Total Synthesis and Biological Profiling of Putative (±)-Marinoaziridine B and (±)-N-Methyl Marinoaziridine A.

The total synthesis of two new marine natural products, (±)-marinoaziridine B 7 and (±)-N-methyl marinoaziridine A 8, was accomplished. The (±)-marinoaziridine 7 was prepared in a six-step linear sequence with a 2% overall yield. The key steps in our strategy were the preparation of the chiral epoxide (±)-5 using the Johnson Corey Chaykovsky reaction, followed by the ring-opening reaction and the Staudinger reaction. The N,N-dimethylation of compound (±)-7 gives (±)-N-methyl marinoaziridine A 8. The NMR spectra of synthetized (±)-marinoaziridine B 7 and isolated natural product did not match. The compounds are biologically characterized using relevant in silico, in vitro and in vivo methods. In silico ADMET and bioactivity profiling predicted toxic and neuromodulatory effects. In vitro screening by MTT assay on three cell lines (MCF-7, H-460, HEK293T) showed that both compounds exhibited moderate to strong antiproliferative and cytotoxic effects. Antimicrobial tests on bacterial cultures of Escherichia coli and Staphylococcus aureus demonstrated the dose-dependent inhibition of the growth of both bacteria. In vivo toxicological tests were performed on zebrafish Danio rerio and showed a significant reduction of zebrafish mortality due to N-methylation in (±)-8.

Novel (±)-trans-ß-lactam ureas: Synthesis, in silico and in vitro biological profiling.

A diastereomeric mixture of racemic 3-phthalimido-b-lactam 2a/2b was synthesized by the Staudinger reaction of carboxylic acid activated with 2-chloro-1-methylpyridinium iodide and imine 1. The amino group at the C3 position of the b-lactam ring was used for further structural upgrade. trans-b-lactam ureas 4a-t were prepared by the condensation reaction of the amino group of b-lactam ring with various aromatic and aliphatic isocyanates. Antimicrobial activity of compounds 4a-t was evaluated in vitro and neither antibacterial nor antifungal activity were observed. Several of the newly synthesized trans-b-lactam ureas 4a-c, 4f, 4h, 4n, 4o, 4p, and 4s were evaluated for in vitro antiproliferative activity against liver hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780), breast adenocarcinoma (MCF7) and untransformed human fibroblasts (HFF1). The b-lactam urea 4o showed the most potent antiproliferative activity against the ovarian carcinoma (A2780) cell line. Compounds 4o and 4p exhibited strong cytotoxic effects against human non-tumor cell line HFF1. The b-lactam ureas 4a-t were estimated to be soluble and membrane permeable, moderately lipophilic molecules (logP 4.6) with a predisposition to be CYP3A4 and P-glycoprotein substrates. The tools PASS and SwissTargetPrediction could not predict biological targets for compounds 4a-t with high probability, pointing to the novelty of their structure. Considering low toxicity risk, molecules 4a and 4f can be selected as the most promising candidates for further structure modifications.

Selected herbicides screened for toxicity and analysed as inhibitors of both cholinesterases.

Sets of 346 herbicides in use and 163 no longer in use were collected from open access online sources and compared in silico with cholinesterases inhibitors (ChI) and drugs in terms of physicochemical profile and estimated toxic effects on human health. The screening revealed at least one potential adverse consequence for each herbicide class assigned according to their mode of action on weeds. The classes with most toxic warnings were K1, K3/N, F1 and E. The selection of 11 commercial herbicides for in vitro biological tests on human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes involved in neurotoxicity and detoxification of various xenobiotics, respectively, was based mainly on the structural similarity with inhibitors of cholinesterases. Organophosphate anilofos and oxyacetanilide flufenacet were the most potent inhibitors of AChE (25 µM) and BChE (6.4 µM), respectively. Glyphosate, oxadiazon, tembotrione and terbuthylazine were poor inhibitors with an estimated IC50 above 100 µM, while for glyphosate the IC50 was above 1 mM. Generally, all of the selected herbicides inhibited with a slight preference towards BChE. Cytotoxicity assays showed that anilofos, bensulide, butamifos, piperophos and oxadiazon were cytotoxic for hepatocytes (HepG2) and neuroblastoma cell line (SH-SY5Y). Time-independent cytotoxicity accompanied with induction of reactive oxygen species indicated rapid cell death in few hours. Our results based on in silico and in vitro analyses give insight into the potential toxic outcome of herbicides in use and can be applied in the design of new molecules with a less impact on humans and the environment.

Redox Active Molecules in Cancer Treatments.

Cancer is one of the leading causes of death worldwide, with nearly 10 million deaths in 2020 [...].

Review and Chemoinformatic Analysis of Ferroptosis Modulators with a Focus on Natural Plant Products.

Ferroptosis is a regular cell death pathway that has been proposed as a suitable therapeutic target in cancer and neurodegenerative diseases. Since its definition in 2012, a few hundred ferroptosis modulators have been reported. Based on a literature search, we collected a set of diverse ferroptosis modulators and analyzed them in terms of their structural features and physicochemical and drug-likeness properties. Ferroptosis modulators are mostly natural products or semisynthetic derivatives. In this review, we focused on the abundant subgroup of polyphenolic modulators, primarily phenylpropanoids. Many natural polyphenolic antioxidants have antiferroptotic activities acting through at least one of the following effects: ROS scavenging and/or iron chelation activities, increased GPX4 and NRF2 expression, and LOX inhibition. Some polyphenols are described as ferroptosis inducers acting through the generation of ROS, intracellular accumulation of iron (II), or the inhibition of GPX4. However, some molecules have a dual mode of action depending on the cell type (cancer versus neural cells) and the (micro)environment. The latter enables their successful use (e.g., apigenin, resveratrol, curcumin, and EGCG) in rationally designed, multifunctional nanoparticles that selectively target cancer cells through ferroptosis induction.

Green One-Pot Synthesis of Coumarin-Hydroxybenzohydrazide Hybrids and Their Antioxidant Potency.

Compounds from the plant world that possess antioxidant abilities are of special importance for the food and pharmaceutical industry. Coumarins are a large, widely distributed group of natural compounds, usually found in plants, often with good antioxidant capacity. The coumarin-hydroxybenzohydrazide derivatives were synthesized using a green, one-pot protocol. This procedure includes the use of an environmentally benign mixture (vinegar and ethanol) as a catalyst and solvent, as well as very easy isolation of the desired products. The obtained compounds were structurally characterized by IR and NMR spectroscopy. The purity of all compounds was determined by HPLC and by elemental microanalysis. In addition, these compounds were evaluated for their in vitro antioxidant activity. Mechanisms of antioxidative activity were theoretically investigated by the density functional theory approach and the calculated values of various thermodynamic parameters, such as bond dissociation enthalpy, proton affinity, frontier molecular orbitals, and ionization potential. In silico calculations indicated that hydrogen atom transfer and sequential proton loss-electron transfer reaction mechanisms are probable, in non-polar and polar solvents respectively. Additionally, it was found that the single-electron transfer followed by proton transfer was not an operative mechanism in either solvent. The conducted tests indicate the excellent antioxidant activity, as well as the low potential toxicity, of the investigated compounds, which makes them good candidates for potential use in food chemistry.

Involvement of NRF2 in Breast Cancer and Possible Therapeutical Role of Polyphenols and Melatonin.

Oxidative stress is defined as a disturbance in the prooxidant/antioxidant balance in favor of the former and a loss of control over redox signaling processes, leading to potential biomolecular damage. It is involved in the etiology of many diseases, varying from diabetes to neurodegenerative diseases and cancer. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor and reported as one of the most important oxidative stress regulators. Due to its regulatory role in the expression of numerous cytoprotective genes involved in the antioxidant and anti-inflammatory responses, the modulation of NRF2 seems to be a promising approach in the prevention and treatment of cancer. Breast cancer is the prevalent type of tumor in women and is the leading cause of death among female cancers. Oxidative stress-related mechanisms are known to be involved in breast cancer, and therefore, NRF2 is considered to be beneficial in its prevention. However, its overactivation may lead to a negative clinical impact on breast cancer therapy by causing chemoresistance. Some known "oxidative stress modulators", such as melatonin and polyphenols, are suggested to play an important role in the prevention and treatment of cancer, where the activation of NRF2 is reported as a possible underlying mechanism. In the present review, the potential involvement of oxidative stress and NRF2 in breast cancer will be reviewed, and the role of the NRF2 modulators-namely, polyphenols and melatonin-in the treatment of breast cancer will be discussed.

Antitumor and antiviral activities of 4-substituted 1,2,3-triazolyl-2,3-dibenzyl-L-ascorbic acid derivatives.

Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.

The Antioxidant and Antiproliferative Activities of 1,2,3-Triazolyl-L-Ascorbic Acid Derivatives.

The novel 4-substituted 1,2,3-triazole L-ascorbic acid (L-ASA) conjugates with hydroxyethylene spacer as well as their conformationally restricted 4,5-unsaturated analogues were synthesized as potential antioxidant and antiproliferative agents. An evaluation of the antioxidant activity of novel compounds showed that the majority of the 4,5-unsaturated L-ASA derivatives showed a better antioxidant activity compared to their saturated counterparts. m-Hydroxyphenyl (7j), p-pentylphenyl (7k) and 2-hydroxyethyl (7q) substituted 4,5-unsaturated 1,2,3-triazole L-ASA derivatives exhibited very efficient and rapid (within 5 min) 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging activity (7j, 7k: IC50 = 0.06 mM; 7q: IC50 = 0.07 mM). In vitro scavenging activity data were supported by in silico quantum-chemical modelling. Thermodynamic parameters for hydrogen-atom transfer and electron-transfer radical scavenging pathways of anions deprotonated at C2-OH or C3-OH groups of L-ASA fragments were calculated. The structure activity analysis (SAR) through principal component analysis indicated radical scavenging activity by the participation of OH group with favorable reaction parameters: the C3-OH group of saturated C4-C5(OH) derivatives and the C2-OH group of their unsaturated C4=C5 analogues. The antiproliferative evaluation showed that p-bromophenyl (4e: IC50 = 6.72 µM) and p-pentylphenyl-substituted 1,2,3-triazole L-ASA conjugate (4k: IC50 = 26.91 µM) had a selective cytotoxic effect on breast adenocarcinoma MCF-7 cells. Moreover, compound 4e did not inhibit the growth of foreskin fibroblasts (IC50 > 100 µM). In MCF-7 cells treated with 4e, a significant increase of hydroxylated hypoxia-inducible transcription factor 1 alpha (HIF-1α) expression and decreased expression of nitric oxide synthase 2 (NOS2) were observed, suggesting the involvement of 4e in the HIF-1α signaling pathway for its strong growth-inhibition effect on MCF-7 cells.

Antioxidant Activities of Alkyl Substituted Pyrazine Derivatives of Chalcones-In Vitro and In Silico Study.

Chalcones are polyphenolic secondary metabolites of plants, many of which have antioxidant activity. Herein, a set of 26 synthetic chalcone derivatives with alkyl substituted pyrazine heterocycle A and four types of the monophenolic ring B, were evaluated for the potential radical scavenging and antioxidant cellular capacity influencing the growth of cells exposed to H2O2. Before that, compounds were screened for cytotoxicity on THP-1 and HepG2 cell lines. Most of them were not cytotoxic in an overnight MTS assay. However, three of them, 4a, 4c and 4e showed 1,1-diphenyl-2-picrylhydrazyl (DPPH●) radical scavenging activity, through single electron transfer followed by a proton transfer (SET-PT) mechanism as revealed by density functional theory (DFT) modeling. DFT modeling of radical scavenging mechanisms was done at the SMD//(U)M052X/6-311++G** level. The in vitro effects of 4a, 4c and 4e on the growth of THP-1 cells during four days pre- or post-treatment with H2O2 were examined daily with the trypan blue exclusion assay. Their various cellular effects reflect differences in their radical scavenging capacity and molecular lipophilicity (clogP) and depend upon the cellular redox status. The applied simple in vitro-in silico screening cascade enables fast identification and initial characterization of potent radical scavengers.

Curcumin and its Potential for Systemic Targeting of Inflamm-Aging and Metabolic Reprogramming in Cancer.

Pleiotropic effects of curcumin have been the subject of intensive research. The interest in this molecule for preventive medicine may further increase because of its potential to modulate inflamm-aging. Although direct data related to its effect on inflamm-aging does not exist, there is a strong possibility that its well-known anti-inflammatory properties may be relevant to this phenomenon. Curcumin's binding to various proteins, which was shown to be dependent on cellular oxidative status, is yet another feature for exploration in depth. Finally, the binding of curcumin to various metabolic enzymes is crucial to curcumin's interference with powerful metabolic machinery, and can also be crucial for metabolic reprogramming of cancer cells. This review offers a synthesis and functional links that may better explain older data, some observational, in light of the most recent findings on curcumin. Our focus is on its modes of action that have the potential to alleviate specific morbidities of the 21st century.

Effects of conjugation metabolism on radical scavenging and transport properties of quercetin - In silico study.

Quercetin (Q) is a natural polyphenol with high radical scavenging capacity, but low in vivo bioavailability. It is extensively transformed by host phase II metabolism and microbiota. Herein, effects of major in vitro and in vivo conjugation transformations of Q on its radical scavenging capacity and human serum albumin (HSA) binding were studied by using appropriate computational approaches, DFT (U)B3LYP/6-31 + G(d,p) and molecular docking, respectively. With regard to radical scavenging capacity of Q, conjugation transformations generally reduce its antioxidant capacity including regeneration efficiency through disproportionation of an intermediate radical species since these structural modifications occur mainly at its radical scavenging -OH groups. They were also found to alter dominant radical scavenging mechanism in a specific way dependent upon conjugation type and site. Concerning distribution by HSA, binding to this main plasma transporter protein may not be dominant transport mechanism for Q and its metabolites in vivo. Like Q aglycon, most of its metabolites are bound non-specifically at multiple binding sites of HSA, with relatively weak affinities. Only sulfo-conjugates including plasma abundant isomer Q-3'-O-SO3-, were predicted to bind specifically in warfarin-like manner, but also with relatively low binding affinity.

The Influence of In Vivo Metabolic Modifications on ADMET Properties of Green Tea Catechins-In Silico Analysis.

The health effects of green tea are associated with catechins: (-)-epigallocatechin-3-O-gallate (EGCG), (-)-epigallocatechin, (-)-epicatechin-3-O-gallate, and (-)-epicatechin. An understanding of compound absorption, distribution, metabolism, excretion, and toxicity characteristics is essential for explaining its biological activities. Herein, absorption, distribution, metabolism, excretion, and toxicity properties of in vivo detected metabolites of green tea catechins (GTCs) have been analyzed in silico. The influence of metabolic transformations on absorption, distribution, metabolism, and excretion profiles of GTCs corresponds to the effects of size, charge, and lipophilicity, as already observed for other small molecules. Mutagenic, carcinogenic, or liver toxic effects were predicted only for a few metabolites. Similar to galloylated GTCs EGCG and (--)-epicatechin-3-O-gallate, the sulfo-conjugates were predicted to bind at the warfarin binding site. The low free plasma concentration of these derivatives may be consequential to their serum albumin binding. The activity cliff detected for methylated conjugates of EGCG indicates that GTCs' pro-oxidative activity in bound state comes primarily from free hydroxyl groups of the pyrogallol ring B.

The 10th Joint Meeting on Medicinal Chemistry (JMMC 2017) Held in Dubrovnik, Croatia.

The Croatian Chemical Society was established in 1926 and has developed over the decades into a society that actively supports all chemical activities in Croatia. The Society has eight divisions, the youngest of which, the Division of Medicinal and Pharmaceutical Chemistry, was established in 2012 and immediately became a member of the European Federation of Medicinal Chemistry (EFMC). The mission of the Medicinal and Pharmaceutical Chemistry Division is the promotion and development of scientific, professional, and educational activities within the medicinal chemistry community in Croatia, as well as to build partnerships and collaborations with other primarily EU-based medicinal chemistry societies. In Croatia, medicinal chemistry research is ongoing at several institutes, including the University of Zagreb (Faculty of Science, Faculty of Pharmacy and Biochemistry, and Faculty of Chemical Engineering and Technology), national institutes of science (Ruder Boskovic Institute), and private-sector drug discovery companies (CRO Fidelta Ltd.). In order to effectively exchange knowledge, ideas, and scientific results, Croatian medicinal chemists meet twice annually.

Synthesis, in vitro anticancer and antibacterial activities and in silico studies of new 4-substituted 1,2,3-triazole-coumarin hybrids.

The 4-substituted 1,2,3-triazole core in designed coumarin hybrids (4-35) with diverse physicochemical properties was introduced by eco-friendly copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition under microwave irradiation. Coumarin-1,2,3-triazole-benzofused heterocycle hybrids emerged as the class of compounds exhibiting the highest antiproliferative activity. The strong relationship between lipophilicity and antiproliferative activities was observed indicating that lipophilic 1,2,3-triazole-coumarin hybrids containing phenylethyl (13), 3,5-difluorophenyl (14), 5-iodoindole (30) and benzimidazole (33 and 35) subunits showed the most potent cytostatic effects. The 7-methylcoumarin-1,2,3-triazole-2-methylbenzimidazole hybrid 33 can be highlighted as a lead that exerted the highest cytotoxicity against hepatocellular carcinoma HepG2 cells with IC50 value of 0.9 µM and high selectivity (SI = 50). This compound induced cell death, mainly due to early apoptosis. Strong antiproliferative effect of 33 could be associated with its inhibition of 5-lipoxygenase (5-LO) activity and perturbation of sphingolipid signaling by interfering with intracellular acid ceramidase (ASAH) activity. Outlined considerable effect of lipophilicity on antiproliferative activity was not observed for antibacterial activity. The compounds with p-pentylphenyl (17), 2-chloro-4-fluorobenzenesulfonamide (23) and dithiocarbamate (27) moiety were endowed with high selectivity against Enterococcus species. Moreover, these compounds were found to be superior in inhibiting the growth of clinically isolated vancomycin-resistant Enterococcus faecium, while the reference antibiotics exhibited the lack of activity. Our findings indicate that coumarin-1,2,3-triazole could be used as the scaffold for structural optimization to develop more potent and selective anticancer agents and encourage further development of novel structurally related analogs of 33 as more effective 5-LO inhibitors.

Synthesis and evaluation of antibacterial and antioxidant activity of novel 2-phenyl-quinoline analogs derivatized at position 4 with aromatically substituted 4H-1,2,4-triazoles.

A set of novel quinolone-triazole conjugates (12-31) were synthesized in three steps in good yields starting from 2-phenylquinoline-4-carboxylic acid. All the intermediates, as well as the final 1,2,4-triazolyl quinolines were fully characterized by their detailed spectral analysis utilizing different techniques such as IR, 1H NMR, 13C NMR, and finally mass spectrometry. All the synthesized compounds were evaluated in vitro for their potential antibacterial activity and their preliminary safety profile was assessed through cytotoxicity assay. Additionally, six selected conjugates were evaluated for their antioxidative properties on the basis of density functional theory calculations, using radical scavenging assay (DPPH) and cellular antioxidant assay. The reported results encourage further investigation of selected compounds and are shading light on their potential pharmacological use.

Selected attributes of polyphenols in targeting oxidative stress in cancer.

Various plant polyphenols have been recognized as redox active molecules. This review discusses some aspects of polyphenols' modes of redox action, corresponding structure-activity relationships and their potential to be applied as adjuvants to conventional cytostatic drugs. Polyphenols' antioxidative capacity has been discussed as the basis for targeting oxidative stress and, consequently, for their chemopreventive and anti-inflammatory activities, which may alleviate side-effects on normal cells arising from oxidative stress caused by cytostatics. Some polyphenols may scavenge various free radicals directly, and some of them are found to suppress free radical production through inhibiting NADPH oxidases and xanthine oxidase. Additionally, polyphenols may increase antioxidative defense in normal cells by increasing the activity of NRF2, transcription factor for many protective proteins. The activation of the NRF2-mediated signaling pathways in cancer cells results in chemoresistance. Luteolin, apigenin and chrysin reduce NRF2 expression and increase the chemosensitivity of cancer cells to cytostatic drugs. Their common 5,7-dihydroxy-4H-chromen-4-one moiety, may represent a starting pharmacophore model for designing novel, non-toxic compounds for overcoming chemoresistance. However, prooxidative activity of some polyphenols (quercetin, EGCG) may also provide a basis for their use as chemotherapeutic adjuvants since they may enhance cytotoxic effects of cytostatics selectively on cancer cells. However, considerable caution is needed in applying polyphenols to anticancer therapy, since their effects greatly depend on the applied dose, the cell type, exposure time and environmental conditions.

Synthesis and in vitro antiproliferative evaluation of novel N-alkylated 6-isobutyl- and propyl pyrimidine derivatives.

A series of novel N-alkylated C-6-isobutyl- or -propyl pyrimidine derivatives were synthesized and their antiproliferative effect was evaluated on a panel of tumor cell lines including leukemia cell line K562 and normal diploid human fibroblasts. N-methoxymethylated 5-methylpyrimidin-2,4-dione with di(benzyloxy)isobutyl at C-6 (14b) showed the strongest effect on the cell growth at micromolar concentrations. Mechanisms of action for the lipophilic compound 14b predicted in silico, pointed to its anticancer and antimetastatic potential exerted through inhibition of DNA or RNA polymerases and adhesion molecules. The latter mechanism has been supported in vitro for adherent tumor cell lines.

Antitumor mechanisms of amino Acid hydroxyurea derivatives in the metastatic colon cancer model.

The paper presents a detailed study of the biological effects of two amino acid hydroxyurea derivatives that showed selective antiproliferative effects in vitro on the growth of human tumor cell line SW620. Tested compounds induced cell cycle perturbations and apoptosis. Proteins were identified by proteomics analyses using two-dimensional gel electrophoresis coupled to mass spectrometry, which provided a complete insight into the most probable mechanism of action on the protein level. Molecular targets for tested compounds were analyzed by cheminformatics tools. Zinc-dependent histone deacetylases were identified as potential targets responsible for the observed antiproliferative effect.

PM6 study of free radical scavenging mechanisms of flavonoids: why does O-H bond dissociation enthalpy effectively represent free radical scavenging activity?

It is well known that the bond dissociation enthalpy (BDE) of the O-H group is related to the hydrogen atom transfer (HAT) mechanism of free radical scavenging that is preferred in gas-phase and non-polar solvents. The present work shows that the BDE may also be related to radical scavenging processes taking place in polar solvents, i.e., single electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). This is so because the total energy requirements related to the SET-PT [sum of the ionization potential (IP) and proton dissociation enthalpy (PDE)] and the SPLET [sum of the proton affinity (PA) and electron transfer enthalpy (ETE)] are perfectly correlated with the BDE. This could explain why the published data for polyphenolic antioxidant activity measured by various assays are better correlated with the BDE than with other reaction enthalpies involved in radical scavenging mechanisms, i.e., the IP, PDE, PA and ETE. The BDE is fairly well able to rank flavonoids as antioxidants in any medium, but to conclude which radical scavenging mechanism represents the most probable reaction pathway from the thermodynamic point of view, the IP and PA (ETE) should also be considered. This is exemplified in the case of the radical scavenging activity of 25 flavonoids.