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Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 39020

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Prof. Czesław Wawrzeńczyk

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Guest Editor

Department of Chemistry, Wrocław University of Environmental and Life Science, Wrocław, Poland
Interests: synthesis of isoprenoid lactones with specified biological activity with special focus on the antifeedant activity towards insect pests and valuable odoriferous properties; structural modifications of lactones in biotransformation processes; enzymatic resolutions of racemic compounds; studies on the influence of configuration of chiral centers of the molecule on biological activity of the compound; natural and modified phospholipids; incorporation of molecules possessing cytotoxic activity against cancer cells (CLA, DHEA, betulin) into phospholipids

Prof. Dr. Witold Gładkowski

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Guest Editor

Department of Chemistry, Wrocław University of Environmental and Life Science, Wrocław, Poland
Interests: biotransformations of organic compounds by whole cells; chemoenzymatic synthesis of optically active lactones with biological activity; determination of absolute configurations of optically active compounds; enzymatic modifications of phospholipids; analytical and spectroscopic methods to establish the structure of new compounds
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Special Issue Information

Dear Colleagues,

Lactones are one of the most numerous compounds isolated from the natural environment. They are secondary metabolites of plants, insects, microorganisms and marine organisms. Lactones are widely distributed in foods and beverages, contributing to their specific tastes and flavors. Natural and synthetic lactones possess a broad spectrum of biological activitity, including antifeedant, antimicrobial, anti-inflammatory and cytotoxic activities. Many lactones exhibit interesting odoriferous properties; they also function as pheromones in the world of animals, insects and microorganisms. In most cases, their structure is very complex—apart from various lactone ring sizes, they also contain additional functional groups, e.g., hydroxyl groups, carbonyl groups, ester groups or epoxide rings, or other structural elements like aromatic rings or halogen atoms. Lactones with isoprenoid structure represent a group of particular importance.

Lactones can be isolated from environmental sources or synthesized by chemical or biotechnological methods. The latter involves chemoenzymatic synthesis of optically pure lactones or biotransformations using different biocatalysts (whole cells, purified enzymes, etc.). Taking into account the influence of configurations of stereogenic centers in the molecule on the biological activity of the compounds, methods for the synthesis of lactones in optically active form are preferred.

Contributions to this Special Issue should cover all aspects of any biological activity of new lactones (anticancer, anti-inflammatory, cytotoxic, antimicrobial) together with their isolation, chemical and chemoenzymatic synthesis and biotransformations by different biological systems.

Prof. Czesław Wawrzeńczyk
Prof. Witold Gładkowski
Guest Editors

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Keywords

lactones
anticancer activity
anti-inflammatory activity
antimicrobial activity
cytotoxic effects
isolation
synthesis
biotransformations
configuration of chiral centers

Published Papers (10 papers)

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Research

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13 pages, 1456 KiB

Open AccessArticle

Investigation of the Anti-Methicillin-Resistant Staphylococcus aureus Activity of (+)-Tanikolide- and (+)-Malyngolide-Based Analogues Prepared by Asymmetric Synthesis

by Joseph Breheny, Cian Kingston, Robert Doran, Joao Anes, Marta Martins, Séamus Fanning and Patrick J. Guiry

Int. J. Mol. Sci. 2021, 22(12), 6400; https://doi.org/10.3390/ijms22126400 - 15 Jun 2021

Cited by 1 | Viewed by 2314

Abstract

Herein, we report antibacterial and antifungal evaluation of a series of previously prepared (+)-tanikolide analogues. One analogue, (4S,6S)-4-methyltanikolide, displayed promising anti-methicillin-resistant Staphylococcus aureus activity with a MIC of 12.5 µg/mL. Based on the antimicrobial properties of the structurally related (−)-malyngolide, two further analogues (4S,6S)-4-methylmalyngolide and (4R,6S)-4-methylmalyngolide bearing a shortened n-nonyl alkyl side chain were prepared in the present study using a ZrCl₄-catalysed deprotection/cyclisation as the key step in their asymmetric synthesis. When these were tested for activity against anti-methicillin-resistant Staphylococcus aureus, the MIC increased to 50 µg/mL. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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19 pages, 12807 KiB

Open AccessArticle

Anti-Inflammatory Effects of Analogues of N-Acyl Homoserine Lactones on Eukaryotic Cells

by Agathe Peyrottes, Garance Coquant, Loïc Brot, Dominique Rainteau, Philippe Seksik, Jean-Pierre Grill and Jean-Maurice Mallet

Int. J. Mol. Sci. 2020, 21(24), 9448; https://doi.org/10.3390/ijms21249448 - 11 Dec 2020

Cited by 8 | Viewed by 2460

Abstract

Background: Since acyl-homoserine lactone (AHL) profiling has been described in the gut of healthy subjects and patients with inflammatory bowel disease (IBD), the potential effects of these molecules on host cells have raised interest in the medical community. In particular, natural AHLs such as the 3-oxo-C12-HSL exhibit anti-inflammatory properties. Our study aimed at finding stable 3-oxo-C12-HSL-derived analogues with improved anti-inflammatory effects on epithelial and immune cells. Methods: We first studied the stability and biological properties of the natural 3-oxo-C12-HSL on eukaryotic cells and a bacterial reporter strain. We then constructed and screened a library of 22 AHL-derived molecules. Anti-inflammatory effects were assessed by cytokine release in an epithelial cell model, Caco-2, and a murine macrophage cell line, RAW264.7, (respectively, IL-8 and IL-6) upon exposure to the molecule and after appropriate stimulation (respectively, TNF-α 50 ng/mL and IFN-γ 50 ng/mL, and LPS 10 ng/mL and IFN-γ 20 U/mL). Results: We found two molecules of interest with amplified anti-inflammatory effects on mammalian cells without bacterial-activating properties in the reporter strain. The molecules furthermore showed improved stability in biological medium compared to the native 3-oxo-C12-HSL. Conclusions: We provide new bio-inspired AHL analogues with strong anti-inflammatory properties that will need further study from a therapeutic perspective. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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16 pages, 1687 KiB

Open AccessArticle

Repellent and Antifeedant Activities of Citral-Derived Lactones against the Peach Potato Aphid

by Katarzyna Dancewicz, Antoni Szumny, Czesław Wawrzeńczyk and Beata Gabryś

Int. J. Mol. Sci. 2020, 21(21), 8029; https://doi.org/10.3390/ijms21218029 - 28 Oct 2020

Cited by 14 | Viewed by 3446

Abstract

Citral is well known for its antimicrobial, antifungal, and insecticidal activities. Natural sesquiterpene α-methylenelactones also exhibit a broad spectrum of biological activities. The aim of the study was to explore the effect of structural changes to citral molecules on citral behavior-modifying activity towards Myzus persicae. Specifically, the effects of the introduction of a γ-lactone moiety and methylene groups in α and γ positions of the lactone ring were investigated. The lactones were obtained in five-step (saturated lactone and γ-methylenelactone) or six-step (α-methylenelactone and α,γ-dimethylenelactone) syntheses from citral. The synthetic procedures and physical and spectral data of the lactones are presented. The settling behavior of freely moving aphids in choice and no-choice situations was monitored. The probing behavior of tethered M. persicae using the Electrical Penetration Graph (EPG) technique was also analyzed. Citral appeared a strong repellent and pre-ingestive and ingestive probing deterrent to M. persicae. The incorporation of a lactone moiety caused the loss of the repellent activity. α-Methylenelactone inhibited aphid settling and probing activities at pre-ingestive and ingestive phases. The saturated γ-lactone and α,γ-dimethylenelactone were the settling post-ingestive deterrents to M. persicae, which did not affect aphid probing activity. γ-Methylenelactone did not affect aphid behavior. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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13 pages, 2522 KiB

Open AccessArticle

Different Conditions for the Modification of Polycaprolactone Films with L-Arginine

by Yuliya Nashchekina, Alina Chabina, Alexey Nashchekin and Natalia Mikhailova

Int. J. Mol. Sci. 2020, 21(19), 6989; https://doi.org/10.3390/ijms21196989 - 23 Sep 2020

Cited by 9 | Viewed by 2488

Abstract

Poly-ε-caprolactone (PCL) is a biodegradable polymer used in regenerative medicine. Mesenchymal stem cells (MSCs) play an important role in the regeneration of different tissues. The hydrophobicity and neutrality of a PCL surface reduce MSCs’ adhesion and proliferation. In this study, PCL films were treated with arginine to improve surface hydrophilicity. The influences of arginine concentration, temperature, and solvent on PCL surface properties were investigated. PCL films treated with a solution of arginine in isopropyl alcohol were found to have the maximum number of amino groups. The greatest number of cells, 2 h after seeding, adhered to such films. It was shown that amino groups affect the interaction of cells with a modified surface and the hydrolysis reaction after treatment with isopropyl alcohol promotes the formation of adhesive focal contacts. Hence, our results illustrate that functional groups on the PCL surface after arginine solution treatment regulate MSC adhesion and focal contact formation. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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Review

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21 pages, 3516 KiB

Open AccessReview

Biological Activity of Selected Natural and Synthetic Terpenoid Lactones

by Alicja K. Surowiak, Lucyna Balcerzak, Stanisław Lochyński and Daniel J. Strub

Int. J. Mol. Sci. 2021, 22(9), 5036; https://doi.org/10.3390/ijms22095036 - 10 May 2021

Cited by 20 | Viewed by 3679

Abstract

Terpenoids with lactone moieties have been indicated to possess high bioactivity. Certain terpenoid lactones exist in nature, in plants and animals, but they can also be obtained by chemical synthesis. Terpenoids possessing lactone moieties are known for their cytotoxic, anti-inflammatory, antimicrobial, anticancer, and antimalarial activities. Moreover, one terpenoid lactone, artemisinin, is used as a drug against malaria. Because of these abilities, there is constant interest in new terpenoid lactones that are both isolated and synthesized, and their biological activities have been verified. In some cases, the activity of the terpenoid lactone is specifically connected to the lactone moiety. Recent works have revealed that new terpenoid lactones can demonstrate such functions and are thus considered to be potential active agents against many diseases. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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48 pages, 22172 KiB

Open AccessReview

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

by Joonseong Hur, Jaebong Jang and Jaehoon Sim

Int. J. Mol. Sci. 2021, 22(5), 2769; https://doi.org/10.3390/ijms22052769 - 09 Mar 2021

Cited by 33 | Viewed by 6461

Abstract

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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40 pages, 8623 KiB

Open AccessReview

Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs

by Constantin Tănase, Lucia Pintilie and Raluca Elena Tănase

Int. J. Mol. Sci. 2021, 22(4), 1572; https://doi.org/10.3390/ijms22041572 - 04 Feb 2021

Cited by 7 | Viewed by 4332

Abstract

In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF_2α and 1,15-PGF_2α lactones, many 1,15-lactones of E₂, E₃, F₂, F₃, A₂, and A₃ were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9β-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9β-PG analogs and future applications, are also discussed. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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67 pages, 42350 KiB

Open AccessReview

Natural and Synthetic Lactones Possessing Antitumor Activities

by Younghoon Kim, Sandip Sengupta and Taebo Sim

Int. J. Mol. Sci. 2021, 22(3), 1052; https://doi.org/10.3390/ijms22031052 - 21 Jan 2021

Cited by 13 | Viewed by 4204

Abstract

Cancer is one of the leading causes of death globally, accounting for an estimated 8 million deaths each year. As a result, there have been urgent unmet medical needs to discover novel oncology drugs. Natural and synthetic lactones have a broad spectrum of biological uses including anti-tumor, anti-helminthic, anti-microbial, and anti-inflammatory activities. Particularly, several natural and synthetic lactones have emerged as anti-cancer agents over the past decades. In this review, we address natural and synthetic lactones focusing on their anti-tumor activities and synthetic routes. Moreover, we aim to highlight our journey towards chemical modification and biological evaluation of a resorcylic acid lactone, L-783277 (4). We anticipate that utilization of the natural and synthetic lactones as novel scaffolds would benefit the process of oncology drug discovery campaigns based on natural products. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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12 pages, 1110 KiB

Open AccessReview

Thapsigargin—From Traditional Medicine to Anticancer Drug

by Agata Jaskulska, Anna Ewa Janecka and Katarzyna Gach-Janczak

Int. J. Mol. Sci. 2021, 22(1), 4; https://doi.org/10.3390/ijms22010004 - 22 Dec 2020

Cited by 62 | Viewed by 5883

Abstract

A sesquiterpene lactone, thapsigargin, is a phytochemical found in the roots and fruits of Mediterranean plants from Thapsia L. species that have been used for centuries in folk medicine to treat rheumatic pain, lung diseases, and female infertility. More recently thapsigargin was found to be a potent cytotoxin that induces apoptosis by inhibiting the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA) pump, which is necessary for cellular viability. This biological activity encouraged studies on the use of thapsigargin as a novel antineoplastic agent, which were, however, hampered due to high toxicity of this compound to normal cells. In this review, we summarized the recent knowledge on the biological activity and molecular mechanisms of thapsigargin action and advances in the synthesis of less-toxic thapsigargin derivatives that are being developed as novel anticancer drugs. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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25 pages, 5911 KiB

Open AccessReview

Intramolecular Lactones of Sialic Acids

by Paola Rota, Paolo La Rocca, Pietro Allevi, Carlo Pappone and Luigi Anastasia

Int. J. Mol. Sci. 2020, 21(21), 8098; https://doi.org/10.3390/ijms21218098 - 30 Oct 2020

Cited by 7 | Viewed by 2342

Abstract

The so-called “sialo-chemical-biology” has become an attractive research area, as an increasing number of natural products containing a sialic acid moiety have been shown to play important roles in biological, pathological, and immunological processes. The intramolecular lactones of sialic acids are a subclass from this crucial family that could have central functions in the discrimination of physiological and pathological conditions. In this review, we report an in-depth analysis of the synthetic achievements in the preparation of the intramolecular lactones of sialic acids (1,4-, 1,7- and γ-lactones), in their free and/or protected form. In particular, recent advances in the synthesis of the 1,7-lactones have allowed the preparation of key sialic acid derivatives. These compounds could be used as authentic reference standards for their correct determination in biological samples, thus overcoming some of the limitations of the previous analytical procedures. Full article

(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)

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