were performed: (1) the study of the influence of the substituents on diimine ligand on physicochemical properties such as half-wave potential (E_1/2) and their relationship with medial lethal dose (LD50) or medial inhibitory concentration (IC50) on several tumor cell lines and (2) the study of the influence of the secondary ligand when acac is changed for glycinate (gly). Results showed that the presence of the central fused aromatic ring in the phen containing complexes is necessary to preserve the antiproliferative activity. The QSAR equations showed a strong relationship between the IC50 and E_1/2; the most active complexes are the weaker oxidants. The change of secondary ligand from acac to gly has less influence on biological activity than the changes on the diimine ligand.     

Synthesis, characterization and antiproliferative studies of the enantiomers of cis-[(1,2-camphordiamine)dichloro]platinum(II) complexes

The platinum(II) complex cis-[(1S,2R,3S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-diamine]dichloroplatinum(II) (1) and its enantiomer (2) have been synthesized and physically and spectroscopically characterized. To obtain the enantiopure complexes the chiral pool approach was applied. The synthetic pathway has four steps, starting from (+/-)-diphenylethylenediamine (DPEDA) (3) and the natural products (1S)-camphorquinone or (1R)-camphorquinone to obtain enantiomers 1 and 2, respectively. The interaction of the Pt(II) complexes with DNA was studied by several techniques: circular dichroism, electrophoresis on agarose gel and atomic force microscopy (AFM). These studies showed differences in the degree of interaction between both enantiomers and DNA (calf thymus DNA and plasmid pBR322 DNA). The cytotoxicity of enantiomers 1 and 2 against the HL-60 cell line was studied by in vitro tests of antiproliferative activity, incubating during both 24 h and 72 h. An important difference of activity was found between both enantiomers regarding the IC50 data at 24 h of incubation. Thus, complex 1 showed to be much more active than its enantiomer 2.     

Pt(II) and Pd(II) derivatives of ter-butylsarcosinedithiocarbamate. Synthesis,chemical and biological characterization and in vitro nephrotoxicity

This work reports on the synthesis, characterization and biological activity of new coordination compounds of the type [M(TSDTM)X(2)] (M=Pt(II), Pd(II); X=Cl, Br; TSDTM=ter-butylsarcosine(S-methyl)dithiocarbamate) and [Pd(TSDT)X](n) (TSDT=ter-butylsarcosinedithiocarbamate) in order to study their behavior as potential antitumor agents. All the synthesized compounds were characterized by means of elemental analysis, FT-IR, (1)H and (13)C-NMR spectroscopy and thermogravimetric analysis, suggesting a chelate S,S' structure of the TSDTM/TSDT ligand in a square-planar geometry. Finally, the synthesized complexes have been tested for in vitro cytotoxic activity against human leukemic HL60 and adenocarcinoma HeLa cells; the most active compound [Pt(TSDTM)Br(2)], characterized by IC(50) values very similar to those of the reference compound (cisplatin), was also tested for in vitro nephrotoxicity showing a very low renal cytotoxicity as compared to cisplatin itself.     

The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1 ,5-a]-pyrimidine: a corticotropin-releasing factor (hCRF1) antagonist

Structure activity relationship studies led to the discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazo lo-[1,5-a]-pyrimidine 11-31 (DMP904), whose pharmacological profile strongly supports the hypothesis that hCRF1 antagonists may be potent anxiolytic drugs. Compound 11-31 (hCRF1 Ki = 1.0+/-0.2 nM (n = 8)) was a potent antagonist of hCRF1-coupled adenylate cyclase activity in HEK293 cells (IC50= 10.0+/-0.01 nM versus 10 nM r/hCRF, n = 8); alpha-helical CRF(9-41) had weaker potency (IC50 = 286+/-63 nM, n = 3). Analogue 11-31 had good oral activity in the rat situational anxiety test; the minimum effective dose for 11-31 was 0.3 mg/kg (po). Maximal efficacy (approximately 57% reduction in latency time in the dark compartment) was observed at this dose. Chlordiazepoxide caused a 72% reduction in latency at 20 mg/kg (po). The literature compound 1 (CP154526-1, 30 mg/kg (po)) was inactive in this test. Compound 11-31 did not inhibit open-field locomotor activity at 10, 30, and 100 mg/kg (po) in rats. In beagle dogs, this compound (5 mg/kg, iv, po) afforded good plasma levels. The key iv pharmacokinetic parameters were t1/2, CL and Vd,ss values equal to 46.4+/-7.6 h. 0.49+/-0.08 L/kg/h and 23.0+/-4.2 L/kg, respectively. After oral dosing, the mean Cmax, Tmax t1/2 and bioavailability values were equal to 1260+/-290 nM, 0.75+/-0.25 h. 45.1+/-10.2 h and 33.1%, respectively. The overall rat behavioral profile of this compound suggests that it may be an anxiolytic drug with a low motor side effect liability.     

Synthesis and anti-tumor activities of N'-benzylidene-2-(4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetohydrazone derivatives

A compound with a cyclic thienopyrimidine moiety and an aceto-hydrazone moiety in its chemical structure was discovered in a cell-based screening to have noticeable cytotoxicity on several tumor cell lines. A total of 38 derivatives of this compound were synthesized at five steps with high yields. These compounds were tested in standard MTT assays, and several compounds exhibited improved cytotoxic activities. The most potent compounds have IC(50) values of 10-20 μM on A549, HeLa, and MBA-MD-231 tumor cells. Flow cytometry analysis of several active compounds and subsequent examination of caspase activation indicate that they induce caspase-dependent apoptosis in tumor cells. In addition, these compounds do not have obvious effect on a normal cell line HEK-293T, demonstrating the desired selectivity against tumor cells. Results from a fluorescence polarization-based in vitro binding assay indicate that this class of compounds does not significantly interrupt the interactions between Mcl-1 and Bid. Their cytotoxicity is achieved presumably through other mechanisms.     

Cytotoxic activities and DNA binding properties of 1-methyl-7H-indeno[1,2-b]quinolinium-7-(4-dimethylamino) benzylidene triflate

The interaction of calf thymus DNA (ct-DNA) with a novel synthesized pyrazolo[1,5-a]indole compound 1-methyl-7H-indeno[1,2-b]quinolinium-7-(4-dimethylamino) benzylidene triflate (MIDBT) was extensively studied by various spectroscopic techniques, viscosity measurements, and gel electrophoresis. The UV-visible observation implied that the compound interacted with ct-DNA by two binding modes, intercalating into the DNA base pairs and attaching to the helix exterior of DNA. The results of the fluorescent quenching and viscosity measurements showed that MIDBT could intercalate into DNA base pairs deeply in a classical intercalative mode. Circular dichroism results showed that the binding of MIDBT shifted ct-DNA conformation from B to A at low concentrations. In the gel electrophoresis, the compound was found to promote the cleavage of plasmid pBR 322 DNA effectively. Furthermore, cytotoxic studies of this compound against eleven selected tumor cell lines have been done. The values of 50% cytotoxic concentration (IC(50)) were in the range of 1.09-18.84?μM, exhibiting the potent cytotoxic properties.     

Synthesis, characterization and cytotoxic activity of substituted benzyl iminoether Pt(II) complexes of the type cis- and trans-[PtCl2{E-N(H)=C(OMe)CH2-C6H4-p-R}2] (R=Me, OMe, F). X-ray structure of trans-[PtCl2{E-N(H)=C(OMe)CH2-C6H4-p-F}2

New substituted benzyl iminoether derivatives of the type cis- and trans-[PtCl(2){E-N(H)C(OMe)CH(2)-C(6)H(4)-p-R}(2)] (R=Me (1a, 2a), OMe (3a, 4a), F (5a, 6a)) have been synthesized and characterized by elemental analyses, FT-IR spectroscopy and NMR techniques. The iminoether ligands are in the E configuration, which is stable in solution and in the solid state, as confirmed by the (1)H NMR data. Complex trans-[PtCl(2){E-N(H)C(OMe)CH(2)-C(6)H(4)-p-F}(2)] (6a) was also characterized by an X-ray diffraction study. Complexes 1a-6a have been tested against a panel of human tumor cell lines in order to evaluate their cytotoxic activity. cis-Isomers were significant more potent than the corresponding trans-isomers against all tumor cell lines tested; moreover, complexes 1a and 5a showed IC(50) values from about 2-fold to 6-fold lower than those exhibited by cisplatin, used as reference platinum anticancer drug.     

Synthesis and characterization of complexes of p-isopropyl benzaldehyde and methyl 2-pyridyl ketone thiosemicarbazones with Zn(II) and Cd(II) metallic centers. Cytotoxic activity and induction of apoptosis in Pam-ras cells.

It is known that metallic complexes of methyl 2-pyridyl ketone thiosemicarbazone (HL1) and p-isopropyl benzaldehyde thiosemicarbazone (HL2) may have potential antitumor activity. We have prepared complexes of HL1 and HL2 with Zn(II) and Cd(II). The cytotoxic activity shown by these compounds against cell lines sensitive and resistant to cis-diamminedichloroplatinum(II) (cis-DDP) indicates that coupling of HL1 and HL2 to Zn(II) and Cd(II) centers may result in metallic complexes with important biological properties since they display IC50 values in a microM range similar to that of the antitumor drug cis-DDP. Moreover, it is interesting to note that the Zn/HL2 complex exhibits specific cytotoxic activity against Pam-ras cells (cis-DDP resistant cells which over-express the H-ras oncogene) with an in vitro therapeutic index of 3.26 versus 0.78 for cis-DDP. Treatment of Pam-ras cells with the IC50 value of the Zn/HL2 compound induces a 'DNA ladder' (fragmentation of genomic DNA in nucleosome units) indicative of apoptosis in this ras-transformed cell line. In contrast, a 'DNA smear' (non-specific fragmentation of genomic DNA) is observed in Pam 212 normal cells treated with the IC50 of this compound. The analysis by circular dichroism (CD) spectroscopy of the interaction of the Zn/HL2 compound with calf thymus DNA (CT DNA) indicates that it produces stronger alterations on the double helix conformation than cis-DDP. So, these results suggest that Zn/HL2 may be considered a potential antitumor agent.     

Study of the interaction of DNA with cisplatin and other Pd(II) and Pt(II) complexes by atomic force microscopy.

Modifications in the structure of a 260 bp DNA (hlyM) fragment from Escherichia coli caused by interaction with Pd(II) and Pt(II) complexes were studied. Cisplatin and transplatin [cis- and trans-PtCl2(NH3)2 respectively], Pt2Cl2(Spym)4 (Spym = 2-mercaptopyrimidine anion), Pd-famotidine and Pt-famotidine were incubated with DNA for 24 h at 37 degrees C and then observed with an atomic force microscope. Atomic force microscopy (AFM) provides the opportunity for nanometer resolution in research on the interaction between nucleic acids and metal complexes. The complexes induced noticeable changes in DNA topography according to their different characteristics and structure. In the case of cisplatin a shortening in DNA strands was observed. Transplatin and Pt2Cl2(Spym)4 caused shortening and compaction, whilst an aggregation of two strands was observed for the Pt-famotidine compound but not for the Pd-famotidine compound or the metal-free famotidine.     

Chemistry of the azine phosphine ligand Z,E-PPh2CH2C(Bu)=N-N=CMe(C6H4NO2-4): crystal structure of [Mo(CO)4{PPh2CH2C(Bu)=N-N=CMe(C6H4NO2-4)}]

Condensation of Z-PPh₂CH₂C(Bu^t)=NNH₂ with 4-nitroacetophenone gave the azine phosphine Z,E-PPh₂CH₂C(Bu^t)=N-N=CMe(C₆H₄NO₂-4) (I). The corresponding phsophine oxide II was prepared by treatment of I with H₂O₂. The phosphine I with [Mo(CO)₄(nbd)] (nbd=norbornadiene) gave [Mo(CO)₄{PPh₂CH₂C(Bu^t)=N-N=CMe(C₆H₄NO₂-4)}] (1a); the corresponding tungsten 1b and chromium 1c complexes were made similarly. The crystal structure of 1a was determined by X-ray diffraction and showed the presence of a six-membered chelate ring with the bulky 4-nitrophenyl group held close to the metal. Oxidation of 1a with bromine gave the seven-coordinate molybdenum (II) complex 2. Treatment of [PtMe₂(cod)] (cod=cycloocta-1,5-diene) with I at 20°C gave the dimethyl-platinum (II) complex [PtMe₂{PPh₂CH₂C(Bu^t)=N-N=CMe(C₆H₄NO₂-4)}] (3a) which with MeI gave the iodotrimethylplatinum(IV) complex 4. Treatment of 3a with C≡O opened the chelate ring to give the dimethyl(carbonyl)platinum(II) complex 5 containing a monodentate phosphine ligand. When 3a was heated in toluene solution at 110°C it gave the cyclometallated methylplatinum(II) complex [PtMe{PPh₂CH₂C(Bu^t)=N-N=CMe(C₆H₃NO₂-4)}] (6). Treatment of 6 with MeI gave the platinum(IV) complex 7. The dichloropalladium(II) complex [PdCl₂{PPh₂CH₂C(Bu^t)=N-N=CMe(C₆H₄NO₂-4)}] (3b) was prepared by treatment of [PdCl₂(NCPh)₂] with I in CH₂Cl₂. Treatment of [PtCl₂(NCMe)₂] with 2 equiv. of I gave the trans-bis(phosphine) complex 8. When 2 equiv. of I were treated with [PtCl₂(cod)] followed by NH₄PF₆ this gave the salt 9a containing two six-membered chelate rings; the analogous palladium(II) 9b) salt was also prepared. Treatment of 2 equiv. of I with [PtCl₂(cod)] followed by NH₄PF₆ gave the PF₆ salt 10 containing a six-membered chelate ring and a monodentate ligand. When 10 was treated with AgNO₃ followed by NH₄PF₆ this gave the bis-chelate complex 11 containing five- and six-membered chelate rings. Treatment of [IrCl(CO)₂(p-toluidine)] with I gave the cyclometallated iridium(III) hydride complex [IrHClCO{PPh₂CH₂C(Bu^t)=N-N=CMe(C₆H₃NO₂-4)}] (12). [RuCl₂(PPh₃)₃] with the phosphine I resulted in the Ru(II) complex 13 in which the ortho hydrogens of the 4-nitrophenyl group are agostically interacting with ruthenium. Proton, Phosphorus-31, some carbon-13 NMR and IR data have been obtained. Crystals of 1a are orthorhombic, space group Pna2₁, with a = 1819.3(2), b = 1050.0(1), c = 1614.8(2) pm and Z = 4; final R = 0.0191 for 2616 observed reflections.     

4-(2-Pyridyl)piperazine-1-benzimidazoles as potent TRPV1 antagonists

A series of 4-(2-pyridyl)piperazine-1-benzimidazole analogues based on compound 1 was synthesized and evaluated for TRPV1 antagonist activity in capsaicin-induced (CAP) and pH5.5-induced (pH) FLIPR assays in a human TRPV1-expressing HEK293 cell line. Potent TRPV1 antagonists were identified through SAR studies. From these studies, several antagonists were found, with IC(50) values ranging from 32 nM to approximately 5000 nM. Among these, 11 [IC(50)=90 nM (CAP) and 104 nM (pH)] was further evaluated and found to be orally available in rats (F%=19.7).     

Cytotoxicity and detection of damage to DNA by 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c] quinazoline on human cancer cell line HeLa

Quinazolines - 1,3-benzodiazines are biological active compounds, which are used in the phamaceutical industry, in agriculture and in the medicine. As documented in the literature, many derivatives demonstrated anticancer activity and they act as multitarget agents. 3-(5-Nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c] quinazoline (NTCHMTQ) - a new synthetically prepared quinazoline derivative was the most effective derivative in our primary cytotoxic screening. In this study, we evaluated cytotoxic/antiproliferative activity of NTCHMTQ using human tumor cell line HeLa. Possible interaction of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c] quinazoline with calf thymus DNA was tested by the DNA - modified screen - printed electrode. Quinazoline derivative acted cytotoxically on tumor cell line HeLa. The IC(100) value was 10 microg/ml. The IC(50) values was found to be less than 4 microg/ml, a limit put forward by the National Cancer Institute (NCI) for classification of he compound as a potential anticancer drug. Quinazoline at micromolar concentrations induced morphological changes and necrosis of HeLa cells. Using the DNA based electrochemical biosensor, we have not found damage to DNA under in vitro conditions at an incubation of the biosensor in mixture with quinazoline.     

Synthesis, biological evaluation and molecular docking studies of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives as inhibitors of HDAC activity

In present study, a series of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives (5a-8d) were designed, synthesized, and evaluated for HDAC inhibition and tumor cell antiproliferation. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyzes. Among the compounds, compound 8c showed the most potent biological activity against HCT116 cancer cell line (IC(50) of 0.42 ± 0.02 μM for HDAC-1 and IC(50)=0.62 ± 0.02 for HCT116). Docking simulation was performed to position compound 8c into the HDAC active site to determine the probable binding model. The results of antiproliferative assay and western-blot demonstrated that compound 8c with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent against HCT116 cancer cell.