In the class of polyene macrolides, there is a subgroup of aromatic heptaenes, which exhibit the highest antifungal activity within this type of antibiotics. Yet, due to their complex nature, aromatic heptaenes were not extensively studied and their potential as drugs is currently underexploited. Moreover, there are many inconsistencies in the literature regarding the composition and the structures of the individual components of the aromatic heptaene complexes. Inspired by one of such cases, herein we conducted the analytical studies on ascosin, candicidin and levorin using HPLC-DAD-(ESI)Q-TOF techniques. The resulting chromatograms and the molecular masses of the individual components of these three complexes strongly indicated that the major components of ascosin, candicidin and levorin are structurally identical. In order to validate these results, the main component of previously structurally uncharacterized ascosin was derivatized, isolated and subjected to 2D NMR studies. The resulting structure of the ascosin’s main component, herein named ascosin A2, was shown to be identical with the earlier reported structures of the main components of candicidin and levorin complexes: candicidin D and levorin A2. In the end, all the structural knowledge regarding these three antibiotic complexes was gathered, systematized and completed, and the new nomenclature was proposed.

The aim of the study was to present the fingerprint of different Lepidium peruvianum tuber extracts showing glucosinolates-containing substances possibly playing an important role in preventinting dementia and other memory disorders. Different phenotypes of Lepidium peruvianum (Brassicaceae) tubers were analysed for their glucosinolate profile using a liquid chromatograph coupled with mass spectrometer (HPLC-ESI-QTOF-MS/MS platform). Qualitative analysis in 50% ethanolic extracts confirmed the presence of ten compounds: aliphatic, indolyl, and aromatic glucosinolates, with glucotropaeolin being the leading one, detected at levels between 0–1.57% depending on phenotype, size, processing, and collection site. The PCA analysis showed important variations in glucosinolate content between the samples and different ratios of the detected compounds. Applied in vitro activity tests confirmed inhibitory properties of extracts and single glucosinolates against acetylcholinesterase (AChE) (15.3–28.9% for the extracts and 55.95–57.60% for individual compounds) and butyrylcholinesterase (BuChE) (71.3–77.2% for the extracts and 36.2–39.9% for individual compounds). The molecular basis for the activity of glucosinolates was explained through molecular docking studies showing that the tested metabolites interacted with tryptophan and histidine residues of the enzymes, most likely blocking their active catalytic side. Based on the obtained results and described mechanism of action, it could be concluded that glucosinolates exhibit inhibitory properties against two cholinesterases present in the synaptic cleft, which indicates that selected phenotypes of L. peruvianum tubers cultivated under well-defined environmental and ecological conditions may present a valuable plant material to be considered for the development of therapeutic products with memory-stimulating properties.

Illumination of the aromatic heptaene macrolide antifungal antibiotic candicicin D with UV light results in an isomerization of the molecule. The product formed after irradiation of the candicidin complex with UV light (λ = 365 nm), namely, iso-candicidin D, was isolated and subjected to 2D NMR studies, consisting of DQF-COSY, ROESY, TOCSY, HSQC, and HMBC experiments. The obtained spectral data unambiguously evidenced that iso-candicidin D was the all-trans isomer of the native antibiotic, and straightening of the heptaenic chromophore was the only light-induced structural change that occurred. Hence, iso-candicidin D was proclaimed to be a prototype of a novel class of polyene macrolide antifungal antibiotics: the all-trans aromatic heptaenes, containing a macrolide ring similar to that of amphotericin B.

Triazoloacridinone C-1305, a potent antitumor agent recommended for Phase I clinical trials, exhibits high activity towards a wide range of experimental colon carcinomas, in many cases associated with complete tumor regression. C-1305 is a well-established dsDNA intercalator, yet no information on its mode of binding into DNA is available to date. Herein, we present the NMR-driven and MD-refined reconstruction of the 3D structures of the d(CGA TAT CG) 2 :C-1305 and d(CCC TAG GG) 2 :C-1305 non-covalent adducts. In both cases, the ligand intercalates at the TA/TA site, forming well-defined dsDNA:drug 1:1 mol/mol complexes. Orientation of the ligand within the binding site was unambiguously established by the DNA/ligand proton-proton NOE contacts. A subsequent, NMR-driven study of the sequence-specificity of C-1305 using a series of DNA duplexes, allowed us to confirm a strong preference towards TA/TA dinucleotide steps, followed by the TG/CA steps. Interestingly, no interaction at all was observed with duplexes containing exclusively the AT/AT, GG/ cc and GA/tc steps. DNA-directed, rational antineoplastic agent development has made an extensive use of the acridine pharmacophore 1. Among many diverse families of acridine derivatives, development of a series of novel triazoloacridinones with potent antitumor activities has been started some time ago 2. The most active triazoloacridinone derivative obtained to date, 5-[[3-(dimethylamino)propyl]amino]-8-hydroxy-6H-v-triazolo[4,5,1-de] acridin-6-one, codenamed C-1305 (Fig. 1), showed high antitumor activity towards a wide range of different experimental tumors in vitro and in vivo, including both murine and human colon carcinomas, which in most cases was associated with complete tumor regression 3. Induction of apoptosis in human leukemia cells after uptake of C-1305 has also been demonstrated 4,5. Its interaction with several molecular targets 6,7 , as well as its metabolism 8-10 , were extensively studied. For instance, this compound was shown to be a topoisomerase II poison, which stabilizes unusually toxic covalent complexes between DNA and the enzyme 11. It was also demonstrated that C-1305 is a viable double stranded DNA (dsDNA) intercalator, yet no sequence-specificity of this potential drug was revealed since UV, CD and ELD studies have shown that it intercalated into ctDNA, p(dAdT) 2 and p(dGdC) 2 polymers at the same ratio 12. Moreover, chemical probing with DEPC, combined with molecular modelling studies suggested that C-1305 is able to induce substantial distortions of a dsDNA duplex while intercalating into the GGG triplets, which is a unique effect among the known topoisomerase II inhibitors.

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