Natural pentacyclic triterpenoid as allosteric modulators of human 5-lipoxygenase with potential anti-inflammatory activity.

This study explored new methods to inhibit human 5-lipoxygenase (5-hLOX) by analyzing natural terpenes that share structural similarities with acetoxyboswellic acid (AKBA). Enzymatic assays were used to evaluate the terpene's ability to inhibit the enzyme, potentially providing anti-inflammatory benefits. Our research focused on how certain types of triterpenes can inhibit 5-hLOX allosterically via a newly discovered allosteric site identified by enzyme crystallization. To determine whether natural boswellic acid analogs mimicked the allosteric known inhibitor AKBA, we combined 5-hLOX inhibition with in silico modeling. Our research has discovered that certain amino acids, specifically Arg 138, Arg 101, Arg 68, and Gln129, located in the allosteric 5-hLOX pocket, play a critical role in stabilizing glycyrrhetinic isomers. These amino acids form hydrogen bonds and hydrophobic interactions that contribute to the inhibitory potency of boswellic acid derivatives. We have found that α and ß glycyrrhetinic acid isomers, carbenoxolone, and to a minor extent, prednisolone, have a potent inhibitory effect against 5-hLOX with IC50 values of 8.64, 3.94, 52.98, and 291.20 µM, respectively. These values are in line with our calculated in silico allosteric site binding energy estimations. In contrast, other steroidal or non-steroidal anti-inflammatory agents exhibited inhibitory potencies larger than 500 µM. However, the specific pharmacodynamic mechanisms are currently unknown. We propose that AKBA analogs may lead to the future development of novel anti-inflammatory agents.Communicated by Ramaswamy H. Sarma.

Evaluating the inhibitory activity of ferrocenyl Schiff bases derivatives on 5-lipoxygenase: Computational and biological studies.

In the search for new 5-LOX inhibitors, two ferrocenyl Schiff base complexes functionalized with catechol ((ƞ5-(E)-C5H4-NCH-3,4-benzodiol)Fe(ƞ5-C5H5) (3a)) and vanillin ((ƞ5-(E)-C5H4-NCH-3-methoxy-4-phenol)Fe(ƞ5-C5H5) (3b)) were obtained. Complexes 3a and 3b were biologically evaluated as 5-LOX inhibitors showed potent inhibition compared to their organic analogs (2a and 2b) and known commercial inhibitors, with IC50 = 0.17 ± 0.05 µM for (3a) and 0.73 ± 0.06 µM for (3b) demonstrated a highly inhibitory and potent effect against 5-LOX due to the incorporation of the ferrocenyl fragment. Molecular dynamic studies showed a preferential orientation of the ferrocenyl fragment toward the non-heme iron of 5-LOX, which, together with electrochemical and in-vitro studies, allowed us to propose a competitive redox deactivation mechanism mediated by water, where Fe(III)-enzyme can be reduced by the ferrocenyl fragment. An Epa/IC50 relationship was observed, and the stability of the Schiff bases was evaluated by SWV in the biological medium, observing that the hydrolysis does not affect the high potency of the complexes, making them interesting alternatives for pharmacological applications.

Influence of the substituent on the phosphine ligand in novel rhenium(i) aldehydes. Synthesis, computational studies and first insights into the antiproliferative activity.

Cyrhetrenyl aldehyde derivatives [(η5-C5H4CHO)Re(CO)2PR3] with R = methyl (Me, 2a), phenyl (Ph, 2b), and cyclohexyl (Cy, 2c) were synthesized by a photochemical reaction from the starting material [(η5-C5H4CHO)Re(CO)3] (1) and the corresponding phosphines. The complexes were fully characterized by FT-IR, 1H, 13C and 31P NMR spectroscopy, elemental analysis and mass spectrometry. The molecular structures of 2a-c have also been determined. Electronic structure calculations by TD-DFT and electrochemical studies are in sound agreement with the effect of the substitution of one carbonyl group by a phosphine ligand. Additionally, the antiproliferative activity of complexes 1 and 2a-c was studied on the human cancer cell lines HT-29 and PT-45 using an MTT assay. Out of all new compounds, only the triphenylphosphine derivative 2b exhibited pronounced cytotoxic effects on both cell lines, being ca. 1.5 times more potent than cisplatin.

New organometallic imines of rhenium(i) as potential ligands of GSK-3ß: synthesis, characterization and biological studies.

Substituted amino-piperazine derivatives were synthesized and used as precursors for the preparation of a series of new organometallic Re(i) imine complexes with the general formula [(η5-C5H4CH[double bond, length as m-dash]N-(CH2)5-Pz-R)Re(CO)3] (Pz-R: -alkyl or aryl piperazine). The piperazine-based ligands were designed to be potential inhibitors of GSK-3ß kinase. All the ligands and complexes were fully characterized and evaluated against the HT-29 and PT-45 cancer cell lines, in which GSK-3ß plays a crucial role. In this context, we carried out biological evaluation using the MTT colorimetric assay. In terms of structure activity relationship, our findings indicated improved biological activity when aromaticity increased in the organic ligands (3d). In addition, the presence of the rhenium fragment in the imines (5a-d) leads to better activity with IC50 values in the range of 25-100 µM. In addition, our experimental studies were complemented by computational studies, where the volume and electrostatic surface of the organic ligands and organometallic compounds as well as their binding to the kinase protein are calculated.