In vitro and in silico evaluation of the inhibitory effect of a curcumin-based oxovanadium (IV) complex on alkaline phosphatase activity and bacterial biofilm formation

Abstract: The scientific interest in the development of novel metal-based compounds as inhibitors of bacterial biofilm-related infections and alkaline phosphatase (ALP) deregulating effects is continuous and rising. In the current study, a novel crystallographically defined heteroleptic V(IV)-curcumin-bipyridine (V-Cur) complex with proven bio-activity was studied as a potential inhibitor of ALP activity and bacterial biofilm. The inhibitory effect of V-Cur was evaluated on bovine ALP, with two different substrates: para-nitrophenyl phosphate (pNPP) and adenosine triphosphate (ATP). The obtained results suggested that V-Cur inhibited the ALP activity in a dose-dependent manner (IC50 = 26.91 ± 1.61 μM for ATP, IC50 = 2.42 ± 0.12 μM for pNPP) exhibiting a mixed/competitive type of inhibition with both substrates tested. The evaluation of the potential V-Cur inhibitory effect on bacterial biofilm formation was performed on Gram (+) bacteria Staphylococcus aureus (S. aureus) and Gram (−) Escherichia coli (E. coli) cultures, and it positively correlated with inhibition of bacterial ALP activity. In silico study proved the binding of V-Cur at eukaryotic and bacterial ALP, and its interaction with crucial amino acids of the active sites, verifying complex’s inhibitory potential. The findings suggested a specific anti-biofilm activity of V-Cur, offering a further dimension in the importance of metal complexes, with naturally derived products as biological ligands, as therapeutic agents against bacterial infections and ALP-associated diseases. Key points: • V-Cur inhibits bovine and bacterial alkaline phosphatases and bacterial biofilm formation. • Alkaline phosphatase activity correlates with biofilm formation. • In silico studies prove binding of the complex on alkaline phosphatase. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Synthesis and evaluation of new steroidal lactam conjugates with aniline mustards as potential antileukemic therapeutics

Alkylating agents are still nowadays one of the most important classes of cytotoxic drugs, which display a wide range of therapeutic use for the treatment of various cancers. We have synthesized and tested four hybrid homo-azasteroidal alkylating esters for antileukemic activity against five sensitive to alkylating agents human leukemia cell lines in vitro and against P388 murine leukemia in vivo. Comparatively, melphalan and 3-(4-(bis(2-chloroethyl)amino)phenoxy)propanoic acid (POPAM) were also examined. All the homo-aza-steroidal alkylators showed relatively lower acute toxicity, very promising and antileukemic activity both in vitro and in vivo. © 2016 Elsevier Inc

Unraveling the binding mechanism of an Oxovanadium(IV) – Curcumin complex on albumin, DNA and DNA gyrase by in vitro and in silico studies and evaluation of its hemocompatibility

An oxovanadium(IV) – curcumin based complex, viz. [VO(cur)(2,2´-bipy)(H2O)] where cur is curcumin and bipy is bipyridine, previously synthesized, has been studied for interaction with albumin and DNA. Fluorescence emission spectroscopy was used to evaluate the interaction of the complex with bovine serum albumin (BSA) and the BSA-binding constant (Kb) was calculated to be 2.56 x 105 M-1, whereas a single great-affinity binding site was revealed. Moreover, the hemocompatibility test demonstrated that the complex presented low hemolytic fraction (mostly below 1%), in all concentrations tested (0-250 μΜ of complex, 5% DMSO) assuring a safe application in interaction with blood. The binding of the complex to DNA was also investigated using absorption, fluorescence, and viscometry methods indicating a binding through a minor groove mode. From competitive studies with ethidium bromide the apparent binding constant value to DNA was estimated to be 4.82 x 106 M-1. Stern-Volmer quenching phenomenon gave a ΚSV constant [1.92 (± 0.05) x 104 M-1] and kq constant [8.33 (± 0.2) x 1011 M-1s-1]. Molecular docking simulations on the crystal structure of BSA, calf thymus DNA, and DNA gyrase, as well as pharmacophore analysis for BSA target, were also employed to study in silico the ability of [VO(cur)(2,2´-bipy)(H2O)] to bind to these target bio-macromolecules and explain the observed in vitro activity. © 2021 Elsevier Inc

Synthesis, structural determination, in vitro and in silico biological evaluation of divalent or trivalent cobalt complexes with indomethacin

The interaction of cobalt chloride with the non-steroidal anti-inflammatory drug indomethacin (Hindo) led to the formation of the polymeric complex [Co(indo-O)2(H2O)2(μ-Cl)]n·n(MeOH·H2O) bearing one chlorido bridge between the cobalt atoms. The presence of the nitrogen-donor co-ligands 2,2′-bipyridine (bipy), 2,2′-bipyridylamine (bipyam), 1,10-phenanthroline (phen) or 1H-imidazole (Himi) resulted in the isolation of complexes [Co2(μ-indo-O,O′)2(indo-O)2(bipy)2(μ-H2O)]·3.3MeOH, [Co(indo-O,O′)2(bipyam)]·0.9MeOH·0.2H2O, [Co(indo-O,O′)2(phen)] (4) and [Co(indo-O)2(Himi)2] (5), respectively, where the indomethacin ligands were coordinated in diverse manners. The study of the affinity of the complexes for calf-thymus DNA revealed their intercalation between the DNA-bases. The binding of the complexes to albumins was also examined and the corresponding binding constants and binding subdomain were determined. The free radical scavenging activity of the compounds was evaluated towards 1,1-diphenyl-picrylhydrazyl and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid). Molecular modeling calculations may usually provide a molecular basis for the understanding of both the impairment of DNA by its binding with the studied complexes and the ability of these compounds to transportation through serum albumin proteins. This study can provide information for the elucidation of the mechanism of action of the compounds in a molecular level. © 2020 Elsevier Inc

Zinc(II) complexes of 3,5–dibromo–salicylaldehyde and α–diimines: Synthesis, characterization and in vitro and in silico biological profile

The synthesis of five neutral zinc(II) complexes of 3,5–dibromo–salicyladehyde (3,5–diBr–saloH) in the presence of nitrogen–donor co-ligands 2,2′–bipyridine (bipy), 1,10–phenanthroline (phen), 2,9–dimethyl–1,10–phenanthroline (neoc), or 2,2′–bipyridylamine (bipyam) was undertaken and complexes [Zn(3,5–diBr–salo)2(H2O)2] (1), [Zn(3,5–diBr–salo)2(bipy)] (2), [Zn(3,5–diBr–salo)2(phen)].3,5–diBr–saloΗ (3), [Zn(3,5–diBr–salo)2(neoc)] (4) and [Zn(3,5–diBr–salo)2(bipyam)] (5) were characterized by various techniques. The crystal structures of complexes 3 and 5 were determined by X–ray crystallography, revealing the co–existence of two different coordination modes of 3,5–diBr–salo− ligands. The new complexes show selective in vitro antibacterial activity against two Gram–positive and two Gram–negative bacterial strains. The complexes may scavenge 1,1–diphenyl–picrylhydrazyl and 2,2′–azinobis(3–ethylbenzothiazoline–6–sulfonic acid) radicals and reduce H2O2. The complexes may intercalate in–between the calf–thymus DNA–bases and have exhibited low–to–moderate ability to cleave supercoiled circular pBR322 plasmid DNA. The complexes may bind tightly and reversibly to bovine and human serum albumins. In order to explain the in vitro activity of the compounds, molecular docking studies were adopted on the crystal structure of calf-thymus DNA, human and bovine serum albumin, Escherichia coli and Staphylococcus aureus DNA–gyrase, 5–lipoxygenase, and 5–lipoxygenase activating protein. The employed in silico studies aimed to explore the ability of the compounds to bind to these target biomacromolecules, establishing a possible mechanism of action and were in accordance with the in vitro studies. © 2021 Elsevier Inc

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 develop bioconjugates with amplified therapeutic window. © 2017, Springer-Verlag GmbH Austria, part of Springer Nature

A unique ternary Ce(III)-quercetin-phenanthroline assembly with antioxidant and anti-inflammatory properties.

From PubMed via Jisc Publications RouterHistory: received 2022-06-19, revised 2022-07-15, accepted 2022-07-24Publication status: ppublishQuercetin is one of the most bioactive and common dietary flavonoids, with a significant repertoire of biological and pharmacological properties. The biological activity of quercetin, however, is influenced by its limited solubility and bioavailability. Driven by the need to enhance quercetin bioavailability and bioactivity through metal ion complexation, synthetic efforts led to a unique ternary Ce(III)-quercetin-(1,10-phenanthroline) (1) compound. Physicochemical characterization (elemental analysis, FT-IR, Thermogravimetric analysis (TGA), UV-Visible, NMR, Electron Spray Ionization-Mass Spectrometry (ESI-MS), Fluorescence, X-rays) revealed its solid-state and solution properties, with significant information emanating from the coordination sphere composition of Ce(III). The experimental data justified further entry of 1 in biological studies involving toxicity, (Reactive Oxygen Species, ROS)-suppressing potential, cell metabolism inhibition in Saccharomyces cerevisiae (S. cerevisiae) cultures, and plasmid DNA degradation. DFT calculations revealed its electronic structure profile, with in silico studies showing binding to DNA, DNA gyrase, and glutathione S-transferase, thus providing useful complementary insight into the elucidation of the mechanism of action of 1 at the molecular level and interpretation of its bio-activity. The collective work projects the importance of physicochemically supported bio-activity profile of well-defined Ce(III)-flavonoid compounds, thereby justifying focused pursuit of new hybrid metal-organic materials, effectively enhancing the role of naturally-occurring flavonoids in physiology and disease. [Abstract copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Azasteroid alkylators as dual inhibitors of akt and erk signaling for the treatment of ovarian carcinoma

(1) Background: Previous findings show that lactam steroidal alkylating esters display improved therapeutic efficacy with reduced toxicity. The aim of this study was to evaluate the anticancer activity of two newly synthesized aza-steroid alkylators (ENGA-L06E and ENGA-L08E) against human ovarian carcinoma cells, and consequently, the dual inhibition of RAS/PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways, both of which are closely associated with ovarian cancer; (2) Methods: The in vitro cytostatic and cytotoxic effects of ENGA-L06E and ENGA-L08E were evaluated in a panel of five human ovarian cancer cell lines, as well as in in vivo studies. ENGA-L06E and ENGA-L08E, in addition to another two aniline-mustard alkylators, POPAM and melphalan (L-PAM), were utilized in order to determine the acute toxicity and antitumor efficacy on two human ovarian xenograft models. Also, in silico studies were performed in order to investigate the dual inhibition of ENGA-L06E and ENGA-L08E on RAS/PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways; (3) Results: Both, in vitro and in vivo studies demonstrated that ENGA-L06E and ENGA-L08E were significantly more effective with a lower toxicity profile in comparison to POPAM and L-PAM alkylators. Moreover, in silico studies demonstrated that the two new aza-steroid alkylators could act as efficient inhibitors of the phosphorylation of AKT and ERK1/2 molecules; and (4) Conclusions: Both ENGA-L06E and ENGA-L08E demonstrated high anticancer activity through the inhibition of the PI3K-AKT and KRAS-ERK signaling pathways against human ovarian carcinoma, and thus constituting strong evidence towards further clinical development. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Biocompatible silver(I) complexes with heterocyclic thioamide ligands for selective killing of cancer cells and high antimicrobial activity – A combined in vitro and in silico study

A series of heteroleptic Ag(I) complexes bearing 4,6-dimethyl-2-pyrimidinethiol (dmp2SH), i.e., [AgCl(dmp2SH)(PPh3)2] (1), [Ag(dmp2SH)(PPh3)2]NO3 (2), [Ag(dmp2SΗ)(xantphos)]NO3 (3), [Ag(μ-dmp2S)(PPh3)]2 (4), [Ag(dmp2S)(xantphos)] (5), [Ag(μ-dmp2S)(DPEphos)]2 (6) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and DPEPhos = bis[(2-diphenylphosphino)phenyl]ether) were synthesized. The complexes display systematic variation of particular structural characteristics which were proved to have a significant impact on their in vitro cytotoxicity and antimicrobial properties. A moderate-to-high potential for bacteria growth inhibition was observed for all complexes, with 2, 3 and 5 being particularly effective against Gram-(+) bacteria (IC50 = 1.6–4.5 μM). The three complexes exhibit high in vitro cytotoxicity against HeLa and MCF-7 cancer cells (IC50 = 0.32–3.00 μΜ), suggesting the importance of coordination unsaturation and cationic charge for effective bioactivity. A very low cytotoxicity against HDFa normal cells was observed, revealing a high degree of selectivity (selectivity index ~10) and, hence, biocompatibility. Fluorescence microscopy using 2 showed effective targeting on the membrane of the HeLa cancer cells, subsequently inducing cell death. Binding of the complexes to serum albumin proteins is reasonably strong for potential uptake and subsequent release to target sites. A moderate in vitro antioxidant capacity for free radicals scavenging was observed and a low potential to destroy the double-strand structure of calf-thymus DNA by intercalation, suggesting likely implication of these properties in the bioactivity mechanisms of these complexes. Further insight into possible mechanisms of bioactivity was obtained by molecular modeling calculations, by exploring their ability to act as potential inhibitors of DNA-gyrase, human estrogen receptor alpha, human cyclin-dependent kinase 6, and human papillomavirus E6 oncoprotein. © 202