Natural ten-membered lactones: sources, structural diversity, biological activity, and intriguing future†

Vsevolod Dubovik , Anna Dalinova and Alexander Berestetskiy *
Laboratory of Phytotoxicology and Biotechnology, All-Russian Institute of Plant Protection, Pushkin, 196608 Saint-Petersburg, Russia. E-mail: aberestetskiy@vizr.spb.ru; vdubovik@vizr.spb.ru; adalinova@vizr.spb.ru

First published on 27th October 2023

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Vsevolod Dubovik

Vsevolod graduated as a Master of Chemical Technology from Saint-Petersburg State University of Industrial Technologies and Design in 2020. He is currently a postgraduate student and works as a junior researcher at the All-Russian Research Institute of Plant Protection in Saint-Petersburg, Russia. His PhD thesis is devoted to phytotoxic ten-membered lactones with the working title “Secondary metabolites of the fungus Stagonospora cirsii and prospects for their use as plant protection agents”. His research focuses on the search for new ten-membered lactones, establishing their chemical structures and development of their application in plant protection.

Anna Dalinova

Anna graduated as a Master of Biotechnology from St. Petersburg State Institute of Technology in 2013 and gained a PhD degree in mycology in 2018. Since 2019 she has been a researcher in Dr Berestetskiy's Department at the All-Russian Research Institute of Plant Protection. Anna specializes in the purification and structural elucidation of biologically active fungal compounds, including ten-membered lactones.

Alexander Berestetskiy

Alexander graduated from Saint-Petersburg State Agrarian University in 1995 and received his PhD in mycology in 2000. Since 2014 he has been the Head of the Department of Phytotoxicology and Biotechnology at the All-Russian Research Institute of Plant Protection. His primary scientific interests include the chemical ecology of phytopathogenic fungi and the development of natural herbicides. Supported by the European Commission, Russian Fund of Basic Research, and Russian Science Foundation, his research has been focused on characterization of fungal bioactive compounds with a special attention to ten-membered lactones.

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1 Introduction

Ten-membered lactones (TMLs) are a large group of natural polyketides. The characteristic structural feature of these compounds is a macrolide lactone core, which is substituted differently with alkyl, aryl, and oxygen groups, depending on the natural source of the compound. Natural products belonging to this group display various biological activities, including cytotoxic, phytotoxic, antimalarial, antifungal, and antibacterial activities as well as inhibitory effects against different enzymes.

The first review devoted to TMLs was presented by Dräger et al. (1996)¹ covering the literature published between 1964 and 1995. This paper described 49 compounds isolated from natural sources during the first 20 years of research. Fifteen years after Dräger's publication, the time was ripe for the next review. In 2012 Sun et al. (2012)² summarized the publications from to 1996–2011 and covered 63 TMLs isolated in these 15 years. Further improvements in chromatographic and structure elucidation techniques have boosted the pace of new natural products publications. Notably, the number of newly published TMLs during the decade 2012–2022 was comparable to that discovered in the entire previous period from 1964 to 2011 (Fig. 1). In addition to the mentioned specialized reviews, there are other papers that include some TMLs as one of the groups under consideration (for example, along with other fungal macrolides³ and benzenediol lactones⁴). In the first part of the present work (Section 2), we summarize the data on new TMLs described between 2012 and 2022 (94 compounds) and highlight some interesting compounds overlooked in previous specialized reviews (ten compounds). The performed literature survey resulted in a list containing nearly all of the described natural TMLs (214 compounds for the entire period of 1964–2022). This allowed us to analyze the distribution of these compounds in nature, their main structural types, common biological activities, trends, and problems in the study of these intriguing natural products. These issues are discussed in the second part of this review (Section 3).

2 Ten-membered lactones described during 2012–2022

This section covers the most recent reports in the literature on the discovery of TMLs from natural sources. We will follow the structural classification of TMLs introduced by Dräger et al. (1996)¹ and further used by Sun et al. (2012),² which is based on the structural features of the molecules, regardless of their origin. The main diversification factor is the carbon chains substitution pattern in the lactone scaffold. The term “simple” refers to TMLs with only one alkyl substituent (at the C-9 atom) and oxygen substituents in other positions (if any). TMLs containing aromatic rings fused with the lactone core are classified as separate groups based on the position of the additional ring – resorcylic acid lactones (RALs) and dihydroxyphenylacetic acid lactones (DALs). Some natural products have complex structures and contain a ten-membered lactone core as the structural unit in a large molecule. These compounds are categorized into the formal group of “complex” TMLs. Notably, nearly all newly isolated TMLs from 2012 to 2022 also fall into these categories, thereby further supporting this classification system (there are some exceptions, which will be discussed in the relevant sections).

2.1 Simple ten-membered lactones with alkyl and oxygen substituents

Fourteen new fungal TMLs possessing a methyl substituent at C-9 were described from 2012 to December 2022: truncatenolide (1), modiolides D–G (2–5), decarestrictine Q (6), cremenolide (7), aspinolides D–G (8–11), and diaporthsins A, F, and H (12–14) (Fig. 2). Truncatenolide (1) was isolated from Colletotrichum truncatum, a causal agent of soybean anthracnose. The compound reduced the roots length of soybean seedlings at a concentration of 2.5 mM by 43% compared to the control. Moreover, compound 1 displayed antifungal activity against the widespread pathogens Colletotrichum nicotianae and Macrophomina phaseolina inhibiting fungal growth by 40% and 100%, respectively, at 2.5 mM.⁵

Modiolides D–G (2–5) isolated from the EtOAc extract of Paraconiothyrium sp. VK-13 were tested for anti-inflammatory activity on LPS-stimulated RAW264.7 cells and did not show any effect.⁶ Decarestrictine Q (6) was described as a secondary metabolite of the marine-derived fungus Pseudopestalotiopsis sp. PSU-AMF45, but its biological activity was not tested.⁷ Cremenolide (7) isolated from culture filtrates of Trichoderma cremeum significantly inhibited mycelial growth of the phytopathogenic fungi Fusarium oxysporum, Botrytis cinerea, and Rhizoctonia solani at concentrations of 1–100 μg per plug. Moreover, compound 7 was able to promote tomato seedlings growth at 1–10 ppm.⁸ Another antagonistic fungus, T. arundinaceum, was shown to be the source of previously known aspinolides A–C,⁹ and new aspinolides D–G (8–11). The activity of these minor aspinolides remains unexplored, whereas aspinolides B and C display antifungal and plant-stimulating activities, respectively.¹⁰ The endophytic Diaporthe sp. strain JC-J7 was found to be a source of several new TMLs, including diaporthsins A (12), F (13), and H (14). The structural similarity to decarestrictines inspired the authors to test the antihyperlipidemic activities of these compounds, but 12–14 did not show lipid-lowering effects on triglycerides in steatotic L02 cells at a concentration of 5 μg mL⁻¹ as well as any cytotoxicity against A-549 cells.¹¹

Mantidactolides A (15) and B (16)¹² as well as luteolide (17)¹³ are the volatile components of the femoral glands of frogs Mantidactylus femoralis and Gephyromantis luteus, respectively. Compound 17 was also found at various concentrations in the mantelline frogs Mantidactylus betsileanus and Gephyromantis moseri.^13,14 These lactones of animal origin, unlike the above-mentioned fungal ones, are characterized by a highly branched scaffold with additional alkyl moieties (Fig. 3). Strictly speaking, these compounds do not fit the given definition of simple TMLs and represent an exception in this category, along with a few compounds that will be further mentioned. These macrolide pheromones play a role in the short-range communication of frogs during mating.^12,13

Over the past 10 years since the review by Sun et al. (2012),² nine new TMLs with propyl substituents at C-9 originated from fungi have been characterized: stagonolides J (18) and K (19), pinolide (20), compound 21, bellidisins B (27) and D (28) (Fig. 4), three xylarolides (29–31), stomopneulactones A (32), and B (33) (Fig. 5). Phomolides D–H (22–26) (Fig. 4) were described earlier (in 2010), but were missed by Sun et al. (2012).² Compounds 18 and 19 are new members of the vast stagonolide family isolated from the phytopathogenic fungus, Stagonospora cirsii. Stagonolide J (18) was the most toxic to wheat aphid at concentration 1 mg mL⁻¹ (∼5 mM or 20 μg cm⁻²), and displayed moderate phytotoxic activity in the leaf puncture assay to Canada thistle, perennial sowthistle and couch-grass at concentration 2 mg mL⁻¹. Compound 19 showed phytotoxicity in the leaf puncture assay but was not toxic in other bioassays. Neither compound was acutely toxic to the infusoria Paramecium caudatum.¹⁵ Stagonolide K (19) as well as previously reported stagonolide A and herbarumin I were evaluated as post-emergent herbicides against perennial sowthistle (Sonchus arvensis). The formulations of stagonolide A and herbarumin I (2 mg mL⁻¹) supplemented with adjuvant Hasten™ (0.1%, v/v) caused the necrosis of 80% and 50% of the leaf surface, respectively. Spraying of the plants with formulations of 19 did not lead to considerable leaf injury.¹⁶ Pinolide (20) was described as a secondary metabolite of Ascochyta pinodes, the causal agent of ascochyta blight of pea. It was not phytotoxic in leaf discs assay on legume crops and three different weeds at a concentration of 1 mg mL⁻¹.¹⁷ Three new TMLs, bellidisins B (27), C, and D (28), were isolated from a solid culture of an endophytic fungus identified as Phoma bellidis. Bellidisin C is discussed below as it possesses a longer alkyl moiety at C-9, whereas bellidisins B and D fall within the scope of this section with a propyl chain at C-9 atom. These compounds are structurally related to co-isolated pinolidoxin. Compound 28 showed significant cytotoxicity against the HL-60, A-549, SMMC-7721, MCF-7, and SW480 cell lines, with IC₅₀ values lower than that of the positive control (cisplatin). Bellidisin A does not possess the lactone core having a fused pyran and cyclohexane ring system, but the authors discuss its possible biogenetic relation to TMLs, in particular to pinolidoxin.¹⁸ It is notable that stagochromene A isolated along with stagonolides A, J, and K from S. cirsii¹⁵ has a similar skeleton and can also be a congener of TMLs.

Natural product 21 as well as phomolides D–H (22–26) were isolated from different endophytic strains of Phomopsis sp. Compound 21 showed phytotoxic activity on germination and radicle growth of Medicago sativa, Trifolium hybridum, and Buchloe dactyloides with IC₅₀ values for germination 15.8, 24.2, and 31.2 mg mL⁻¹, and for radicle growth 31.9, 63.3, 130.9 mg mL⁻¹, respectively.¹⁹ Phomolides D–H (22–26) had no effects on the growth of E. coli, B. subtilis, B. pumilus, S. aureus, and C. albicans at 30 μg per plate using the Oxford plate assay system.²⁰ The absolute configurations of phomolides G and H were revised by McNulty et al. (2016), and McNulty and McLeod (2017) using enantioselective total synthesis (Fig. 4).^21,22 Xylarolide (29) was found to be a component of still culture of Xylaria sp. 101.²³ According to Li et al. (2011)²³ compound 29 did not possess antimicrobial activity against E. coli, B. subtilis, B. pumilus, S. aureus and C. albicans. Sharma et al. (2018)²⁴ isolated xylarolides A (30) and B (31) along with 29 from the culture of endophytic fungus Diaporthe sp. treated with valproic acid as a histone deacetylases inhibitor. Notably, the altered secondary metabolism of the fungus under these conditions resulted in the biosynthesis of 30 that possesses the unusual C-8-modified scaffold (another compound that does not fall into the category of simple TMLs). In experiments conducted by Sharma et al. (2018),²⁴ xylarolide A (30) and xylarolide (29) demonstrated significant cytotoxicity to MIAPaCa-2 and PC-3 cells at micromolar concentrations. Moreover, 30 showed promising DPPH scavenging activity, with an EC₅₀ of 10.3 μM.

During the search for new anti-inflammatory agents from marine organisms, four new macrolides were isolated from the long-spined sea urchin Stomopneustes variolaris, among which stomopneulactones A (32) and B (33) belong to TMLs. Like many class members of animal origin (for example, 15–17), these compounds possess an additional alkyl chain at positions other than C-9. The compounds displayed significant antioxidant (IC₅₀ 1.60–1.80 mM) and anti-inflammatory activities (IC₅₀ 2.20–2.91 mM), which were additionally confirmed by molecular docking analyses using the inflammatory enzymes 5-LOX and COX-2.²⁵

Between 2012 and December 2022, 19 new fungal TMLs with a pentyl substituent at C-9 were described, including cytospolides A–P (34–49), bellidisin C (50), diaportheolide A (51), and penicillinolide A (52) (Fig. 6). Additionally, in this review, we consider the structure and biological activity of phomol (53) (Fig. 6), which has been overlooked in previous reviews. The endophytic fungus Cytospora sp. is a producer of a large family of TMLs called cytospolides A–P (34–49). This family has one chemical feature that is unique for fungal TMLs – the presence of a methyl group at C-2. Lu et al. (2011)²⁶ showed that cytospolides A (34), C (36) and D (37) did not display cytotoxic activity against the A-549 cell line at 50.0 μg mL⁻¹, whereas cytospolides B (35) and E (38) demonstrated strong cytotoxic activity with IC₅₀ values of 5.15 and 7.09 μg mL⁻¹, respectively. The structure–activity relationships (SAR) analysis of the next family members (34–49) by Lu et al. (2011)²⁷ confirmed the observation that the absolute configuration at C-2 affected the cytotoxic activity. Among the cytospolides, compounds 35, 38, and 49, which possess the 2S configuration, were the most cytotoxic to A549 tumor cells and were able to mediate G1 arrest in A549 tumor cells. Cytospolides K (44), M–O (46–48) were one order of magnitude less active than cytospolides B (35), E (38) and P (49).^27,28

Bellidisin C (50) isolated from P. bellidis did not display cytotoxicity, but bellidisins (50 and its congeners 27, 28) along with diaportheolides and podospins are an interesting example of a family of TMLs with various lengths of the C-9 alkyl chain isolated from one fungal culture.¹⁸ This observation can be important for biosynthetic studies of TMLs in fungi.

Diaportheolide A (51) and along with diaportheolide B (60) (not to be confused with diaportholides A and B²⁹) were isolated from the endophytic fungus Diaporthe sp. SXZ-19 of Camptotheca acuminata. Compounds 51 and 60 exhibited antimicrobial activity against Staphylococcus aureus at a concentration of 10 μg per disc., but showed almost no inhibitory activities in the minimum inhibitory concentration (MIC) tests (MIC > 128 μg mL⁻¹).³⁰ Chemical investigation of the marine-derived fungus Penicillium sp. SF-5292 led to isolation of penicillinolide A (52). This compound displayed potent anti-inflammatory activity in murine peritoneal macrophages stimulated with LPS, such as inhibition of inducible nitric oxide synthase and pro-inflammatory cyclooxygenase-2 expression, and decrease of tumor necrosis factor-α, interleukin-1β, and interleukin-6 production.^31,32 Phomol (53) was described as a secondary metabolite of the endophytic fungus Phomopsis sp. strain E02018, isolated from the medicinal plant Erythrina crista-galli.³³ Compound 53 exhibited topical anti-inflammatory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse ear edema at a dose of 1 mg per ear. Phomol (53) reduced cell proliferation by up to 50% at concentrations between 20 μg mL⁻¹ for L1210 and 50 μg mL⁻¹ for Colo-320 and MDA MB-231 cell lines. Moreover, compound 53 exhibited antimicrobial activity against the bacteria Arthrobacter citreus and Corynebacterium insidiosum, as well as 13 fungal species. No phytotoxic effects were observed against seedlings Setaria italica and Lepidium sativum.³³ A new TML of insect origin (5Z,9S)-tetradec-5-en-9-olide (54), was described in the headspace of fertile queens of the higher termite Silvestritermes minutus and was shown to be queen-specific. The compound did not affect the behavior of other termite colony members in electrophysiological experiments as well as in electroantennographic and behavioral assays.³⁴

Nine TMLs with long alkyl chains (C₇–C₉) at C-9 (55–63) were isolated from different fungi over the past 10 years (Fig. 7). Xyolide (55) was purified from extracts of the endophytic isolate Xylaria feejeensis.³⁵ This compound inhibited the growth of plant pathogenic Pythium ultimum with MIC 425 μM. Hypocreolide A (56) was isolated from culture filtrates of the ascomycete Hypocrea lactea. It exhibited moderate antimicrobial activity against seven fungal species (MIC 15–50 μg mL⁻¹) and eight bacterial species (MIC 50 μg mL⁻¹). At a concentration of up to 300 μg mL⁻¹, compound 56 was not phytotoxic to Setaria italica and Lepidium sativum seeds, but affected the saprophytic nematode Caenorhabditis elegans at 50 μg mL⁻¹. In a cytotoxicity assay, 90% of HepG2 and HeLa S3 cells were killed at 10 μg mL⁻¹.³⁶ Mangiferaelactone (57), isolated from a solid culture of the endophytic fungus Pestalotiopsis manguiferae, showed a MIC of 1.7 mg mL⁻¹ against Listeria monocytogenes, and 0.6 mg mL⁻¹ against B. cereus. Compound 57 did not show any activity against Plasmodium falciparum or Trypanosoma cruzi nor was it cytotoxic to A2058 and H522-T1 cells.³⁷ Achaetolide-II (58) was found as a major component of the extract from the mycelium of Helminthosporium velutinum TS28. It showed no antifungal activity against Cochliobolus miyabeanus (IC₅₀ > 100 μg mL⁻¹). A cytotoxicity assay of 58 revealed moderate growth inhibition of human colon adenocarcinoma (COLO 201) cells (IC₅₀ 370 μg mL⁻¹). In a phytotoxicity assay, compound 58 inhibited root growth of Lactuca sativa at 500 μg mL⁻¹.³⁸ TML 59 originated from the sponge-associated fungus, Xylaria feejeensis. An in vitro assay revealed the significant down-regulating activity of 59 on osteoclast cell differentiation at 0.5 and 1 μM.³⁹ Diaportheolide B (60) was discussed in the previous paragraph along with co-isolated diaportheolide A (51) that possesses a shorter alkyl chain at C-9 atom. In the search for new inhibitors of peroxisome proliferator-activated receptors (PPAR), a potent target in the treatment of type 2 diabetes, inflammatory disease, and certain cancers, seimatopolides A (61) and B (62) were isolated from Seimatosporium discosioides.⁴⁰ The absolute configurations of 61 and 62 were revised in a correction published by the same authors⁴¹ and several synthetic studies.^42–44 The story of the revision was scrupulously reviewed by Schmidt in 2021.⁴⁵ These metabolites activated (PPAR)-γ with EC₅₀ values of 1.15 and 11.05 μM, respectively. Under the same experimental conditions, the EC₅₀ of troglitazone, a PPAR-γ agonist used as a positive control, was 0.44 μM.^40,41

Colletotriolide (63) was isolated from the endophytic fungus Colletotrichum sp. isolated from the fragrant screw pine (Pandanus amaryllifolius). Compound 63 showed weak activity against E. coli, with an IC₅₀ 500 μg mL⁻¹, and was not cytotoxic to A549, HT29, and HCT116 cell lines. The relative configuration of 63 has not been determined.⁴⁶

2.2 Ten-membered resorcylic acid lactones and dihydroxyphenylacetic acid lactones

Resorcylic acid lactones (RALs) and dihydroxyphenylacetic acid lactones (DALs) are unique families of naturally occurring homologous macrolides, which are characterized by possessing a macrolide core structure fused to a resorcinol aromatic ring. Fourteen TMLs belonging to this family (64–77) were characterized over the last decade (Fig. 8). Chemical exploration of the endophytic fungus Chaetosphaeronema hispidulum led to isolation of hispidulactones A–C (64–66) and compound 68. The latter inhibited the growth of the seedlings of Arabidopsis thaliana, Digitaria sanguinalis, and Echinochloa crus-galli at concentrations of 8–32 μg mL⁻¹. It was also toxic to HCT116, HeLa, and MCF7 cells, with IC₅₀ values of 55, 5, and 20 μM, respectively.⁴⁷ The absolute configuration of hispidulactone B was revised after the isolation of its epimer hispidulactone F (67) from the same endophytic fungus, and its structure was confirmed using a modified Mosher's reaction. Compound 67 was able to significantly inhibit HepG2 cell proliferation with IC₅₀ 61.05 μM.⁴⁸

Podospins A–C (69–71) were obtained from a solid rice-based culture of Podospora sp. G214. Only podospin A (69) exhibited potent immunosuppressive activities against concanavalin A-induced T cell proliferation with IC₅₀ values ranging from 6.0 to 25.1 μM and lipopolysaccharide-induced B cell proliferation with IC₅₀ values ranging from 6.2 to 29.1 μM. Further studies have revealed that compound 69 induces apoptosis in activated T cells through the JNK-mediated mitochondrial pathway.⁴⁹ Two new RALs, sumalactones A (72) and B (73), were isolated from the marine fungus Penicillium sumatrense, along with four curvularin-type macrolides. These compounds were tested for their inhibitory activities against LPS-induced NO production in RAW 264.7 macrophages, but they were not active.⁵⁰ Aldaulactone (74) was shown to be the aggressiveness factor of the pathogen Alternaria dauci’s virulence towards carrot. The concentration of 74 in the crude fungal extracts was positively correlated with their toxicity to the cells of the susceptible cultivar, but not to the resistant one. In a bioassay on susceptible cultivar cells, aldaulactone (74) significantly decreased carrot cell viability at concentrations of 12.5–50.0 μg mL⁻¹, thus confirming the phytotoxicity of the compound.⁵¹ In 2018, the phytotoxicity of 74in planta remained unexplored due to the carrot leaf fragility.⁵¹ In 2022 this phytotoxin was shown to be toxic to tobacco leaves at 50 μg mL⁻¹ in a leaf infiltration assay.⁵²

Xestodecalactones D (75), E (76) and F (77), isolated from a mangrove endophyte Corynespora cassiicola, are closely related to xestodecalactones A–C, isolated from marine fungus Penicillium cf. montanense. These compounds are rare examples of TMLs that were subjected to a panel of bioassays: cytotoxic activity against murine L5178Y cells, antibacterial activity against multidrug-resistant strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecium, and E. cloacae, antifungal activity against drug resistant strains of Aspergillus fumigatus, A. faecalis, Candida albicans, and C. krusei, antitrypanosomal activity. Unfortunately, 75–77 were inactive in all performed bioassays.⁵³ Some ten-membered RALs and DALs were reviewed by Xu et al. (2014) along with other macrolides of this type.⁵⁴

2.3 Structurally complex ten-membered lactones with additional rings

Different bacterial strains are the main sources of structurally complex TMLs, including new members of the group 78–96 (Fig. 9). Saccharothriolides A–F (78–82) are unique phenyl-substituted ten-membered macrolide structures isolated from the rare actinomycete Saccharothrix sp. A1506. Among these compounds, only saccharothriolide B (79), saccharothriolide E (82), and saccharothriolide F (83) showed moderate cytotoxicity against human fibrosarcoma HT1080 cells with IC₅₀ values of 13.9, 29.2 and 66.4 μM, respectively. Other saccharothriolides, A (78), C (80), and D (81), were inactive, even at 100 μM. Moreover, compound 80 exhibited moderate cytotoxicity against HeLa cancer cells, with an IC₅₀ value of 17.9 μM and weak antibacterial activity at 50 mg per disc against Staphylococcus aureus in a paper disc assay. In this regard, Lu et al. (2015)⁵⁵ suggested that saccharothriolides are capable of regulating their biological activities by modifying the functional group at the C-7 position. In a further structure–activity relationship (SAR) study, Lu et al. (2016)⁵⁶ showed that the phenolic hydroxyl group at C-2′′ is important for cytotoxicity, while the stereochemistry of C-2 also plays an important role. Further SAR studies of this family of natural products allowed the isolation of the precursor molecule, presaccharothriolide X (84), from a modified tryptophan-free culture of Saccharothrix sp. A1506. This molecule showed moderate activity against human fibrosarcoma HT1080 cells (IC₅₀ 12.3 μM) and fission yeast cells (IC₅₀ 89.2 μM). Then two approaches were used by this scientific group to increase the chemical diversity of saccharothriolides. First, the high reactivity of the precursors allowed the scientists to obtain five new semi-synthetic members, saccharothriolides G–K, which were generated using precursor-directed in situ synthesis by adding nucleophiles to the culture broth of Saccharothrix sp. A1506.^57,58 Second, the producer (Saccharothrix sp. A1506) was co-cultivated with the mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596, which can induce the production of cryptic metabolites in a broad range of Streptomyces strains by combined-culture. This approach led to the enhancement of saccharothriolide production and isolation of saccharothriolide C2 (85), a new C-2 epimer of saccharothriolide C. Unlike previous studies, the stereochemistry of C-2 did not affect the cytotoxicity in this case: neither saccharothriolide C1 nor its C-2 epimer saccharothriolide C2 (85) was cytotoxic even at 100 μM.⁵⁹

Neo-debromoaplysiatoxin C (86) was obtained from the marine cyanobacterium, Lyngbya sp. This compound contains a ten-membered lactone ring derived from debromoaplysiatoxin via a structural rearrangement. Neo-debromoaplysiatoxin C did not show cytotoxicity against PC-9 and HepG2 cell lines at 10 μM. Subsequently, Tang et al. (2019)⁶⁰ evaluated neo-debromoaplysiatoxin C (86) for its interactions with protein kinase C (PKC) and its effects on voltage-gated potassium channels, but the results indicated no significant effect in any of these assays.

Not only bacterial cultures are able to produce the structurally complex TMLs (Fig. 10). Another structural type of fungal lactones, along with simple lactones, is the 5/6/10-fused ring lactones. Three new natural products of this group, glabramycins A–C (87–89) were isolated from the fungus Neosartorya glabra by rational screening of antibiotics that target bacterial protein synthesis. Among the isolated compounds, glabramycin C (89) displayed the most potent antimicrobial activity; Streptococcus pneumoniae, S. aureus, and B. subtilis were the most sensitive at MICs of 2, 16, and 16 μg mL⁻¹, respectively. Interestingly, in additional mechanistic studies, glabramycin A (87) showed 2–3-fold preferential inhibition of RNA synthesis (IC₅₀ 10 μg mL⁻¹) compared with DNA and protein synthesis despite glabramycins being discovered in a protein inhibition assay.⁶¹ The relative configuration of glabramycins B and C was revised using DFT calculations of NMR chemical shifts and coupling constants⁶² and fully established after total synthesis.⁶³ Three new natural products, colletotrichalactones A–Ca (90–92), which possess a rare 5/6/10-fused tricyclic lactone skeleton, were isolated from Colletotrichum sp. JS-0361, an endophyte of Morus alba. It was shown that 92 was an artifact originating from the aldehyde form (colletotrichalactone C) in the solvents. These compounds are structurally related to complex TMLs described in previous reviews: colletofragarones A1 and A2 from Colletotrichum fragariae,⁶⁴ the previously mentioned glabramycins A–C,⁶¹ and dictyosphaeric acids A and B from Penicillium sp.⁶⁵ Compounds A (90) and Ca (92) displayed moderate cytotoxicity against MCF-7 cells with IC₅₀ 25.20 and 35.06 μM respectively.⁶⁶

Three new tricyclic (5/6/10) macrolides, colletoins A–C (93–95) (Fig. 11), were recently isolated from Colletotrichum sp. 13S020 during the search for natural inhibitors of mutant p53, which frequently occurs in cancer cells. Colletoin A (93) as well as previously known colletofragarone A2⁶⁴ was shown to inhibit the growth of Saos-2 (p53^R175H) cells (IC₅₀ values of 0.35 and 0.36 μM) and decrease mutant p53 in the cells.⁶⁷ Four structurally related compounds, shikinefragalides A–D (96–99) (Fig. 11), originated from the soil fungus Stachybotryaceae sp. FKI-9632. Shikinefragalides A (96) and B (97) displayed weak antimalarial and cytotoxic activities in vitro. None of the shikinefragalides showed antimicrobial activity.⁶⁸

The deep-sea derived fungus Phomopsis lithocarpus FS508 became the source of unique highly oxygenated tenellone-macrolide conjugated dimers, lithocarpins A–D (100–103) (Fig. 12),⁶⁹ which contains a humicolactone derivative as a ten-membered lactone core.⁷⁰ Lithocarpins C (102) and D (103) showed moderate inhibitory activity against three tumor cell lines (SF268 – human glioma cell line, MCF-7 – human breast adenocarcinoma cell line, HepG-2 – human liver hepatocellular carcinoma) with IC₅₀ values ranging from 17.0 to 21.6 μM.⁶⁹

Hypoxylide (104) (Fig. 13) was obtained from another endophytic fungus Annulohypoxylon sp., which was isolated from the Mangrove plant Rhizophora racemosa. This compound possesses a unique trihydroxynaphthalene-dione moiety fused to a ten-membered lactone ring. Liu et al. (2018)⁷¹ established the absolute configuration of the compound, and proposed a route for its biosynthesis, but the biological properties of this compound remained unexplored.⁷¹

3 Analysis of ten-membered lactones described for the entire period of study (1964–2022)

The search results for natural TMLs in the literature are summarized in Table S1 in the ESI,† which contains 214 natural TMLs described from to 1964–2022. A thorough analysis of this dataset revealed the main problems and common trends concerning the natural sources of TMLs, their structural types, biological activities, and the future prospects of these compounds. Moreover, some non-natural TMLs obtained by chemical synthesis,^72,73 non-enzymatic transformations,⁷⁴ precursor-directed in situ synthesis⁵⁷ (and other techniques that do not imply classic biosynthesis) have been documented in the literature. Such cases were not covered in this review, but this fact is worth mentioning. Interestingly, two natural TMLs from Chaetosphaeronema hispidulur⁴⁷ and Stagonospora cirsii¹⁵ coincidentally matched with previously described synthetic compounds.^75,76

3.1 Nomenclature of TMLs

The search for previously described TMLs in the literature is hampered by the historical lack of a uniform nomenclature, including the absence of a single name for this group of these natural products. According to the previous edition of the IUPAC rules, macrolides were called by the adding of “-olide” to the name of the hydrocarbon with the same number of carbon atoms as in the aliphatic acid forming the lactone core, and locants were added to define the position of ring closure (IUPAC, Rule C-472.2). This rule, in its various interpretations, gave rise to such names for TMLs as nonanolides,^2,26 nonenolides,^{5,15,19,23,35} decanolides.^1,18,45,77

Current IUPAC rules refer to lactones as heterocyclic pseudoketones,⁷⁸ so TMLs should be named as derivatives of oxecin-2-one.^5,20 Considering these nomenclature difficulties, the group name “ten-membered lactones” most unambiguously conveys the main structural feature of the compounds, described in different years. Therefore, when publishing new compounds of this group, we recommend applying the current IUPAC rules, but at the same time refer them to the TML group in order to facilitate the web search for these substances.

The trivial nomenclature of the TMLs is no less confusing. The intention of researchers to necessarily reflect the name of the producing organism in the trivial name of the lactone has led to many problems. Structurally similar TMLs belong to completely different families of natural products (Fig. 14). This tendency may seem common, but nevertheless for some natural compounds trivial names for similar structures continue to be assigned by the following letters of the alphabet, despite the fact that the root of a trivial name is no longer associated with new producers. For example, a new natural product isolated by Arayama et al. (2015)³⁸ from Helminthosporium velutinum TS28 was discovered to be an acylated analogue of achaetolide, a secondary metabolite of Achaetomium sp.⁷⁹ This new TML has been named achaetolide-II despite being isolated from a new producer. Interestingly, Sharma et al. (2018)²⁴ working on Diaporthe sp. metabolites noted the structural similarity of isolated compounds with xylarolide from Xylaria sp. 101,²³ but confusingly named the new compounds xylarolides A and B.²⁴ Some structures are duplicated in the literature and have several synonymic trivial names after each producer's name (for example, tuckolide = decarestrictine D, mueggelone = gloeolactone) (Table S1 in the ESI†). Moreover, the names of the TMLs originating from the same fungal genera turned out to be confusingly similar, so that the difference in names can be mistaken for a typo. Diaportheolide A (51) and diaportheolide B (60)³⁰ as well as diaportholides A and B²⁹ were isolated from different species of the genus Diaporthe. Different strains of Curvularia sp. are the sources of curvulides A, B1, B2⁸⁰ as well as curvulalide.⁸¹

3.2 Structural diversity of TMLs

The literature survey indicated that the most common subgroup of TMLs is simple lactones with a methyl substituent at the C-9 atom (35.8%). The alkyl chain in simple TMLs typically contains an odd number of carbon atoms, and the total proportion of simple lactones among the described TMLs is approximately 69%. The RALs and DALs subgroups are significantly smaller: 4.7 and 5.2%, respectively. The analysis of the formal group of “complex” TMLs allowed the division of it into smaller groups of structurally related compounds – derivatives of 5/6/10-fused ring (8.0%), nargenicin-type antibiotics (4.2%) and saccharothriolide-type TMLs (3.8%). The natural products that did not fall into any of the listed groups were categorized as “unique” (5.2%), including the aforementioned neo-debromoaplysiatoxin C (86), lithocarpins A–D (100–103) and hypoxylide (104) (Fig. 15).

It is worth mentioning several TMLs exhibit interesting structural features. The first described TML jasmine ketolactone contains an unusual 5/10-fused ring.⁸² Thiobiscephalosporolide A produced by Cephalosporium aphidicola is a dimeric TML consisting of two cephalosporolide A molecules joined by a sulfur bridge.⁸³ A chlorine-containing TML, (3Z,5S,6E,9S,10R)-8-chloro-5,9-dihydroxy-10-methyl-5,8,9,10-tetrahydro-2H-oxecin-2-one, has been described in Curvularia sp. 768 extract.⁸⁰ Phomolide C, isolated from Phomopsis sp. B27 includes a tetrahydropyran ring fused with a ten-membered lactone core.⁸⁴

3.3 Natural sources of TMLs

The first naturally occurring TML, jasmine ketolactone, was isolated in 1942 and its structure was elucidated in 1964.⁸² To date, this compound remains the only example of a plant secondary metabolite belonging to this group. Since 1964, approximately 214 TMLs have been isolated from various sources. The most of all described representatives of this class (84.0%) were derived from fungi, 9.2% were bacterial secondary metabolites, and 6.3% were isolated from animals (i.e. colonial tunicate,⁸⁵ sea urchins,²⁵ insects,^34,86 and frogs^12,13,87) (Fig. 16). The structural features of a TML are determined by its origin. RALs, DALs, 5/6/10-fused rings containing TMLs, and most of the unique and simple TMLs are produced by fungi. The scaffold of a typical simple fungal ten-membered lactone contains a lactone core with an alkyl substituent at C-9 (consisting of an uneven number of carbon atoms as a rule) supplemented with double bonds and oxygen groups in nearly all possible combinations. Exceptions are cytospolides from the endophytic fungus Cytospora sp. that possess a C-2 methyl group and xylarolide A obtained as a result of modified secondary metabolism in Diaporthe sp. TMLs isolated from other sources (animals, actinomycetes, and cyanobacteria) are often more structurally complex and/or possess alkyl/aryl moieties at positions C-2–C-8 or fused additional rings.

Some TMLs are more frequent throughout the fungal kingdom than others. Our literature survey indicated that modiolide A, cephalosporolide C, and 2-epi-herbarumin II seems to be the most common among micromycetes. Modiolide A was isolated from phylogenetically distant fungal species such as Paraphaeosphaeria sp. N-119,⁸⁸Periconia siamensis,⁸⁹Stagonospora cirsii,⁹⁰Curvularia sp. M12,⁹¹Curvularia sp. PSU-F22,⁸¹Paraconiothyrium sp. VK-13,^6,92 and Microsphaeropsis arundinis.⁹³ Cephalosporolide C was found in extracts obtained from cultures of closely related Cephalosporium aphidicola ACC 3490,⁹⁴Cordyceps militaris BCC 2816,⁹⁵ and Isaria fumosorosea ACCC 37775.⁹⁶ Considering the structural revision of cephalosporolide J and bassianolone proving their identity as cephalosporolide C, this compound can be also produced by Armillaria tabescens JNB-OZ344⁹⁷ and Beauveria bassiana.⁹⁸ One more TML, 2-epi-herbarumin II, also was isolated from the different species of pycnidia-forming fungi: Phoma bellidis,¹⁸Didymella pinodes,¹⁷Pestalotiopsis clavispora,⁹⁹ and Paraphaeosphaeria recurvifoliae.¹⁰⁰ Interestingly, decarestrictine J was discovered in not only Penicillium simplicissimum FH-A 6090,¹⁰¹ but also in bacteria Pseudoxanthomonas japonensis ZKB-2.¹⁰²

Several fungal genera seem to be more talented in the biosynthesis of TMLs than others. The literature survey revealed fungi from the genera Penicillium spp., and Cytospora spp. as well as so-called Phoma-like fungi (for instance, genera Phoma, Diaporthe, Stagonospora) to be the richest sources of TMLs (by number of described compounds) (Fig. 17). At the same time, the distribution of TML-producers in fungi (total of 77 strains) seems quite random (Fig. 18). The main fungal producers of TMLs belong to families Diaporthaceae (14.3%), Aspergillaceae (10.4%), Didymellaceae (6.5%), and Glomerellaceae (6.5%), but there are many cases when only one representative of the family was documented as a TML-producer (Physalacriaceae (Armillaria tabescens JNB-OZ344),⁹⁷Botryosphaeriaceae (Diplodia pinea IF0 6472),¹⁰³Corynesporascaceae (Corynespora cassiicola),⁵³ and others).

It is worth mentioning that Fig. 17 and 18 represent the taxonomy of the producing organisms, as it was identified in the corresponding publications. The correct identification of the producing strain is essential for further research on the isolated natural product, particularly, for the search for more productive strains and for re-isolation of the compound by other research groups.¹⁰⁴ This is a very important aspect considering the fact that most TMLs described in the literature were unique for producing fungal (or bacterial) strains. In most previous studies, the identification of microorganisms was based solely on morphology, for example, producers of decarestrictines Penicillium simplicissimum and P. corylophilum;¹⁰⁵Phoma herbarum, a first source of herbarumins I–III;^106,107Fusarium sp., a producer of fusanolides A and B,¹⁰⁸ and others. However, many fungal species are morphologically similar and hence discrimination of the species based on morphological criteria is challenging. In the past decades, taxonomic identification based on molecular phylogenetic analysis has come into use. The internal transcribed spacer rDNA regions (ITS) are widely sequenced as an official DNA barcode when discriminating between fungal species, including TML-producers.^18–20,69 However, ITS is not sufficiently robust to identify species in many fungal genera; therefore, the species-level identification using only one locus might also lead to incorrect identification. For instance, our efforts to isolate or even to find herbarumins^106,107 or bellidisins¹⁸ in cultures of Phoma herbarum and Ph. bellidis identified by morphological and molecular (ITS sequences) were unsuccessful (unpublished information). For precise species-level identification of different taxa (Didymellaceae, Phaeosphaeriaceae, Penicillium spp., Diaporthe spp.) the analysis of DNA sequence datasets is recommended.^109–113

3.4 Biosynthesis of TMLs

Obviously, the different structural styles of TMLs produced by fungi, bacteria, and animals are due to their typical biosynthetic routes in different organisms. However, information on the biosynthesis of TMLs is still very limited. The first attempts at biosynthetic studies of fungal simple TMLs were made in the mid-1980s when the polyketide biosynthesis pathway was demonstrated for achaetolide using the incorporation of ¹³C labeled acetates⁷⁹ (Fig. 19A). The beginning of the 1990s was marked by the study of the modular structure of polyketide synthase (PKS) required for erythromycin biosynthesis in Saccharopolyspora erythraea.¹¹⁴ This prompted Mayer and Thiericke (1993) to study the unusual oxygenation pattern in the decarestrictines family using incorporation experiments with precursors exhibiting the ¹⁸O-label.¹¹⁵ They showed the origin of these unusually located substituents from molecular oxygen, not from malonyl-CoA units, and assumed that the ten-membered precursor of decarestrictines undergoes subsequent post-PKS modifications, including reduction and epoxidation. Moreover, the authors deduced that the modular (domain) organization of PKS is involved in decarestrictines biosynthesis.¹¹⁶ Later, a similar study of aspinolides A and B also demonstrated the biogenesis of some oxygen atoms from an ¹⁸O-enriched atmosphere⁹ (Fig. 19B). The newly discovered potent antifungal activity of aspinolides enhanced the interest in their biosynthesis in T. arundinaceum. A recent study revealed two PKS genes (asp1 and asp2) that occur in both T. arundinaceum and A. ochraceus, producers of aspinolides. ASP2 is responsible for the formation of a ten-membered lactone ring, whereas ASP1 is required for the formation of a butenoyl substituent at position 8 of the lactone ring. The authors demonstrated that ASP1 and ASP2 belong to the group of reducing PKS (R-PKS) and suggested the biosynthetic route of aspinolides through the PKS step and post-PKS modifications as previously predicted¹¹⁶ (Fig. 19C). The present review provides information on different producers of the same TMLs (Table S1 in the ESI†), which can be included in similar biosynthetic studies using comparative genomics to identify common PKS genes that are involved in TMLs biosynthesis.

It is well known that RALs and DALs with a larger size of lactone ring (radicicol, zearalenone, dehydrocurvularin and others) are synthesized by non-reducing PKSs (NR-PKS) which utilize unusual starter units supplied directly by a R-PKS or highly-reducing PKS (HR-PKS).^117–120 The similar biosynthetic pathway involving at least two types of PKSs was suggested for hispidulactones in Chaetosphaeronema hispidulur.⁴⁷ Recently, Courtial et al. (2022)⁵² described the secondary metabolism cluster in A. dauci that is responsible for aldaulactone biosynthesis. It contains AdPKS7 and AdPKS8 encoding a R-PKS and a NR-PKS, respectively. The reduced triketide produced by AdPKS7 is used as a starter unit for AdPKS8 which elongates the nascent polyketide chain with four more malonyl-CoA units, catalyzes C3–C8 aldol condensation and the macrolactone cyclisation⁵² (Fig. 20). Thus, the biosynthesis of ten-membered RALs and DALs seems to follow the same pattern as for other benzenediol lactones.¹²⁰

Among TMLs from other sources, the biosynthesis of nargenicin-type antibiotics has been well studied in Nocardia sp.^121–123 The evolution of ideas about the biosynthesis of nargenicins and nodusmicins in actinobacteria is similar to that of aspinolides described above.^121,122 The most recent works demonstrated that three PKSs (NgnA–NgnC) are responsible for construction of a polyketide chain which then undergoes cyclization by a bispericyclase enzyme NgnD with the formation of a cis-decalin moiety and macrolactone core. The latter is further modified by diverse post-PKS tailoring enzymes which led to the production of nargenicin analogues.^123,124

The biosynthesis of TMLs in animals has not yet been studied in detail. Some compounds have been detected across unrelated species of Madagascar frogs,^12–14 which may indicate the conservation of the macrolide biosynthetic genes in this group of amphibians. Lactones found in these frogs include saturated and unsaturated compounds ranging in size between C-10 and C-16, varying in the degree and position of methyl groups, and appear to be derivatives of fatty acids or terpene biosynthetic pathways.¹³

3.5 Biological activity of TMLs

The random discovery of TMLs by scientific groups with various interests worldwide resulted in patchy information about their biological activity; and most compounds were tested for one activity type that could be quite specific (for example, inhibition of pine pollen germination¹⁰⁸ or osteoclast cell differentiation³⁹ (Table S1 in the ESI†)). Currently, 37.4% of all TMLs have been tested for only one type of activity. The activity of 14.5% of TMLs is still unknown, and only 14.5% of compounds have been assayed for more than three types of activity (Fig. 21).

New biological activities of previously known compounds are discovered each year due to their isolation from new producers, as well as emerging new challenges in medicine and plant protection. Masi et al. (2022)⁵ reported the antifungal activity of closely related TMLs available for this scientific group – pinolidoxin and epi-pinolidoxin from Didymella pinodes, its semi-synthetic derivative 7,8-O,O′-diacetylpinolidoxin, stagonolide C, modiolide A and stagonolide H isolated from Stagonospora cirsii. Modiolide A completely inhibited the growth of Cercospora nicotianae, pinolidoxin was able to inhibit the fungal growth by 75%, and the other compounds were inactive. Macrophomina phaseolina was sensitive only to pinolidoxin at 2.5 mM. It was recently shown that 8-O-acetylmultiplolide A isolated from Diaporthe sp. JC-J7 exhibited a lipid-lowering effect with an inhibition ratio of 24%.¹¹ The isolation of herbarumin I from Stagonospora cirsii at the biotechnological level (compared with that of the primary producer Phoma herbarum) allowed Dubovik et al. (2020)¹⁶ to test the herbicidal activity of this compound in pot experiments. T. arundinaceum was shown to be a new source of previously known aspinolides A–C,⁹ along with aspinolides D–G (8–11).¹⁰ When aspinolides A–C were first isolated from A. ochraceous, their biological activity remained unexplored.⁹ Malmierca et al. (2014)¹⁰ showed that aspinolide C inhibited the growth of B. cinerea and F. sporotrichioides with MIC 0.34 and 0.21 mg mL⁻¹, respectively, and showed a significant reduction in the tomato seedlings’ growth and in the number of lateral roots at concentration 50 μg mL⁻¹. Aspinolide B did not display antifungal activity but had a positive effect on the root architecture of tomato seedlings, without any negative effects on plant growth.

The COVID-19 pandemic starting in 2020 became the most challenging problem for medicine in the past decades and demanded the development of new therapeutic agents. In 2021 Padhi et al.¹²⁵ screened 415 natural (plant, bacterial and fungal) metabolites as selective inhibitors against the SARS-CoV-2. Seven compounds were predicted to have considerable absorption, metabolism, distribution, and excretion parameters as well as appropriate toxicity profiles. Notably, four of the seven selected compounds belonged to the TMLs family – putaminoxins A, B, D, and stagonolide K (9). Molecular docking studies showed that putaminoxin D seemed to be largely favorable for inhibiting the SARS-CoV-2 main protease and could be explored as a potential SARS-CoV-2 inhibitor.¹²⁵

3.6 Ecological role of TMLs

The different origins, structural features, and biological activities of TMLs indicate the different possible ecological roles of these compounds. The TML-producing fungi belong to different ecological groups, including phyto- and entomopathogens, endophytes of terrestrial and aquatic plants, and saprotrophs from soil and marine sediments (Fig. 22). Phytopathogenic fungi are the main source of phytotoxic TMLs,^{51,90,106,126,127} and some of them probably play an important role in pathogenesis. Nevertheless, the relationship between phytotoxin production and the aggressiveness of the pathogen to the host-plant was demonstrated only for aldaulactone (74), its producer A. dauci, and carrot as the host-plant. Notably, carrot resistance to leaf blight involves mechanisms of resistance to aldaulactone.⁵¹ Most phytotoxic TMLs are non-specific (pinolidoxin,¹⁷ stagonolide A,¹²⁶ and herbarumin I¹⁶), but some compounds are more toxic to the host than to other plants, for example, putaminoxin produced by Phoma putaminum, a pathogen of Erigeron annuus,¹²⁷ and stagonolide H isolated from Stagonospora cirsii C-163, a pathogen of Canada thistle.⁹⁰ The roles of these phytotoxins in corresponding plant diseases should be explored in the future.

Several antifungal TMLs originated from antagonistic Trichoderma spp. (cremenolide (7) and aspinolides). Thus, these compounds may play a role in the environmental interactions of Trichoderma spp. as beneficial microbes with plants and phytopathogenic microorganisms. A possible ecological role for truncatenolide (1) and pinolidoxin in C. truncatum and Ascochyta pinodes respectively is as a “chemical weapon” in a competitive fight for the host plant with other phytopathogenic fungi.⁵

Interestingly, cephalosporolide C was detected mainly in entomopathogenic fungi (Cephalosporium aphidicola ACC 3490,⁹⁴Cordyceps militaris BCC 2816,⁹⁵Isaria fumosorosea ACCC 37775,⁹⁶ and Beauveria bassiana⁹⁸). The ecological role of this TML has not been studied, but it may be associated with the TMLs’ specialized ecological niche considering the fact that some TMLs of insect origin are described.^12,34,86,87

The volatile TMLs discovered in femoral glands of frogs (15–17, phoracantholide J) might act as pheromones and play a role in intraspecific communication, although their exact function is currently unknown. According to Poth et al. (2012),⁸⁷ males showed a higher activity when exposed to phoracantholide J compared to control. (5Z,9S)-Tetradec-5-en-9-olide (54) did not affected the behavior of termites, but was supposed to play the role of a queen primer pheromone, arresting the sexual maturation of other females under the presence of fertile queens.³⁴

3.7 Chemical synthesis of TMLs

In the case when the potent compound is unavailable as a natural product, it is rational to develop a scheme for its chemical synthesis. Some TMLs can be obtained by total synthesis,^77,128–130 but the synthetic studies usually do not consider the biological activity of the products and do not enrich the data about its biological activity. The main synthetic approaches used to construct different TMLs were described in the previous reviews by Dräger et al. (1996)¹ and Sun et al. (2012).² The synthesis of the lactone core in TML is not straightforward and is frequently more difficult to achieve than that of other macrocyclic lactones. The synthesis is also complicated by the presence of several chiral centers in molecules of interest. Most of the proposed synthetic schemes do not imply the obtaining of TMLs on an industrial scale, but total synthesis often makes it possible to unambiguously determine their absolute configuration. B. Schmidt in 2021 published a comprehensive survey summarizing the most prominent cases of revised relative and absolute configurations of TMLs as a result of total synthesis.⁴⁵

The most challenging task is to elucidate the relative and absolute configurations of TMLs that possess complicated structures and originated from poorly identified producers. The re-isolation of such compounds from other sources is pure chance. Achaetolide was described in 1983 as a metabolite of Achaetomium cristalliferum⁷⁹ and its relative and absolute configuration remained unknown until 2009, when this TML was isolated from Ophiobolus sp.¹³¹ Interestingly, the next year (in 2010) the absolute configuration of achaetolide was confirmed by total synthesis,¹³² so both approaches have been used in that case. In contrast, the relative configuration of six stereocenters in phomol (53) isolated from Phomopsis sp. E02018 is still unknown, despite its interesting in vivo anti-inflammatory activity.³³ Thus, many TMLs have yet to be re-isolated or synthesized to provide a complete description of their structure and/or biological activity.

3.8 Structure–activity relationships of TMLs

The intriguing biological activities of the members of this class are obviously closely related to their structures. However, the insufficient information about biological activity mentioned above makes structure–activity relationships (SAR) analysis challenging within this class using literature data. Currently, there are only a few publications in which the authors try to explain the manifestation of activity with the structural features of isolated TMLs, and most of these studies are devoted to phytotoxins. Evidente et al. (2008) proposed that the C-2–C-4 moiety of the lactone ring induces a decrease or total loss of phytotoxic activity in the examples of stagonolides and herbarumins.¹³³ Furthermore, an n-propyl group in phytotoxic TMLs, instead of a methyl group, also appears to be an important structural feature to manifest activity. In continuation of this research Berestetskiy et al. (2008)⁷³ tested the phytotoxic activity of three natural and two semisynthetic TMLs and revealed that the functional groups and conformational freedom of the lactone core appear to be important structural features for phytotoxicity. Semisynthesis was also used for the enlargement of compounds library by Dalinova et al. (2021).⁷² Eleven natural and semisynthetic TMLs differing from each other in the C-7–C-9 region in the lactone ring were tested in different bioassays for target (phytotoxic) and non-target activity. The results of their studies showed that the oxidation of the C-7 hydroxyl group to carbonyl led to an increase in non-selective toxicity in all used bioassays for phytotoxicity, cytotoxicity, and antimicrobial activity, regardless of the configuration of the C-9 propyl chain.⁷² Some phytotoxicity issues of TMLs were reviewed by Cimmino et al. (2015),¹³⁴ Evidente et al. (2019),¹³⁵ and Evidente (2022).³ In contrast, there are practically no targeted studies on SAR analysis for other types of activity. For example, Lu et al. (2011)^26,27 discussed the possible SAR of cytospolides (34–49) and stated that the configuration of C-2 is important for cytotoxic activity. Among the family of bellidisins (27, 28, 50) and co-isolated compounds from Phoma bellidis, the 4S,5S-4,5-epoxyhexenoyl group in the ester moiety of bellidisin D (28) is probably the key pharmacophore for its cytotoxicity.¹⁸ Koike et al. (2022) discussed the SAR of TMLs containing a 5/6/10-fused ring system and concluded that the α,β-unsaturated carbonyl group in their six-membered ring is essential for their activity.⁶⁸ Lu et al. in 2015–2019 studied the relationships between the cytotoxicity and structure of saccharothriolides A–F and related compounds obtained by different biotechnological approaches from Saccharothrix sp. A1506.^55–59 The aforementioned examples of SAR observations are often limited to compounds isolated from one fungal culture, and do not imply the involvement of structurally related compounds from other sources.

4 Conclusion

The present review demonstrates the growing interest in biological activities, producers, biosynthesis, structure–activity relationships, and other issues concerning TMLs. It is a relatively large group of natural products and it deserves a closer and more detailed study. In the near future, complex studies of TMLs will expand the possible areas of their application. Currently, approximately 214 diverse natural TMLs are known, and regularly scientists worldwide continue to discover and describe new members of this class of compounds. Many of them have promising biological properties, but several factors prevent their full and comprehensive study. The controversial nomenclature of TMLs, incorrect or erroneous structure elucidation, poor identification of producing fungi, and scattered information on the biological activity of compounds – all these factors have led to problems with rapid dereplication and the search for structurally related natural products. Complete information (for instance, exactly identified producers, absolute configuration, and biological activity) about members of this intriguing class of natural compounds is critical for further understanding their ecological roles and practical implications.

5 Abbreviations

DAL	Dihydroxyphenylacetic acid lactone
RAL	Resorcylic acid lactone
SAR	Structure–activity relationships
TML	Ten-membered lactone

6 Author contributions

All authors conceived the idea for this review. AD and VD contributed equally to the writing of the first draft. AB made critical revisions to subsequent drafts. All authors made substantial contributions to the final draft.

7 Conflicts of interest

The authors have no conflicts of interest to declare.

8 Acknowledgements

This work was supported by the Russian Science Foundation, grant number 22-16-00038.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3np00013c

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