Synthesis, crystal structures, and biological evaluation of Cu(II) and Zn(II) complexes of 2-benzoylpyridine Schiff bases derived from S-methyl- and S-phenyldithiocarbazates

Two NNS tridentate Schiff base ligands of 2-benzoylpyridine S-methyldithiocarbazate (HL¹) and 2-benzoylpyridine S-phenyldithiocarbazate (HL²) and their transition metal complexes [Cu₂(L¹)₂(CH₃COO)](ClO₄) (1), [Zn₂(L¹)₂(ClO₄)₂] (2), [Zn(L²)₂](3) have been prepared and characterized by elemental analysis, IR, MS, NMR and single-crystal X-ray diffraction studies. In the solid state, each of two Schiff bases remains in its thione tautomeric form with the thione sulfur atom trans to the azomethine nitrogen atom. Under similar prepared conditions, three new complexes showed distinctly different coordination modes depending on their coordinating preferences. Each copper atom in S-bridged dinuclear complex [Cu₂(L¹)₂(CH₃COO)](ClO₄) (1) is surrounded by five donor atoms in a square-pyramidal fashion (4 + 1). [Zn₂(L¹)₂(ClO₄)₂] (2) is a dimer in which each zinc atom adopts a seven-coordinate distorted pentagonal bipyramidal geometry, while mononuclear [Zn(L²)₂] (3) has octahedral coordination geometry. Biological studies, carried out in vitro against selected bacteria, fungi, and K562 leukaemia cell line, respectively, have shown that different substituted groups attached at the dithiocarbazate moieties and metals showed distinctive differences in the biological property. Zinc(II) complexes 2 and 3 could distinguish K562 leukaemia cell line from normal hepatocyte QSG7701 cell line. Effect of the title compounds on Mitochondria membrane potential (MMP) and PI-associated fluorescence intensity in K562 leukaemia cell line are also studied. The title compounds may exert their cytotoxicity activity via induced loss of MMP.     

DNA binding property, nuclease activity and cytotoxicity of Zn(II) complexes of terpyridine derivatives

Two zinc(II) terpyridine complexes Zn(atpy)₂(PF₆)₂ (1) (atpy = 4′-p-N9′-adeninylmethylphenyl-2,2′:6,2′′-terpyridine) and Zn(ttpy)₂(PF₆)₂ (2) (ttpy = 4′-p-tolyl-2,2′:6,2′′-terpyridine) have been synthesized and characterized by elemental analysis, ¹H NMR and electrospray mass spectroscopy. The structure of complex 2 was also determined by X-ray crystallography, which revealed a ZnN₆ coordination in an octahedral geometry with two terpyridine acting as equatorial ligands. The circular dichroism data showed that complex 1 exhibited an ICD signal at around 300 nm and induced more evident disturbances on DNA base stacking than complex 2, reflecting the impact of the adenine moiety on DNA binding modes. Complex 1 exhibited higher cleavage activity to supercoiled pUC 19 DNA than complex 2 under aerobic conditions, suggesting a promotional effect of adenine moiety in DNA nuclease ability. Interestingly, both complexes demonstrated potent in vitro cytotoxicity against a series human tumor cell lines such as human cervix carcinoma cell line (HeLa), human liver carcinoma cell line (HepG2), human galactophore carcinoma cell line (MCF-7) and human prostate carcinoma cell line (pc-3). The cytotoxicity is averagely 10 times more active than the anticancer drug cisplatin. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Microcalorimetric evaluation of the biological activity of polyene complexes with divalent metal ions: Mg(II), Ca(II), Ni(II), Cu(II) and Zn(II)

Polyene complexes with Mg(II), Ca(II), Ni(II), Cu(II) and Zn(II) have been prepared and evaluated for biological activity in a flow microcalorimetric study. The bioactivities are all lower per g of complex than is the bioactivity of the patent polyene, nystatin. However extrapolation of the linear bioassay data suggests that because of enhanced solubilities the metal ion complexes may be able to yield higher overall bioactivity than can nystatin alone.     

Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect

A series of novel angiotensin II type 1 receptor antagonists were prepared. Radioligand binding assay suggested that compounds 1b and 1c could be recognized by the AT(1) receptor with an IC(50) value of 1.6 ± 0.09 nM and 2.64 ± 0.7 nM, respectively. In vivo anti-hypertension experiments showed that compounds (1a, 1b, 1c, 1e) elicited a significant decrease in SBP and DBP of spontaneous hypertensive rats (SHRs). The antihypertensive effects maintained for 10 h, which indicated that these compounds had a favorable blood pressure-lowering effect. Acute toxicity testing suggested that the LD(50) value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD(50)=307.50 mg/kg) but higher than losartan (LD(50)=2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation.     

Synthesis and biological evaluation of Matijing-Su derivatives as potent anti-HBV agents

A series of Matijing-Su (MTS, N-(N-benzoyl-l-phenylalanyl)-O-acetyl-L-phenylalanol) derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity in 2.2.15 cells. The IC(50) of compounds 14a (0.71 μM), 13c (2.85 μM), 13b (4.37 μM), etc. and the selective index of 13g (161.01), 13c (90.45), 13a (85.09) etc. of the inhibition on the replication of HBV DNA were better than those of the positive control lamivudine (IC(50): 82.42 μM, SI: 41.59). Compounds 13o, 13p, and 16a also exhibited significant anti-HBV activity.     

Synthesis and biological evaluation of cinnamyl compounds as potent antitumor agents

A series of cinnamyl compounds related to 2'-hydroxycinnamaldehyde were synthesized and their antitumor effects against human cancer cells evaluated. Hydroxylamine derivative 6 inhibited the growth of human cancer cells and human colon tumor xenograft in nude mice. Its antitumor effects belong to the induction of apoptosis and arresting cell cycle at G(2)/M phase, which is confirmed by detection of apoptosis markers and cell cycle analysis.     

Synthesis, characterization and biological activity of trans-platinum(II) complexes with chloroquine

Three platinum-chloroquine complexes, trans-Pt(CQDP)₂(I)₂ [1], trans-Pt(CQDP)₂(Cl)₂ [2] and trans-Pt(CQ)₂(Cl)₂ [3], were prepared and their most probable structure was established through a combination of spectroscopic analysis and density functional theory (DFT) calculations. Their interaction with DNA was studied and their activity against 6 tumor cell lines was evaluated. Compounds 1 and 2 interact with DNA primarily through electrostatic contacts and hydrogen bonding, with a minor contribution of a covalent interaction, while compound 3 binds to DNA predominantly in a covalent fashion, with weaker secondary electrostatic interactions and possibly hydrogen bonding, this complex also exerted greater cytotoxic activity against the tumor cell lines.     

Thiazole-based chalcones as potent antimicrobial agents. Synthesis and biological evaluation

As part of ongoing studies in developing new antimicrobials, we report the synthesis of a new class of structurally novel derivatives, that incorporate two known bioactive structures a thiazole and chalcone, to yield a class of compounds with interesting antimicrobial properties. Evaluation of antibacterial activity showed that almost all the compounds exhibited greater activity than reference drugs and thus could be promising novel drug candidates.     

Synthesis, spectroscopic and biological aspects of iron(II) complexes

Five novel coordinated complexes of iron(II) with ciprofloxacin and neutral bidentate ligands have been prepared and characterized using elemental analyses, magnetic measurements, IR spectra, UV-VIS spectral, thermogravimetric analyses, 1H-NMR and 13C-NMR. The antimicrobial activity of the individual ligands, metal salt and metal complexes with respect to Bacillus subtilis, Escherichia coli, Bacillus cereus, Staphylococcus aureus, Salmonella typhi, Serratia marcescens, Aspergillus niger, Aspergillus flavus and Lasiodiplodia theobromae were evaluated by the agar-plate technique in comparison to reference standard drugs (ofloxacin, levofloxacin and fluconozole). Binding of the complexes to DNA was studied and is discussed.     

Platinum(II) chloride indenyl complexes: electrochemical and biological evaluation

Four platinum(II) complexes of general formula [PtCl(??¹-C₉H₇)L₂] [where L₂ is 1,2-bis(diphenylphosphino)ethane (dppe) 1 or cycloocta-1,5-diene (cod) 3] and [PtCl₂L₂] (where L₂ is dppe 2 or cod 4) were studied. Inhibition growth assays on human tumor cell lines evidenced for 1 and 3 an antiproliferative effect and, interestingly, the cytotoxic effect exerted by 1 is similar to that of cisplatin. Electrochemical and NMR measurements allowed us to determine the structural and redox properties. Investigation of the mechanism of action responsible for the cytotoxicity demonstrated a weak capacity of interacting with DNA. Some experiments performed on rat liver mitochondria indicate that 1 acts as an inducer of the mitochondrial permeability transition, thus leading to the release of proapoptotic factors, such as cytochrome?c and apoptosis-inducing factor.     

Synthesis,structure and nuclease properties of several ternary copper(II) peptide complexes with 1,10-phenanthroline

Three new ternary peptide-Cu(II)-1,10-phenanthroline (phen) complexes, [Cu(L-ala-gly)(phen)].3.5H(2)O 1, [Cu(L-val-gly)(phen)] 2 and [Cu(gly-L-trp)(phen)].2H(2)O 3, have been prepared and structurally characterised. These compounds exist as distorted square pyramidal complexes with the five co-ordination sites occupied by the tridentate peptide dianion and the two heterocyclic nitrogens of the phenanthroline ligand. The bulk of the lateral chain in the peptide moiety determines the relative disposition of the phen ligand. Thus, in [Cu(L-val-gly)(phen)] 2, the phenanthroline plane is deviated towards the opposite side of the isopropyl group of the L-valine moiety. On the other hand, in [Cu(gly-L-trp)(phen)].2H(2)O 3 the absence of stacking interactions between phen and indole rings and the presence of an intramolecular CH...pi interaction should be pointed out. These complexes exhibit significant differences in their nuclease activity which depends on the nature of the peptidic moiety, the complex [Cu(gly-L-trp) (phen)].2H(2)O 3 being the most active.     

Synthesis and biological evaluation of N-(7-indolyl)-3-pyridinesulfonamide derivatives as potent antitumor agents

We herein report the synthesis and antitumor activity of E7070 analogues containing a 3-pyridinesulfonamide moiety. E7070 was selected from our sulfonamide-based compound collections, currently undergoing Phase II clinical trials because of its tolerable toxicity profile and some antitumor responses in the Phase I setting. Of the analogues examined, ER-35745, a 6-amino-3-pyridinesulfonamide derivative, demonstrated significant oral efficacy against the HCT116 human colon carcinoma xenograft in nude mice.     

Synthesis and biological evaluation of N-phosphoryl dipeptide derivatives as potent apoptosis inducers

A series of N-phosphoryl dipeptide derivatives with trimethoxyaniline moiety were synthesized, in which compound 2a DIPP-Val-Phe-Ar exhibited the best inhibitory activity against K562 cells with the IC(50) at 9.7 microM. Its antitumor effects are due to the induction of apoptosis which was further confirmed by morphological study and flow cytometry analysis.     

Synthesis, characterization and crystal structures of Cd(II) and Zn(II) complexes with 2,2′-biimidazole

The reactions of zinc and cadmium salts with 2,2′-biimidazole (H₂biim) yielded a series of compounds in which the ligand is coordinated in the chelating bidentate mode. ZnCl₂ and [Ag(H₂biim)](NO₃) in methanol in a 2:1 proportion produced Zn(H₂biim)Cl₂, in which the metal has a distorted tetrahedral coordination. A 1:2 ratio led to [Zn(H₂biim)₂(CH₃OH)₂](NO₃)₂, containing an octahedrally coordinated Zn(II) center with the O-bonded methanol ligands occupying trans positions. The corresponding [Cd(H₂biim)₂(CH₃OH)₂](NO₃)₂ compound was obtained from CdCl₂. By starting with Cd(NO₃)₂ and Cd(ClO₄)₂ in aqueous media, the related octahedral bis-chelate compounds [Cd(H₂biim)₂(NO₃)(H₂O)](NO₃) and Cd(H₂biim)₂(ClO₄)₂, respectively, were isolated, the apical positions being filled by perchlorate oxygens in the latter case. With Cd(BF₄)₂, the glass container participated in the reaction and a tris-chelate complex [Cd(H₂biim)₃]₂(SiF₆)(BF₄)₂ · 6EtOH was isolated. The [Cd(H₂biim)₃]²⁺ and ions define an extended hydrogen-bonded network, in which ions surrounded by disordered ethanol molecules occupy large cavities. The two free N-H groups provide H₂biim with a unique ability to form hydrogen bonds and their interactions with counter anions or other acceptors play a determining role in controlling molecular packing. The IR spectra of all compounds are discussed.     

Synthesis and biological evaluation of modified pentapeptides as potent proteinase K inhibitors

This communication reports the first demonstration of synthesis and biological validation of modified pentapeptides, such as methoxysuccinyl-Ala-Ala-Ala-Pro-Leu-chloromethyl ketone 6b as a potent proteinase K inhibitor. The efficacy of MeOSuc-AAAPL-CH₂Cl 6b analog in inhibiting the proteolytic activity of proteinase K was compared with the known MeOSuc-AAPV-CH₂Cl analog. The examination of inhibitory activity using RT-PCR assay in the presence of proteinase K revealed that the MeOSuc-AAAPL-CH₂Cl 6b inhibitor at a concentration of 0.05 mM allows a signal to be obtained for an exogenous target (‘Xeno RNA’) at 30 cycles (i.e., Ct = 30), whereas the control MeOSuc-AAPV-CH₂Cl requires a fivefold higher concentration (0.25 mM) to produce the same Ct. A plausible explanation for the higher efficiency of MeOSuc-AAAPL-CH₂Cl 6b over control is proposed based on the molecular modeling studies.     

Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors

A series of novel benzyl-substituted (S)-phenylalanine derivatives were synthesized and evaluated for their dipeptidyl peptidase 4 (DPP-4) inhibitory activity and selectivity. It was found that most synthesized target compounds were potent DPP-4 inhibitors with IC₅₀ values in 3.79–25.52 nM, which were significantly superior to that of the marketed drug sitagliptin. Furthermore, the 4-fluorobenzyl substituted phenylalanine derivative 6g not only displayed the potent DPP-4 inhibition with an IC₅₀ value of 3.79 nM, but also showed better selectivity against DPP-4 over other related enzymes including DPP-7, DPP-8, and DPP-9. In an oral glucose tolerance test (OGTT) in normal Sprague Dawley rats, compound 6g reduced blood glucose excursion in a dose-dependent manner.     

Synthesis, structure and biological activity of copper(II) complexes with oxolinic acid

The neutral mononuclear copper complexes with the quinolone antibacterial drug oxolinic acid in the presence or not of a nitrogen donor heterocyclic ligand 1,10-phenanthroline, 2,2'-bipyridine or 2,2'-dipyridylamine have been synthesized and characterized with infrared, UV-visible and electron paramagnetic resonance spectroscopies. The experimental data suggest that oxolinic acid acts as a deprotonated bidentate ligand and is coordinated to the metal ion through the pyridone and one carboxylate oxygen atoms. The crystal structure of (chloro)(1,10-phenanthroline)(oxolinato) copper(II), 2, has been determined with X-ray crystallography. For all complexes a distorted square pyramidal environment around Cu(II) is suggested. The EPR (electron paramagnetic resonance) behavior of 2 in aqueous solutions indicates mixture of dimeric and monomeric species. The investigation of the interaction of the complexes with calf-thymus DNA has been performed with diverse spectroscopic techniques and showed that the complexes are bound to calf-thymus DNA. The antimicrobial activity of the complexes has been tested on three different microorganisms. The complexes show a decreased biological activity in comparison to the free oxolinic acid.     

Nicotianamine forms complexes with Zn(II) in vivo

The non-proteinogenic amino acid nicotianamine (NA) is a major player in plant metal homeostasis. It is known to form complexes with different transition metals in vitro. Available evidence associates NA with translocation of Fe, and possibly other micronutrients, to and between different plant cells and tissues. To date, however, it is still extremely challenging to detect metal-ligand complexes in vivo because tissue disruption immediately changes the chemical environment and thereby the availability of binding partners. In order to overcome this limitation we used various Schizosaccharomyces pombe strains expressing a plant NAS gene to study formation of metal-NA complexes in vivo. Tolerance, accumulation and competition data clearly indicated formation of Zn(ii)-NA but not of Cu(ii)-NA complexes. Zn(ii)-NA was then identified by X-ray absorption spectroscopy (XAS). About half of the cellular Zn was found to be bound by NA in NAS-expressing cells while no NA-like ligands were detected by XAS in control cells not expressing NAS. Given the high conservation of eukaryotic metal homeostasis components, these results strongly suggest the possible existence of Zn(ii)-NA complexes also in planta. Reported observations implicating NA in plant Zn homeostasis would then indeed be attributable to direct interaction of Zn(ii) with NA rather than only indirectly to perturbations in Fe metabolism. Re-evaluation of extended X-ray absorption fine structure (EXAFS) spectra for the Zn hyperaccumulator Thlaspi caerulescens showed that NA is as expected not a major storage ligand for Zn. Instead it is hypothesized to be involved in efficient translocation of Zn to above-ground tissues in hyperaccumulators.     

Synthesis, characterization and biological activity evaluation of Pt(II), Pd(II), Co(III) and Ni(II) complexes with N-heteroaromatic selenosemicarbazones

Five new complexes of Pt(II), Pd(II), Co(III) and Ni(II) with 2-pyridine(quinoline)carboxaldehyde selenosemicarbazones were synthesized and characterized. Crystal structures of Pt(II) complex with the pyridine derivative and Co(III) complex with the quinoline derivative were determined. In all complexes the ligands were coordinated through N₂Se donor atom set forming either square-planar (Pt, Pd) or octahedral (Co, Ni) geometry. All complexes showed biological activity.