Isoflavonoids Modified with Oxygen-containing Heterocycles with One Oxygen Atom

Lactoferrin (LF) is an iron-binding secretory protein, which is distributed in the secondary granules of polynuclear lymphocytes as well as in the milk produced by female mammals. Although it has multiple functions, for example antimicrobial, immunomodulatory, antiviral, and anti-tumor metastasis activities, the receptors responsible for these activities are not fully understood. In this study, the binding epitopes for human LF were first isolated from a hexameric random peptide library displayed on T7 phage. Interestingly, two of the four isolated peptides had a representative cell adhesion motif, Arg-Gly-Asp (RGD), implying that human LF interacts with proteins with the RGD motif. We found that human LF bound to the RGD-containing human extracellular matrix proteins, fibronectin and vitronectin. Furthermore, human LF inhibited cell adhesion to these matrix proteins in a concentration-dependent manner but not to the RGD-independent cell adhesion molecule like laminin or collagen. These results indicate that a function of human LF is to block the various interactions between the cell surface and adhesion molecules. This may explain the multifunctionality of LF.

The purpose of this study is to underline the progression and development of research regarding oxygen-containing heterocycles as well as the contribution that some oxygen-containing heterocycles have made as anticancer medicines. A series of publications about the antitumor effects of derivatives of heterocyclic compounds containing an oxygen atom, such as furan, benzofuran, oxazole, benzoxazole, and oxadiazole, were evaluated, and their anticancer activities showed encouraging results when compared to those of established standard treatments.

Triterpenoids are nature-derived compounds, broadly distributed in plant kingdom in a free form as well as in a form of numerous glycosides. The complex structures of triterpenoids chiefly involve squalene derivatives, lanostanes, cycloartanes, dammaranes, euphanes, tirucallanes, tetranortriterpenoids, quassinoids, lupanes, oleananes, friedelanes, ursanes, hopanes, serratanes and another less known groups. These compounds present interesting and perspective subject for experiments, chemical and biological as well. As it is known from literature data, triterpenoids and their saponins with respect to their multitude pharmacological activities could be involved in several areas such as chemistry, medicine and pharmacology, biomedicine and agrochemical sciences. The special structure of triterpenic skeletons allows to perform numerous chemical transformations in order to obtain many new derivatives with pharmacological activity. Taking under consideration the above data, chemistry, biology and pharmacology of triterpenoids and their saponins appear to be riped for revisiting. Therefore, this special issue aims to review the advances in triterpenoids science during the last decade. Carcinomas are probably the second leading cause of death in humans, so scientists intense their research upon the development of new biological sources with antitumor activity. Medicinal plants are now the most promising sources of new potent substances in cytotoxic drug development. As Csuk presented in his work, such compound of anticancer activity is glycyrrhetinic acid, obtained e.g. from liquorice, known as sweetwood (Glycyrrhiza glabra) and some derivatives obtained from this triterpenic acid. Antitumor activity also exhibits, as presented by Paduch and Kandefer-Szerszeń, other triterpenes, such as: asiatic acid, betulinic acid, boswellic acid, lupeol, oleanolic acid or ursolic acid and their analogs and derivatives. These compounds exhibit a cytotoxicity against a variety of tumor cell lines comparable to some clinically used drugs. Most of them also have important antiviral properties, especially anti-HIV activity, which makes them potentially useful additives to current anti-HIV therapy. Another group of triterpenoids with anticancer and antiviral activity is limonoids family, belonging to tetranortriterpenoids. As Pękala and co-workers present, limonoids are a very valuable group of triterpenoids because of a wide spectrum of biological properties, such as cytotoxic, antimalarial, anti-inflammatory, antifeedant, antiviral, neuroprotective, antimicrobial, antibacterial, antifungal and other activities. Limonoids present rich variety of structures: until 2011, about 1300 limonoids with more than 35 carbon frameworks had been isolated from four families (Meliaceae, Rutaceae, Simaroubaceae, and Cneoraceae). The unique structural features of these terpenoids have attracted continuous attention of chemists and pharmacologists. Triterpenoids often occur as ingredients of daily diet or of herbal products used for therapeutic purposes. These phytochemicals occur in nature in free form or as glycosylated compounds, known as saponins, due to their characteristic foaming properties. Pharmacological activities of saponins are very broad and include numerous directions of action which were discussed in many works. Podolak and Janeczko summarize pharmacological properties of natural, non-glycosylated triterpenoids, that were reported over the last five years. The work discusses e.g. antimicrobial, cytotoxic, anti-inflammatory, antinociceptive, antidiabetic, hepatoprotective, wound healing and other activities of triterpenoids, focusing on less known compounds. Plants remain as the most viable source of triterpenoid saponins. As plants are the source of pharmacologically active saponins and free triterpenoids, it is obvious that the development of new methodologies to improve saponin yields is a significant issue. As Yendo et al. state in their work current challenges to improve triterpenoid saponin production including a better understanding of the signal transduction pathways leading to their accumulation, isolation and heterologous expression of biosynthetic genes, as well as structural and modeling studies of biosynthetic enzymes and their catalytic mechanisms. Some triterpenoids and their semi-synthetic derivatives can be identified as potential therapeutics against neurodegenerative diseases. Ruszkowski and Bobkiewicz-Kozlowska discuss the ability of celastrol, oleanolic acid, ursolic acid, asiatic acid, erythrodiol, and some triterpenoid saponins to protect the brain against neurodegeneration and neuroinflammation processes. The authors focus on triterpenoids as possible drugs to treat or slow the progression of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis (MS). Further, pharmacological activities of naturally-derived triterpenenoids and some of their synthetic derivatives are discussed by Jeong and Bae, Jaworska-Paszel et al. and by Luo et al. The anti-inflammatory effect is a common property of many triterpenoids. Jeong and Bae discuss the anti-inflammatory property of several triterpenoids derived from natural sources and from chemical synthesis. These triterpenoids include avicins, boswellic acid, celastrol, diosgenin, escin, ginsenosides, glycyrrhizin, lupeol, oleanolic acid, platycodon D, saikosaponins, ursolic acid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and some of their derivatives. Jaworska-Paszel et al. describe anti-inflammatory, antioxidative, antitumor, antileukemic, hepatoprotective, gastroprotective, cardioprotective and many other important pharmacological activities of oleanolic acid. Luo et al. focus on recent advances in enone and NOreleasing derivatives of oleanolic acid with anti-cancer activity. Other compounds exhibiting numerous pharmacological activities are betulin and betulinic acid, both with pentacyclic lupane-type skeleton. Betulin, betulinic acid and their derivatives have been studied in the last decades for their diversified pharmacological activities like anti-HIV, anticancer, antibacterial, anti-inflammatory and many others. In the last few years, great progress had been made on the synthesis and biological activity of triterpenoids derived from betulin and betulinic acid. Shi and co-workers discuss recent research and development in chemistry of betulin and betulinic acid and present recent modification within A-ring, E-ring, both, at the C-3 and at the C-28 position as well as at the C-30 position of betulin and betulinic acid. The authors also present methods of conjunction of the above triterpenes with drugs. Supercritical fluid extraction has been a widely studied green technology to obtain triterpenoids enriched extracts from various vegetable matrices. De Melo and co-workers discuss research advances regarding the supercritical fluid extraction of triterpenoids in terms of biomass sources, operating conditions and their optimization, and modeling. The authors provide overview concerning the recent works (both publications and patents) upon supercritical fluid extraction of plant material leading to triterpenoids with the most important experimental and/or theoretical information. Many families of bioactive natural products are usually extracted from numerous plant sources in low yields. Triterpenic acids belong to a group of the most often studied compounds, mainly because of their abundance in a large number of food and medicinal plants. Domingues et al. in their work present overview of the biogenetic origin of some triterpenic acids, on the analytical extraction and hyphenated methodologies (mainly GC-MS) used on their identification and quantification. The authors also present an overview of the major sources of some triterpenic acids, indicating their potential large scale production pathways, with especial emphasis on abundant agroforestry biomass residues. The future perspectives towards improved therapeutic strategies using these triterpenic acids are also discussed herein. The root bark of the Chinese medicine Tripterygium wilfordii contains a quinone methide triterpenoid - celastrol. Literature data presents, that celastrol is one of the most potent antitumor activity compounds among the natural triterpenoids. Salvador et al. discuss different mechanisms of antitumor activity of celastrol, such as abilities of inhibing proliferation, inducing apoptosis and suppressing invasion and metastasis of tumor cells. The authors also describe the anticancer property of semi-synthetic celastrol derivatives. As they noticed, the quinone methide moiety is required for its antitumor activity. I thank all the contributors or this special issue and hope that the progresses highlighted in the topics covered will inspire more research in this challenging area of organic synthesis. I thank Prof. Atta-ur-Raman for the kind invitation to be the Guest Editor of this issue and all the reviewers for their time and valuable comments. I also thank Ms. Hina Wahaj (Publications Manager, Bentham Science Publishers) for the help in organizing this issue.

<div>Most of the currently marketed and approved drugs possess nitrogen and</div><div>oxygen-containing heterocycles in their scaffolds. The importance of metal</div><div>nanoparticles (MNPs) catalyzed synthesis of such aza- and oxa-heterocycles should not</div><div>be underestimated due to their versatile applications. Previously, we reported the</div><div>decennary update on MNPs catalyzed synthesis of N- and O-containing heterocycles</div><div>reported during 2010-2019. In the present work, attempts have been made to</div><div>summarize the prospects to highlight those promising MNPs of worthy catalytic</div><div>potential reported during the year, 2020. The present compilation shall provide the new</div><div>thought processes to address the unmet synthetic needs for the construction of nitrogen</div><div>and oxygen-containing heterocyclic scaffolds.</div>

The ansamacrolides or ansamycins are a family of antibiotics characterized by an aliphatic ansa‐bridge that connects two nonadjacent positions of an the aromatic nucleus. Ansamacrolides can be divided into two groups. One contains a naphthoquinoid nucleus and includes the streptovaricins, the rifamycins, tolypomycin, the halomycins, the naphthomycins, actamycin, the diastovaricins, kanglemycin, awamycin, and ansathiazin. The other contains a benzoquinoid nucleus and includes geldanamycin, the maytansinoids, the herbimycins, the macbecins, the mycotrienins, the trienomycins, the ansatrienins, and the maytansinoids and maytansides. Among the naphthoquinoids, the streptovaricins are produced by Streptomyces Spectablis n. sp. and all except streptovaricin D react with one mole of sodium periodate to yield the corresponding streptovals. The streptovaricins undergo thermal isomerization to the corresponding atropisostreptovaricins. The rifamycins were first isolated from a broth of Nocardia mediterranei. Only rifamycin B can be isolated easily as a stable crystalline compound. The structures of the rifamycins were arrived at by chemical degradation studies and confirmed by x‐ray crystallography. There have been thousands of rifamycin derivatives prepared in an attempt to obtain a broader‐spectrum antibiotic having good oral absorption. Several of the semisynthetic derivatives are therapeutically more effective than the parent antibiotics. Tolypomycin Y shows strong antibacterial activity against gram‐positive bacteria and Neisseria gonorrheae. The halomycins, a group of four antibiotics produced by Micromonospora halophytica, are active against gram‐positive bacteria. The halomycin complex exhibited high activity against bacterial strains resistant to penicillin G. The naphthomycins are a group of closely related antibiotics differing in the substituent at C‐2 and C‐30, and in the geometry about the C‐4 and C‐6 double bonds. The naphthoquinomycins, diastovaricins, and actamycin are all closely related to the naphthomycins. Kanglemycin is isolated from the fermentation broth filtrate of Nocardia mediterranei var. kanglensis and its structure determined by x‐ray crystallographic studies. The antibiotic is active against gram‐positive bacteria. Awaymycin and ansathiazin are produced by Streptomyces sp. No. 80‐217. Both are active against gram‐positive bacteria; awamycin is reported to have antitumor activity. Among the benzoquinoids, geldanamycin is isolated from the filtered beer of Streptomyces hygroscopicus var. geldanus var. nova. Unlike the naphthoquinoid ansamacrolides, geldanamycin has little antibacterial activity, being primarily active against protozoa and fungi, especially Tetrahymena pyriformis and Crithidia fasciculata. Geldanamycin also has herbicidal activity. Herbimycins A, B, and C along with some derivatives, are isolated from the fermentation broth of Streptomyces hygroscopicus AM‐3672. The herbimycins possess strong herbicidal activity and exhibit some antitumor and antiviral activity. Several derivatives of herbimycin A possess greater antitumor activity than the parent. Macbecin I and II are isolated from the fermentation broth of Nocardia sp. C‐14919. The macbecins are active against gram‐positive bacteria, fungi, and protozoa and exhibit in vitro antitumor activity against murine leukemia P 388 and melanoma B 16. The mycotrienins are produced by Streptomyces rishiriensis T‐23. They possess no antibacterial activity but are active against fungi and yeasts and exhibit weak antitumor activity. Trienomycins are isolated from Streptomyces sp. 83‐16. The trienomycins have no antimicrobial activity but have good antitumor activity. Trienomycin A is the most active. The ansatrienins are produced by Streptomyces collinus Tü 1982. The ansatrienins are active against fungi. The maytansinoids were the first ansamacrolides to be found in plants. The term maytansinoids refers to those ansamacrolides related to maytansine, whereas the term maytansides refers to maytansinoids lacking the ester side chain at C‐3 as well as the corresponding elimination products. Maytansine, colubrinol and colubrinol acetate, and normaytansine are maytansinoids. Another large group of maytansinoids are produced by the microorganism Nocardia sp. C‐25003 (N‐1) and are designated ansamitocins. Several semisynthetic maytansinoids have been prepared by acylating the C‐3 hydroxyl group of maytansinol. Some of these derivatives have antiprotozoal and antitumor activity similar to maytansine and ansamitocin P‐3. The maytansinoids possess antitumor activity, particularly against P 388 lymphocytic leukemia, B 16 melanocarcinoma, and Lewis lung carcinoma. A number of semisynthetic esters of maytansinol have been prepared and exhibit good antileukemic activity. The maytansides lack antitumor activity. Besides having antitumor activity, the ansamitocins have antiprotozoal and antifungal activity. The mode of action of the naphthoquinoid ansamacrolides is one whereby they inhibit bacterial growth by inhibiting RNA synthesis. This is accomplished by their forming a tight complex with DNA‐dependent RNA polymerase. The ansamacrolides form no such complex with mammalian RNA polymerase and thus have low mammalian toxicity. The antiviral activity of the ansamacrolides results from the inhibition of the assembly of the virus particles. The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis. The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. Rifampicin, the only commercially available ansamacrolide, is manufactured by Merrell Dow under the trade name Rifadin, and by CIBA under the trade name Rimactane. Rifampicin is also supplied in combination with isoniazid or pyrazinamide.

Both refrigeration and blanching of red-stage tomatoes are common practices in Japan home kitchens and in food service operations. However, little is reported on the impact of such practices on aroma profiles in tomato fruits. In this study, ‘FL 47’ tomatoes at red stage were dipped in 50 °C hot water for 5 minutes or exposed to 5 °C for 4 days to simulate consumer handling of tomato in food service or home kitchens, respectively. Of the 42 volatile compounds detected, refrigeration generally suppressed production of aldehydes, alcohols, oxygen-containing heterocyclic compounds, and nitrogen- and oxygen-containing heterocyclic compounds, including the following abundant and/or important volatiles: pentanal, 3-methylbutanal, 2-methylbutanal, hexanal, cis -3-hexenal, trans -2-hexenal, 2-phenylacetaldehyde, pentanol, 3-methylbutanol, 2-phenylethanol, 1-penten-3-one, geranial, and geranylacetone. On the other hand, the production of aldehydes, alcohols, hydrocarbons, oxygen-containing heterocyclic compounds, and nitrogen- and oxygen-containing heterocyclic compounds was reduced by blanching, associated with low concentrations of 2-methylbutanal, pentanal, cis -3-hexenal, trans -2-hexenal, 2-phenylacetaldehyde, pentanol, 2-methylbutanol, and 2-phenylethanol. These results indicate that a short blanching or refrigeration of tomatoes substantially impacts tomato aroma quality.

Polyphenols are a family of organic compounds characterized by a wide range of biological activities. Among natural polyphenols, the products derived from shikimic and polyketide biogenic pathways, such as lignans, neolignans, cardanols and flavonoids are of special interest owing to their powerful antioxidant, antitumoral, antimitotic, antiviral, cardiovascular and immunosuppressive activity. The biological activity of polyphenols can be finely tuned by the oxidation state of the molecule. Polyphenols are subject to oxidative metabolism in the cell by cytochrome p-450 dependent enzymes, mainly at reactive benzyl and aryl positions of the molecule, to yield highly oxidised derivatives, namely quinones, hydroquinones, semiquinones, catechols and others, whose biological activity can greatly differ from that of the parental compound. In fact, these derivatives are characterized by peculiar antitumoral, antioxidant and antiviral activities and show different chemical properties toward nucleophiles and electrophiles active sites in the cell. This behavior is dependent on the specific value of the redox potential in the cell. The low concentration of these metabolites in nature, and the difficulty to recover them from mammalian cells or fluids require novel procedures for their synthesis to collect adequate amounts of compounds for biological assays. On the other hand, only a few attentions has been devoted to design novel oxidative procedures for the synthesis of highly oxidised polyphenols characterized by higher biological activity. In this review, advances and challenges in the synthesis of natural and semi-synthetic highly oxidised polyphenols are reported focusing the attention in the recent years. Data on the antiviral, antioxidant and cytotoxic activities in vivo and in vitro systems for natural and semi-synthetic highly oxidised polyphenols are also reported, and the effect on the biological activity due to the introduction of one or more oxygen atoms in different reactive sites of the molecule, is discussed.

Comparison of antiviral and antitumor activity of activated macrophages

Isoeleutherin and eleutherinol, naturally occurring selective modulators of Th cell-mediated immune responses

A comprehensive review on polysaccharides with hypolipidemic activity: Occurrence, chemistry and molecular mechanism

Cyclobutanes containing one oxygen atom in a molecule are called oxetane-containing compounds (OCC). More than 600 different OCC are found in nature; they are produced by microorganisms, and also found in marine invertebrates and algae. The greatest number of them is found in plants belonging to the genus Taxus. Oxetanes are high-energy oxygen-containing non-aromatic heterocycles that are of great interest as new potential pharmacophores with a significant spectrum of biological activities. The biological activity of OCC that is produced by bacteria and Actinomycetes demonstrates antineoplastic, antiviral (arbovirus), and antifungal activity with confidence an angiogenesis stimulator, respiratory analeptic, and antiallergic activity dominate with confidence from 81 to 99%.

Due to increased antimicrobial resistance against current drugs, new alternatives are sought. Endophytic bacteria associated with medicinal plants are recognized as valuable sources of novel secondary metabolites possessing antimicrobial, antitumor, insecticidal, and antiviral activities. In this study, five bacterial endophytes were isolated and identified from the medicinal plant, Alectra sessiliflora, and their antibacterial and antitumor activities were investigated. In addition, the crude extracts of the endophytes were analyzed using gas chromatography (GC) coupled with time-of-flight mass spectrometry (TOF-MS). The identified bacterial endophytes belong to three genera viz Lysinibacillus, Peribacillus, and Bacillus, with the latter as the dominant genus with three species. Ethyl acetate extracts from the endophytes were used for antimicrobial activity against eleven pathogenic strains through minimum inhibitory concentration (MIC). The antitumor activity against the Hela cervical, Hek 293 kidney, and A549 lung carcinoma cells was determined by the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. Lysinibacillus sp. strain AS_1 exhibited broad antibacterial activity against the pathogenic strains with MIC values ranging from 4 to 8 mg/ml, while Bacillus sp. strain AS_3 displayed MIC of 0.25 mg/ml. Crude extracts of Lysinibacillus sp. strain AS_1, Peribacillus sp. strain AS_2, and Bacillus sp. strain AS_3 showed growth inhibition of more than 90% against all the cancer cell lines at a concentration of 1,000 μg/ml. Untargeted secondary metabolite profiling of the crude extracts revealed the presence of compounds with reported biological activity, such as antimicrobial, antioxidant, anti-inflammatory, antitumor, and antidiabetic properties. This study reported for the first time, bacterial endophytes associated with A. sessiliflora with antibacterial and antitumor activities.

In recent decades, the utilization of microwave energy has experienced an extraordinary surge, leading to the introduction of innovative and revolutionary applications across various fields of chemistry such as medicinal chemistry, materials science, organic synthesis and heterocyclic chemistry. Herein, we provide a comprehensive literature review on the microwave-assisted organic synthesis of selected heterocycles. We highlight the use of microwave irradiation as an effective method for constructing a diverse range of molecules with high yield and selectivity. We also emphasize the impact of microwave irradiation on the efficient synthesis of N- and O-containing heterocycles that possess bioactive properties, such as anti-cancer, anti-proliferative, and anti-tumor activities. Specific attention is given to the efficient synthesis of pyrazolopyrimidines-, coumarin-, quinoline-, and isatin-based scaffolds, which have been extensively studied for their potential in drug discovery. The article provides valuable insights into the recent synthetic protocols and trends for the development of new drugs using heterocyclic molecules.

Oxygen-containing heterocycles are largely distributed in natural and synthetic compounds. Coumarins are among the most famous heterocycles which possess one oxygen atom in their rings. Coumarins are classified as multifunctional scaffold and are used as anti-oxidant reagents, anti-inflammatory, anti-microbial, anti-fungal, anti-HIV active, analgesic, anti-histaminic, insecticides, dyes, herbicides, sensitizers, perfumes, cosmetics and food additives. Due to their diverse applications in industrial and pharmaceutical fields, many chemists have given significant interest to these compounds. Herein, the review highlights various methods for the synthesis and interactions of coumarin moiety as one of the most efficient categories of heterocycles.

Oxygen-containing heterocycles were reviewed as privileged scaffolds that had driven recent advances in rational drug design and synthetic methodology. The manuscript synthesized literature (2015-2025) on oxadiazoles, coumarins, morpholines, pyrans, furans, benzofurans and chromones and summarized how these scaffolds were engineered to optimize potency, selectivity and CNS drug-like properties. Mechanistic analyses demonstrated that oxygen atoms and carbonyl or ether functionalities consistently mediated key hydrogen-bonding and π-interactions within the catalytic anionic site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), rationalizing observed AChE/BChE SAR and dual-site binding. Representative medicinal chemistry campaigns were highlighted: coumarin and coumarin-hybrid series provided potent dual-site inhibitors; 1,2-oxadiazoles or 1,3,4-oxadiazoles produced sub to low-nanomolar AChE/BChE leads; morpholine-bearing scaffolds afforded favourable BBB permeability and mixed-type inhibition; and pyranone-carbamate hybrids delivered highly BChE-selective inhibitors with promising in vivo cognitive effects. Synthetic strategies (multicomponent reactions, metal-catalysed cyclizations and green/one-pot protocols) were reviewed and correlated with scaffold diversification and improved ADME profiles. The review concluded by identifying gaps limited unified docking/SAR databases and sparse translational safety data and proposed a workflow combining fragment-based design, dual-site targeting and early ADME profiling to accelerate lead optimisation toward clinically relevant cholinesterase modulators. This focused synthesis of structure activity, mechanism and synthetic access was intended to inform future heterocycle-centric programs against neurodegenerative targets.