Search Results (55)

This study aimed to monitor the biomechanical development of an artistic swimming duet across a macrocycle through an individualised training approach. Two swimmers (17.5 ± 0.5 years), members of the Los Angeles 2028 National Olympic Project, were assessed in December 2023 (M1) and April 2024 (M2), corresponding to the beginning and the end of the macrocycle. Maximal (Fmax) and mean (Fmean) force in the prone sculling and kick pull action were measured using a 20 s tethered test. Split velocity (vSplit) was assessed in free format based on video recording. Dry-land strength included assessments of internal (IR) and external (ER) shoulder rotation strength of the dominant (D) and non-dominant (ND) limbs, and countermovement jump (CMJ) power. The standard duet choreography was analysed in competition at both time points. Percentage variation (∆%) between swimmers was calculated for M1 vs. M2. Results showed convergence (M1 vs. M2) in Fmean of the sculling (21.6% vs. 9.9%) and kick pull (45.1% vs. 29.1%), accompanied by greater similarity in vSplit (15.9% vs. 15.5%). Further convergence was observed in IR_ND (33.7% vs. 13.9%), ER_D (11.6% vs. 4.4%) and CMJ (7.4% vs. 3.6%). The duet’s competition score increased from 168.9943 to 190.7183 points. It can be concluded that individualised training was useful for the duet to become more homogeneous in in-water strength, in-water kinematics and dryland strength, resulting in improved competitive performance. Full article

Anthelmintic resistance (AR) in gastrointestinal nematodes is a growing global concern that threatens effective parasite control in livestock farming. This study aimed to assess gastrointestinal nematode (GIN) control practices and identify risk factors associated with AR development on Lithuanian sheep farms. A cross-sectional survey was conducted between 2022 and 2023 among 71 members of the Lithuanian Sheep Breeders Association, covering farm management, grazing, and deworming practices. Anthelmintics were used by 90.2% of farmers, with most treating their flocks twice a year. Only 18.3% of farmers performed parasitological testing to guide treatments, with significantly more organic farms applying this approach than traditional farms. Treatment frequencies were significantly higher in traditional farms. Most farmers (45.1%) relied on the visual appraisal of sheep weight for dosing, while 35.2% dosed according to the weight of a medium-sized animal. Macrocyclic lactones were the most commonly used anthelmintics (50.7%). Quarantine procedures for new animals were implemented by less than half of the farmers (44.4%), while others treated without isolation (56.6%). These findings indicate reliance on non-strategic parasite control methods and limited use of diagnostics, highlighting the need for improved farmer education to promote sustainable parasite control and reduce AR risk in Lithuanian sheep farms. Full article

The reaction of bipyridine 3,7-di(3-pyridyl)-1,5-dioxa-3,7-diazacyclooctane (L) with copper thiocyanate produces a discrete metallamacrocycle [Cu(L)(SCN)₂(DMF)]₂ (1). In complex 1, two cis-coordinated ligands combine with two copper ions to form an unabridged 24-membered macrocycle. Each copper ion is five-coordinated with two nitrogens from separate ligands, two nitrogens from thiocyanates and one oxygen from the dimethylformamide (DMF) solvent. Complex 1 has been characterized using single-crystal X-ray diffraction, optical and thermal analyses and antimicrobial activity measurements. The solid electron paramagnetic resonance (EPR) analysis of complex 1 yielded a characteristic structural g factor value of 2.147. In addition, the thermal analysis established that the complex is thermally stable at up to 176 °C. The antimicrobial activity measurements demonstrated that both the ligand and complex 1 exhibit an inhibitory effect on two strains, where the complex exhibits a significantly greater inhibition relative to that of the free ligand (p < 0.05). Full article

Signal-dependent transport into and out of the nucleus mediated by members of the importin (IMP) superfamily is crucial for eukaryotic function, with inhibitors targeting IMPα being of key interest as anti-infectious agents, including against the apicomplexan Plasmodium species and Toxoplasma gondii, causative agents of malaria and toxoplasmosis, respectively. We recently showed that the FDA-approved macrocyclic lactone ivermectin, as well as several other different small molecule inhibitors, can specifically bind to and inhibit P. falciparum and T. gondii IMPα functions, as well as limit parasite growth. Here we focus on the FDA-approved antiparasitic moxidectin, a structural analogue of ivermectin, for its IMPα-targeting and anti-apicomplexan properties for the first time. We use circular dichroism and intrinsic tryptophan fluorescence measurements to show that moxidectin can bind directly to apicomplexan IMPαs, thereby inhibiting their key binding functions at low μM concentrations, as well as possessing anti-parasitic activity against P. falciparum in culture. The results imply a class effect in terms of IMPα’s ability to be targeted by macrocyclic lactone compounds. Importantly, in the face of rising global emergence of resistance to approved anti-parasitic agents, the findings highlight the potential of moxidectin and possibly other macrocyclic lactone compounds as antimalarial agents. Full article

Macrocycles bridge the gap between conventional small molecules and polymers. Drawing inspiration from successful carbon heteroatom-containing macrocycles, peroxide-containing macrocycles are gaining attention for enhanced bioactivity, potential chelating properties, and applications in energetic materials. This review presents the following strategies for the construction of cyclic peroxides with 10- to 36-membered frameworks: (1) the intramolecular iodocyclization of hydroperoxides, (2) the intermolecular cyclization of hydroperoxides with alkyl dihalides or carbonyls, (3) the acid-catalyzed rearrangements of ozonides or 11-membered cyclic triperoxides via oxy- or peroxycarbenium ions, and (4) the peroxidation of carbonyls targeting macrocyclic peroxides. The specific agents that allow for the selective construction of the medium and large cycles are also analyzed. Full article

Using quantum chemical calculation data obtained by the DFT method with the B3PW91/TZVP and M062X/def2TZVP theory levels, the possibility of the existence of four Be(II) coordination compounds, each of which contains in the inner coordination sphere and the double deprotonated forms of subporphyrazine (H₂SP), mono[benzo]subporphyrazine (H₂MBSP), di[benzo]subporphyrazine (H₂DBSP), and tri[benzo]subporphyrazine (subphthalocyanine) (H₂TBSP) with a ratio Be(II) ion/ligand = 1:1, were examined Selected geometric parameters of the molecular structures of these (666)macrotricyclic complexes with closed contours are given; it was noted that BeN3 chelate nodes have a trigonal–pyramidal structure and exhibit a very significant (almost 30°) deviation from coplanarity; however, all three 6-membered metal-chelate and three 5-membered non-chelate rings in each of these compounds are practically planar and deviate from coplanarity by no more than 2.5°. The bond angles between two nitrogen atoms and a Be atom are equal to 60° (in the [BeSP] and [BeTBSP]) or less by no more than 0.5° (in the [BeMBSP] and [BeDBSP]). The presence of annulated benzo groups has little effect on the parameters of the molecular structures of these complexes. Good agreement between the structural data obtained using the above two versions of the DFT method was noticed. NBO analysis data for these complexes are presented; it was noted that, according to both DFT methods used, the ground state of the each of complexes under study is a spin singlet. Standard thermodynamic parameters of formation (standard enthalpy Δ_fH⁰, entropy S⁰, and Gibbs free energy Δ_fG⁰) for the above-mentioned macrocyclic compounds were calculated. Full article

Hexaazamacrocyclic Schiff bases have been extensively combined with lanthanoid (Ln) ions to obtain complexes with a highly axial geometry. However, the use of flexible hexaazatetraamine macrocycles containing two pyridines and acyclic spacers is rather uncommon. Accordingly, we obtained [DyL(OAc)₂]OAc·7H₂O·EtOH and [DyL^Me2(Cl)₂]Cl·2H₂O, where L and L^Me2 are the 18-membered macrocycles 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane and 3,10-dimethyl-3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane, respectively, which contain ethylene and methylethylene spacers between their N₃ moieties. [DyL(OAc)₂]OAc·7H₂O·EtOH represents the first crystallographically characterized lanthanoid complex of L, while [DyL^Me2(Cl)₂]Cl·2H₂O contributes to increasing the scarce number of Ln^III compounds containing L^Me2. Furthermore, the crystal structure of L·12H₂O was solved, and it was compared with those of other related macrocycles previously published. Likewise, the crystal structures of the Dy^III complexes were compared with those of the lanthanoid and d-metal complexes of other 18-membered N₆ donor macrocycles. This comparison showed some effect of the spacers employed, as well as the influence of the size of the ancillary ligands and the metal ion. Additionally, the distinct folding behaviors of these macrocycles influenced their coordination geometries. Moreover, the luminescent properties of [DyL(OAc)₂]OAc·7H₂O·EtOH and [DyL^Me2(Cl)₂]Cl·2H₂O were also investigated, showing that both complexes are fluorescent, with the emission being sensitized by the ligands. Full article

Cobalt(III) compounds with tetradentate ligands have been widely employed to deliver cytotoxic and imaging agents into cells. A large body of work has focused on using cobalt(III)–cyclam scaffolds for this purpose. Here, we investigate the cytotoxic properties of cobalt(III) complexes containing 14-membered macrocycles related to cyclam. A breast cancer stem cell (CSC) in vitro model was used to gauge efficacy. Specifically, [Co(1,4,7,11-tetraazacyclotetradecane)Cl₂]⁺ (1) and [Co(1-oxa-4,8,12-triazacyclotetradecane)Cl₂]⁺ (2) were synthesised and characterised, and their breast CSC activity was determined. The cobalt(III) complexes 1 and 2 displayed micromolar potency towards bulk breast cancer cells and breast CSCs grown in monolayers. Notably, 1 and 2 displayed selective potency towards breast CSCs over bulk breast cancer cells (up to 4.5-fold), which was similar to salinomycin (an established breast CSC-selective agent). The cobalt(III) complexes 1 and 2 were also able to inhibit mammosphere formation at low micromolar doses (with respect to size and number). The mammopshere inhibitory effect of 2 was similar to that of salinomycin. Our studies show that cobalt(III) complexes with 1,4,7,11-tetraazacyclotetradecane and 1-oxa-4,8,12-triazacyclotetradecane macrocycles could be useful starting points for the development of new cobalt-based delivery systems that can transport cytotoxic and imaging agents into breast CSCs. Full article

A Sonogashira coupling of meta-iodocalix[4]arene with various terminal acetylenes confirmed that the meta position of calixarene is well addressable, and that both thermal and microwave protocols led to good yields of alkynylcalixarenes. Alkynes thus obtained were subjected to the ferric chloride and diphenyl diselenide-promoted electrophilic closure. It turns out that the calix[4]arenes give completely different bridging products than those described for the non-macrocyclic starting compounds. This can be demonstrated not only by the isolation of products with a six-membered ring (6-exo-dig), but mainly by the smooth formation of the 5-endo-dig cyclization, which has never been observed in the aliphatic series. An attempt at electrocyclization led to a high yield of the 1,2-diketone (oxidation of the starting alkyne), again in contrast to the reaction described for the acyclic derivatives. The structures of the unexpected products were unequivocally established by X-ray analysis and clearly demonstrate how the preorganized macrocyclic skeleton favors a completely different regioselectivity of cyclization reactions compared to common aliphatic compounds. Full article

Ascomylactam C (AsC) is a new 13-membered-ring macrocyclic alkaloid, which was first isolated and identified in 2019 from the secondary metabolites of the mangrove endophytic fungus Didymella sp. CYSK-4 in the South China Sea. AsC has been found to have a broad-spectrum cytotoxic activity. However, the antitumor effects in vivo and mechanisms of AsC remain unclear. The aim of this study was to describe the effects of AsC on lung cancer and melanoma cells and to explore the antitumor molecular mechanism of AsC. In vitro, we used plate colony formation experiments and demonstrated the ability of AsC to inhibit low-density tumor growth. An Annexin V/PI cell apoptosis detection experiment revealed that AsC induced tumor cell apoptosis. In vivo, AsC suppressed the tumor growth of LLC and B16F10 allograft significantly in mice, and promoted the infiltration of CD4⁺ T and CD8⁺ T cells in tumor tissues. Mechanistically, by analyses of Western blotting, immunofluorescence and ELISA analysis, we found that AsC increased ROS formation, induced endoplasmic reticulum (ER) stress, activated the protein kinase RNA-like ER kinase (PERK)/eukaryotic translation initiation factor (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) signaling pathway, and induced immunogenic cell death (ICD) of tumor cells. Our results suggest that AsC may be a potentially promising antitumor drug candidate. Full article

Due to the different crystallization methods, two Hg(II) complexes of a 19-membered NO₂S₂-macrocycle (L) and its oxidized ligand (HL_ox), exhibiting different stoichiometries, were prepared. First, mercury(II) iodide reacts with L to afford a dinuclear metallacycle complex [Hg₂(L)₂I₄] (1) in which the mercury(II) exists outside the macrocyclic cavity. Meanwhile, the slow diffusion reaction gave an unusual pseudo-square planar-induced mercury(II) complex, which shows three separated parts with the formula [Hg₂(HL_ox)I₅]₂[HgI₂] (2). There are two complex cation units that are exo-coordinated, along with one unit consisting of a metal cluster anion. Surprisingly, L was oxidized in the disulfoxidized form (HL_ox) in this condition. NMR titration was used to monitor both the structural and binding characteristics of the complex formed between L and mercury(II) iodide in a solution. Full article

Avermectins are a group of macrocyclic lactones that are commonly used as pesticides to treat pests and parasitic worms. Some members of the avermectin family, such as ivermectin, have been found to exhibit anti-proliferative activity toward cancer cells. This study aimed to investigate the potential anti-cancer activities of avermectin B1a using the HCT-116 colon cancer cell line. The MTT assay was used to calculate the IC₅₀ by incubating cells with increasing doses of avermectin B1a for 24, 48, and 72 h. Flow cytometry was used to evaluate apoptosis following the 24 h incubation of cells. The migration capacity of the HCT-116 cells in the absence or presence of avermectin B1a was also investigated. Finally, tubulin polymerization in the presence of avermectin B1a was evaluated. Avermectin B1a presented anti-proliferative activity with an IC₅₀ value of 30 μM. Avermectin B1a was found to promote tubulin polymerization at 30 μM. In addition, avermectin B1a induced apoptosis in HCT-116 cells and substantially diminished their ability to migrate. Avermectin B1a exhibits significant anti-cancer activity and enhances tubulin polymerization, suggesting that it can be used as a promising microtubule-targeting agent for the development of future anticancer drugs. Full article

Avermectins (AVMs), a family of 16-membered macrocyclic macrolides produced by Streptomyces avermitilis, have been the most successful microbial natural antiparasitic agents in recent decades. Doramectin, an AVM derivative produced by S. avermitilis bkd⁻ mutants through cyclohexanecarboxylic acid (CHC) feeding, was commercialized as a veterinary antiparasitic drug by Pfizer Inc. Our previous results show that the production of avermectin and actinorhodin was affected by several other polyketide biosynthetic gene clusters in S. avermitilis and Streptomyces coelicolor, respectively. Thus, here, we propose a rational strategy to improve doramectin production via the termination of competing polyketide biosynthetic pathways combined with the overexpression of CoA ligase, providing precursors for polyketide biosynthesis. fadD17, an annotated putative cyclohex-1-ene-1-carboxylate:CoA ligase-encoding gene, was proven to be involved in the biosynthesis of doramectin. By sequentially removing three PKS (polyketide synthase) gene clusters and overexpressing FadD17 in the strain DM203, the resulting strain DM223 produced approximately 723 mg/L of doramectin in flasks, which was approximately 260% that of the original strain DM203 (approximately 280 mg/L). To summarize, our work demonstrates a novel viable approach to engineer doramectin overproducers, which might contribute to the reduction in the cost of this valuable compound in the future. Full article

A reaction of acyl chlorides derived from 1,10-phenanthroline-2,9-dicarboxylic acids with piperazine allows the preparation of the corresponding 24-membered macrocycles in good yield. The structural and spectral properties of these new macrocyclic ligands were thoroughly investigated, revealing promising coordination properties towards f-elements (Am, Eu). It was shown that the prepared ligands can be used for selective extraction of Am(III) from alkaline–carbonate media in presence of Eu(III) with an SF_Am/Eu up to 40. Their extraction efficiency is higher than calixarene-type extraction of the Am(III) and Eu(III) pair. Composition of macrocycle–metal complex with Eu(III) was investigated by luminescence and UV-vis spectroscopy. The possibility of such ligands to form complexes of L:Eu = 1:2 stoichiometry is revealed. Full article

The reaction of mer-(Ru(H)₂(CO)(PPh₃)₃) (1) with one equivalent of thymine acetic acid (THAcH) unexpectedly produces the macrocyclic dimer k¹(O), k²(N,O)-(Ru(CO)(PPh₃)₂THAc)₂ (4) and, concomitantly, the doubly coordinated species k¹(O), k²(O,O)-(Ru(CO)(PPh₃)₂THAc) (5). The reaction promptly forms a complicated mixture of Ru-coordinated mononuclear species. With the aim of shedding some light in this context, two plausible reaction paths were proposed by attributing the isolated or spectroscopically intercepted intermediates on the basis of DFT-calculated energetic considerations. The cleavage of the sterically demanding equatorial phosphine in the mer-species releases enough energy to enable self-aggregation, producing the stable, symmetric 14-membered binuclear macrocycle of 4. The k¹-acetate iminol (C=N-OH) unit of the mer-tautomer k¹(O)-(Ru(CO)(PPh₃)₂(THAc)) (2) likely exhibits a stronger nucleophilic aptitude than the prevalent N(H)-C(O) amido species, thus accomplishing extra stabilization through concomitant k²(N,O)-thymine heteroleptic side-chelation. Furthermore, both the ESI-Ms and IR simulation spectra validated the related dimeric arrangement in solution, in agreement with the X-ray determination of the structure. The latter showed tautomerization to the iminol form. The ¹H NMR spectra in chlorinated solvents of the kinetic mixture showed the simultaneous presence of 4 and the doubly coordinated 5, in rather similar amounts. THAcH added in excess preferentially reacts with 2 or trans-k²(O,O)-(RuH(CO)(PPh₃)₂THAc) (3) rather than attacking the starting Complex 1, promptly forming the species of 5. The proposed reaction paths were inferred by spectroscopically monitoring the intermediate species, for which the results were strongly dependent on the of conditions the reaction (stoichiometry, solvent polarity, time, and the concentration of the mixture). The selected mechanism proved to be more reliable, due to the final dimeric product stereochemistry. Full article