George D. Geromichalos

Diorganotin(IV) complexes of dipeptides containing the α-aminoisobutyryl residue (Aib): Preparation, structural characterization, antibacterial and antiproliferative activities of [(n-Bu)2Sn(H−1L)] (LH = H-Aib-L-Leu-OH, H-Aib-L-Ala-OH)

Two new organotin(IV) complexes with dianionic dipeptides containing the alpha-aminoisobutyryl residue (Aib) as ligands are described. The solid complexes [(n-Bu)(2)Sn(H(-1)L(A))] x 2MeOH (1 x 2MeOH) (L(A)H=H-Aib-L-Leu-OH) and [(n-Bu)(2)Sn(H(-1)L(B))] x MeOH (2 x MeOH) (L(B)H=H-Aib-L-Ala-OH) have been isolated and characterized by single-crystal X-ray crystallography and spectroscopic techniques (H(-1)L(2-) is the dianionic form of the corresponding dipeptide). Complexes 1 x 2MeOH and 2 x MeOH are monomeric with similar molecular structures. The doubly deprotonated dipeptide behaves as a N(amino), N(peptide), O(carboxylate) ligand and binds to the Sn(IV) atom. The five-coordinate metal ion has a distorted trigonal bipyramidal geometry. A different network of intermolecular hydrogen bonds in each compound results in very dissimilar supramolecular features. The IR, far-IR, Raman and (119)Sn NMR data are discussed in terms of the nature of bonding and known structures. The antibacterial and antiproliferative activities as well as the effect of the new compounds on pDNA were examined. Complexes 1 and 2 are active against the gram-positive bacteria Bacillus subtilis and Bacillus cereus. The IC(50) values reveal that the two compounds express promising cytotoxic activity in vitro against a series of cell lines.

Effects of melatonin on proliferation of cancer cell lines

Papazisis KT, Kouretas D, Geromichalos GD, Sivridis E, Tsekreli OK, Dimitriadis KA, Kortsaris A.H. Effects of melatonin on proliferation of cancer cell lines. J. Pineal Res. 1998; 25:211–218.

Anticarcinogenic activity of polyphenolic extracts from grape stems against breast, colon, renal and thyroid cancer cells.

A major part of the wineries wastes is composed of grape stems which are discarded mainly in open fields and cause environmental problems due mainly to their high polyphenolic content. The grape stem extracts use as a source of high added value polyphenols presents great interest because this combines a profitable venture with environmental protection close to wine-producing zones. In the present study, at first, the Total Polyphenolic Content (TPC) and the polyphenolic composition of grape stem extracts from four different Greek Vitis vinifera varieties were determined by HPLC methods. Afterwards, the grape stem extracts were examined for their ability to inhibit growth of colon (HT29), breast (MCF-7 and MDA-MB-23), renal (786-0 and Caki-1) and thyroid (K1) cancer cells. The cancer cells were exposed to the extracts for 72 h and the effects on cell growth were evaluated using the SRB assay. The results indicated that all extracts inhibited cell proliferation, with IC₅₀ values of 121-230 μg/ml (MCF-7), 121-184 μg/ml (MDA-MD-23), 175-309 μg/ml (HT29), 159-314 μg/ml (K1), 180-225 μg/ml (786-0) and 134->400 μg/ml (Caki-1). This is the first study presenting the inhibitory activity of grape stem extracts against growth of colon, breast, renal and thyroid cancer cells.

Cobalt(II) complexes with the quinolone antimicrobial drug oxolinic acid: structure and biological perspectives

The interaction of cobalt(II) with the quinolone antimicrobial agent oxolinic acid (Hoxo) in the absence or presence of the Lewis bases 2,2′-bipyridine (bipy), 2,2′-bipyridylamine (bipyam), 1,10-phenanthroline (phen), pyridine (py) or 4-benzylpyridine (4bzpy) resulted in the formation of a series of mononuclear complexes which were characterized with physicochemical and spectroscopic techniques. The crystal structure of [Co(oxo)2(bipy)]·3MeOH was determined by X-ray crystallography. The interaction of the complexes with calf-thymus DNA (CT DNA) was investigated by UV spectroscopy, viscosity measurements and cyclic voltammetry in order to evaluate the possible DNA-binding mode and to calculate the corresponding DNA-binding constants. The binding of the complexes to human or bovine serum albumin was monitored by fluorescence emission spectroscopy and relatively high binding constant values were determined. The antimicrobial activity of the complexes was tested against four different microorganisms (Escherichia coli, Xanthomonas campestris, Staphylococcus aureus and Bacillus subtilis) and was found to be similar to that of free Hoxo. Molecular docking simulations on the crystal structure of CT DNA, HSA and BSA were employed in order to study in silico the ability of the resultant complexes to bind biomacromolecules. This is the first report for metal–quinolone complexes combining experimental data and molecular docking simulations of their interaction with DNA and serum albumins.

Effect of cobalt(II) complexes with dipyridylamine and salicylaldehydes on cultured tumor and non-tumor cells: Synthesis, crystal structure investigations and biological activity

The synthesis of eight mixed-ligand cobalt(II) complexes with 2,2-dipyridylamine (dpamH) and substituted salicylaldehydes (X-saloH) was undertaken in an effort to discover new compounds with anticancer activity. The complexes with the general formula [Co(dpamH)(2)(X-salo)]Y, (Y=Br or Cl) were characterized by elemental analyses, FT-IR and UV-visible spectroscopy, magnetic and conductivity measurements. The structures of two of them [Co(dpamH)(2)(5-CH(3)-salo)]Br and [Co(dpamH)(2)(3-OCH(3)-salo)]Cl, as well as of the precursors [Co(dpamH)(3)]Br(2) and [Co(dpamH)(2)Cl(H(2)O)]Cl, were determined by X-ray crystallography revealing octahedral coordination of cobalt(II) and mononuclear complexes. The complexes were thermally stable up to 200 °C in nitrogen atmosphere, studied by simultaneous TG/DTG-DTA technique. The two precursor Co compounds, as well as four of the title compounds, were evaluated for their efficacy as anticancer agents against different cancer and normal human cell lines. The in vitro chemosensitivity of various human cell lines to these Co complexes was evaluated by measuring cell growth inhibition by employing the SRB colorimetric assay. A series of experiments showed a dose-dependent cytotoxic activity of the complexes against all cell lines used. These findings represent a prompting to search for possible interaction of these complexes with other cellular elements of fundamental importance in cell proliferation.

CDK-inhibitor olomoucine inhibits cell death after exposure of cell lines to cytosine-arabinoside.

Signal transduction for apoptosis or programmed cell death, after DNA damage in mammalian cells, is believed to involve activation of cyclin-dependent kinases (CDKs), especially CDK-1 (cdc2) and CDK-2. We used CDK-inhibitor olomoucine, a purine analogue to evaluate the role CDK inhibition on cytosine-arabinoside (Ara-C)-induced cell death. The two drugs showed an antagonistic effect, suggesting that apoptosis after exposure to Ara-C is inhibited by olomoucine. DNA-electrophoresis showed a clear inhibition of the apoptotic pattern when olomoucine was added to Ara-C. We conclude that CDK-inhibitor olomoucine inhibits cell death induced by Ara-C.

A step-ladder manganese(III) metallacrown hosting mefenamic acid and a manganese(II)–mefanamato complex: synthesis, characterization and cytotoxic activity

The interaction of Mn(II) with the non-steroidal anti-inflammatory drug mefenamic acid (Hmef) in the presence or absence of salicylaldoxime (H2sao) leads to the formation of the hexanuclear Mn(III) cluster [Mn6(O)2(mef)2(sao)6(CH3OH)4] 1, characterized as stepladder inverse-9-metallacrown-3 accommodating mefenamato ligands, or the mononuclear Mn(II) complex [Mn(mef)2(CH3OH)4], 2, respectively. Both complexes were characterized by physicochemical and spectroscopic techniques and the structure of complex 1 was characterized by X-ray crystallography. The overall magnetic behavior of compound 1 is antiferromagnetic with a high-spin well-isolated ground state S = 4. The in vitro cytotoxic effects of the complexes were evaluated against three cancer cell lines (HeLa, MCF-7 and A549 cells) as well as their combinatory activity with the well-known chemotherapeutic drugs cisplatin and 5-fluorouracil. Furthermore, in silico predictive tools have been employed to study the properties and acute rat toxicity and cell line cytotoxicity of the most active complex.

In vitro and in silico study of the biological activity of manganese(III) inverse-[9-MC-3]-metallacrowns and manganese(II) complexes with the anti-inflammatory drugs diclofenac or indomethacin

In the present contribution, the biological properties of four manganese complexes with the non-steroidal anti-inflammatory drugs sodium diclofenac (Nadicl) or indomethacin (Hindo) in the presence or absence of salicylaldoxime (Η2sao), i.e. [Μn6(O)2(dicl)2(sao)6(CH3OH)6] 1, [Μn6(O)2(indo)2(sao)6(H2O)4], 2, [Μn(dicl)2(CH3OH)4], 3, and [Μn(indo)2(CH3OH)4], 4 are presented. More specifically, the in vitro cytotoxic effects of the complexes were evaluated against three cancer cell lines (HeLa, MCF-7 and A549 cells) as well as their combinatory activity with the well-known chemotherapeutic drugs irinotecan, cisplatin, paclitaxel and 5-fluorouracil. The biological activity of the complexes was investigated in vitro by studying their affinity to calf-thymus DNA and their binding towards bovine or human serum albumin (HSA). Molecular docking simulations on the crystal structure of HSA and human estrogen receptor alpha (hERa) were employed in order to study in silico the ability of the studied complexes to bind to these proteins.

Amplifying and broadening the cytotoxic profile of quercetin in cancer cell lines through bioconjugation

Quercetin is a flavonoid presenting cytotoxicity against different cancer cell lines. We hypothesized that its core could serve as a scaffold for generating more potent compounds. A quercetin–alanine bioconjugate was synthesized, its cellular internalization was monitored through confocal microscopy and its cytotoxic activity was explored against ten different cell lines. The bioconjugate consistently illustrated enhanced cytotoxic activity with respect to the parent compound. A threefold enhancement in its cytotoxicity was revealed for HeLa, A549, MCF-7 and LNCaP cells. In silico studies suggested that quercetin–alanine possesses enhanced binding affinity to human estrogen receptor alpha corroborating to its activity to MCF-7, overexpressing this receptor. Spectrofluorimetric, calorimetric and in silico studies revealed that quercetin–alanine binds primarily to Sudlow site I of serum albumin mainly through hydrogen bonding. Through this array of experiments we discovered that the specific compound bears a more refined pharmaceutical profile in contrast to quercetin in terms of cytotoxicity, while at the same time preserves its affinity to serum albumin. Natural products could thus offer a potent scaffold to developxa0bioconjugates with amplified therapeutic window.

Manganese coordination compounds of mefenamic acid: In vitro screening and in silico prediction of biological activity

The in vitro and in silico biological properties of two manganese complexes with the non-steroidal anti-inflammatory drug mefenamic acid (Hmef) in the presence or absence of salicylaldoxime (Η2sao), i.e. [Μn6(O)2(mef)2(sao)6(CH3OH)4] 1, and [Μn(mef)2(CH3OH)4] 2, respectively, are presented in the present contribution. More specifically, the in vitro biological activity of the complexes was investigated by studying their affinity to calf-thymus DNA (by diverse spectroscopic and physicochemical techniques) and their binding towards bovine (BSA) or human serum albumin (HSA) (by fluorescence emission spectroscopy). Molecular docking simulations on the crystal structures of HSA and DNA, exploring in silico the ability of the complexes to bind to these macromolecules, were also employed in order to explain the described in vitro activity of the compounds. Furthermore, in silico predictive tools have been employed to study the properties of the most active complex 2 to act as anticancer agent, in continuation of the previously reported cytotoxic activity. It is adopted in silico studies on a multitude of proteins involved in cancer growth, as well as prediction of drug-induced changes of gene expression profile, protein- and mRNA-based prediction results, prediction of sites of metabolism, quantitative prediction of antitarget interaction profiles etc.