Members of a novel class of anticancer compounds, exhibiting high antitumor activity, i.e. the unsymmetrical bisacridines (UAs), consist of two heteroaromatic ring systems. One of the ring systems is an imidazoacridinone moiety, with the skeleton identical to the structural base of Symadex. The second one is a 1-nitroacridine moiety, hence it may be regarded as Nitracrine’s structural basis. These monoacridine units are connected by an aminoalkyl linker, which vary in structure. In theory, these unsymmetrical dimers should act as double-stranded DNA (dsDNA) bis-intercalators, since the monomeric units constituting the UAs were previously reported to exhibit an intercalating mode of binding into dsDNA. On the contrary, our earlier, preliminary studies have suggested that specific and/or structurally well-defined binding of UAs into DNA duplexes might not be the case. In this contribution, we have revisited and carefully examined the dsDNA-binding properties of monoacridines C-1305, C-1311 (Symadex), C-283 (Ledakrin/Nitracrine) and C-1748, as well as bisacridines C-2028, C-2041, C-2045 and C-2053 using advanced NMR techniques, aided by molecular modelling calculations and the analysis of UV–VIS spectra, decomposed by chemometric techniques. These studies allowed us to explain, why the properties of UAs are not a simple sum of the features exhibited by the acridine monomers.

Lepidium peruvianum—an edible herbaceous biennial plant distributed in the Andes—has been used for centuries as food and as a natural medicine in treating hormonal disorders, as an antidepressant, and as an anti-osteoporotic agent. The presented study aims to prove its beneficial cosmetic and chemopreventive properties by testing the antiradical, whitening, cytotoxic, and anticancer properties of differently colored phenotypes that were extracted using three solvents: methanol, water, and chloroform, with the help of the chemometric approach to provide evidence on the impact of single glucosinolanes (seven identified compounds in the HPLC-ESI-QTOF-MS/MS analysis) on the biological activity of the total extracts. The tested extracts exhibited moderate antiradical activity, with the methanolic extract from yellow and grey maca phenotypes scavenging 49.9 ± 8.96% and 48.8% ± 0.44% of DPPH radical solution at a concentration of 1 mg/mL, respectively. Grey maca was the most active tyrosinase inhibitor, with 72.86 ± 3.42% of the enzyme activity calculated for the water extract and 75.66 ± 6.21% for the chloroform extract. The studies in cells showed no cytotoxicity towards the human keratinocyte line HaCaT in all studied extracts and a marked inhibition of cell viability towards the G361 melanoma cell line, which the presence of pent-4-enylglucosinolate, glucotropaeolin, and glucoalyssin in the samples could have caused. Given all biological activity tests combined, the three mentioned compounds were shown to be the most significant positive contributors to the results obtained, and the grey maca water extract was found to be the best source of the former compound among the tested samples.

What was once assigned as GGG intercalation can, in retrospect, be read as G-quadruplex recognition. Here, we reframe the clinically investigated triazoloacridinone C-1305 as a high-affinity ligand of the c-MYC promoter G4 model Pu22. UV-Vis speciation resolved four spectral forms and yielded three macroscopic pK_a values, demonstrating that the dominant protonation state is retained under our NMR conditions and near physiological pH. Two orthogonal titration readouts─imino ¹H NMR and UV-Vis global analysis─converge on a well-defined 2:1 Pu22:C-1305 complex with submicromolar affinity and a distinctive ligand-induced "destabilize-refold" NMR signature. Variable-temperature NMR reveals pronounced thermal stabilization of Pu22 upon binding. Intermolecular NOEs together with 3D well-tempered metadynamics map a recognition mode dominated by end-stacking on both terminal G-tetrads, with flanking segments forming secondary pockets and enabling alternative bound substates. In cell assays, C-1305 shows low-micromolar cytotoxicity across multiple cancer cell lines while being markedly less toxic to normal cells, outperforming cisplatin in potency. These results reposition C-1305 from a putative GGG intercalator to a G4-targeting pharmacophore and outline a route to side-chain engineering for improved G4 selectivity.

Aromatic heptaene macrolides are structurally related to amphotericin B, an agent of reference in treatment of systemic fungal infections, but contain an additional aromatic side chain and a native cis–trans polyene chromophore. Their strong biological activity and toxicity are likely influenced not only by molecular structure, but also by supramolecular organization in aqueous media. Here, we combined concentration-dependent UV–Vis and circular dichroism (CD) spectroscopy with molecular simulations to characterize the self-association of native partricins and their all-trans photoisomers. PCA-assisted spectral decomposition showed that all four antibiotics undergo self-association in phosphate buffer over the investigated concentration range. UV–Vis data were satisfactorily described by an effective two-state isodesmic model, indicating redistribution from low-order species to a broadly associated population. CD spectroscopy revealed stronger sensitivity to chiral supramolecular organization, with all-trans isoforms displaying higher apparent aggregation constants than their native counterparts. Umbrella-sampling simulations showed favorable pairwise association at short interchromophore distances for all compounds, with all-trans isomerization preserving the preferred association distance while slightly stabilizing the associated state. Two-dimensional well-tempered metadynamics further demonstrated that these distance-defined dimers are orientationally heterogeneous and include near-periplanar, antiparallel-like, and intermediate chromophore arrangements, with isoParB showing the most distinct orientational landscape. Unbiased multi-molecule simulations confirmed spontaneous aggregation beyond dimer formation and revealed dynamic growth of higher-order assemblies, particularly for isoParB. Overall, the results support a hierarchical model in which partricins form favorable, orientationally diverse low-order contacts that evolve into larger supramolecular aggregates. All-trans isomerization modulates this aggregation landscape without abolishing the intrinsic tendency toward self-association.