Development of potent and effective SARS-CoV-2 main protease inhibitors based on maleimide analogs for the potential treatment of COVID-19.

In the present work, we report a new series of potent SARS-CoV-2 Main Protease (Mpro) inhibitors based on maleimide derivatives. The inhibitory activities were tested in an enzymatic assay using recombinant Mpro (3CL Protease from coronavirus SARS-CoV-2). Within the set of new Mpro inhibitors, 6e demonstrated the highest activity in the enzymatic assay with an IC50 value of 8.52 ± 0.44 µM. The IC50 value for Nirmatrelvir (PF-07321332, used as a reference) was 0.84 ± 0.37 µM. The cytotoxic properties were determined in the MTT assay using MRC-5 and HEK-293 cell lines. In the course of the investigation, we found that the newly obtained maleimide derivatives are not substantially cytotoxic (IC50 values for most compounds were above 200 µM).

Oxidovanadium(V) Schiff Base Complexes Derived from Chiral 3-amino-1,2-propanediol Enantiomers: Synthesis, Spectroscopic Studies, Catalytic and Biological Activity.

Oxidovanadium(V) complexes, [(+)VOL1-5] and [(-)VOL1-5], with chiral tetradentate Schiff bases, which are products of monocondensation of S(‒)-3-amino-1,2-propanediol or R(+)-3-amino-1,2-propanediol with salicylaldehyde derivatives, have been synthesized. Different spectroscopic methods, viz. 1H and 51V NMR, IR, UV-Vis, and circular dichroism, as well as elemental analysis, have been used for their detailed characterization. Furthermore, the epoxidation of styrene, cyclohexene, and two monoterpenes, S(‒)-limonene and (‒)-α-pinene, using two oxidants, aqueous 30% H2O2 or tert-butyl hydroperoxide (TBHP) in decane, has been studied with catalytic amounts of all complexes. Finally, biological cytotoxicity studies have also been performed with these oxidovanadium(V) compounds for comparison with cis-dioxidomolybdenum(VI) Schiff base complexes with the same chiral ligands, as well as to determine the cytoprotection against the oxidative damage caused by 30% H2O2 in the HT-22 hippocampal neuronal cells in the range of their 10-100 µM concentration.

Synthesis, Spectroscopic Characterization, Catalytic and Biological Activity of Oxidovanadium(V) Complexes with Chiral Tetradentate Schiff Bases.

New oxidovanadium(V) complexes, VOL1-VOL10, with chiral tetradentate Schiff bases obtained by monocondensation reaction of salicylaldehyde derivatives with 1S,2S-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. All complexes have been characterized using different spectroscopic methods, viz. IR, UV-Vis, circular dichroism, one- (1H, 51V) and two-dimensional (COSY, NOESY) NMR spectroscopy, and elemental analysis. Furthermore, the catalytic ability of all compounds in the epoxidation of styrene, cyclohexene, and its naturally occurring monoterpene derivatives, i.e., S(-)-limonene and (-)-α-pinene has also been studied, using two different oxidants, i.e., aqueous 30% H2O2 or tert-butyl hydroperoxide (TBHP). In addition, the biological properties of these chiral oxidovanadium(V) compounds, but also cis-dioxidomolybdenum(VI) complexes with the same chiral Schiff bases, were studied. Their cytotoxic and cytoprotective activity studies with the HT-22 hippocampal neuronal cells revealed a concentration-dependent effect in the range of 10-100 µM. Moreover, vanadium(V) complexes, in contrast to cis-dioxidomolybdenum(VI) compounds, demonstrated higher cytotoxicity and lack of cytoprotective ability against H2O2-induced cytotoxicity.

Design, Synthesis, and Antitumor Evaluation of an Opioid Growth Factor Bioconjugate Targeting Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge with high lethality and limited effective drug treatments. Its heightened metastatic potential further complicates the prognosis. Owing to the significant toxicity of current chemotherapeutics, compounds like [Met5]-enkephalin, known as opioid growth factor (OGF), have emerged in oncology clinical trials. OGF, an endogenous peptide interacting with the OGF receptor (OGFr), plays a crucial role in inhibiting cell proliferation across various cancer types. This in vitro study explores the potential anticancer efficacy of a newly synthesized OGF bioconjugate in synergy with the classic chemotherapeutic agent, gemcitabine (OGF-Gem). The study delves into assessing the impact of the OGF-Gem conjugate on cell proliferation inhibition, cell cycle regulation, the induction of cellular senescence, and apoptosis. Furthermore, the antimetastatic potential of the OGF-Gem conjugate was demonstrated through evaluations using blood platelets and AsPC-1 cells with a light aggregometer. In summary, this article demonstrates the cytotoxic impact of the innovative OGF-Gem conjugate on pancreatic cancer cells in both 2D and 3D models. We highlight the potential of both the OGF-Gem conjugate and OGF alone in effectively inhibiting the ex vivo pancreatic tumor cell-induced platelet aggregation (TCIPA) process, a phenomenon not observed with Gem alone. Furthermore, the confirmed hemocompatibility of OGF-Gem with platelets reinforces its promising potential. We anticipate that this conjugation strategy will open avenues for the development of potent anticancer agents.

Opioid Growth Factor and its Derivatives as Potential Non-toxic Multifunctional Anticancer and Analgesic Compounds.

Despite significant research progress on the pathogenesis, molecular biology, diagnosis, treatment, and prevention of cancer, its morbidity and mortality are still high around the world. The emerging resistance of cancer cells to anticancer drugs remains still a significant problem in oncology today. Furthermore, an important challenge is the inability of anticancer drugs to selectively target tumor cells thus sparing healthy cells. One of the new potential options for efficient and safe therapy can be provided by opioid growth factor (OGF), chemically termed Met-enkephalin. It is an endogenous pentapeptide (Tyr-Gly-Gly-Phe-Met) with antitumor, analgesic, and immune-boosting properties. Clinical trials have demonstrated that OGF therapy alone, as well as in combination with standard chemotherapies, is a safe, non-toxic anticancer agent that reduces tumor size. In this paper, we review the structure-activity relationship of OGF and its analogues. We highlight also OGF derivatives with analgesic, immunomodulatory activity and the ability to penetrate the blood-brain barrier and may be used as safe agents enhancing chemotherapy efficacy and improving quality of life in cancer patients. The reviewed papers indicate that Met-enkephalin and its analogues are interesting candidates for the development of novel, non-toxic, and endowed with an analgesic activity anticancer drugs. More preclinical and clinical studies are needed to explore these opportunities.