The incorporation of ferrocene into established pharmacophores represents a promising strategy for combining targeted activity with the properties of the organometallic scaffold. Building on our previous work on ferrocene-modified tyrosine kinase inhibitors (TKIs), this study presents the synthesis, biological evaluation and molecular docking analysis of four novel 1,1′-desymmetrized ferrocenyl derivatives of imatinib and nilotinib, designed to investigate how subtle structural modifications of the ferrocenyl moiety influence their cytotoxic activity and predicted interactions with the ABL1 kinase domain. The imatinib-derived compounds 5 and 6 contain amino and acetamido substituents, respectively, whereas the nilotinib-derived compounds 16 and 17 incorporate acetyl and benzoyl functionalities. Their cytotoxic activity was evaluated against four BCR::ABL1-positive leukemia cell lines with distinct molecular characteristics (BV-173, K-562, AR-230, and LAMA-84), with non-malignant CCL-1 fibroblasts included for assessment of selectivity and imatinib used as a reference drug. All four derivatives exhibited cytotoxic activity, with pronounced structure- and cell line-dependent differences. Compound 5 showed the most favorable activity profile, with pronounced cytotoxicity against AR-230 cells and activity comparable to or greater than imatinib in BV-173 and K-562 cells. In contrast, compound 17 was the most active derivative in LAMA-84 cells and exhibited the highest selectivity among all analogues in the series across the entire leukemia panel. Molecular docking indicated that ferrocenyl incorporation altered the binding orientation within the ABL1 kinase domain, while compound 5 showed the smallest positional deviation, consistent with its favorable cytotoxic profile. The results demonstrate that additional functionalization of the ferrocenyl moiety produces cell-line-dependent changes in cytotoxic activity without consistently improving potency or selectivity compared with previously reported monosubstituted analogues. Nevertheless, the successful synthesis of 1,1′-desymmetrized ferrocene conjugates provides new opportunities for structural diversification and further optimization of this class of compounds.
Pladienolide B (1), a macrocyclic polyketide isolated from Streptomyces platensis Mer-11107, displays potent antiproliferative and antitumor activities through its interaction with the SF3b subunit of the spliceosome. Herein, we report a divergent, stereoselective synthetic route to access both the C1–C8 and C9–C13 fragments of the core moiety of Pladienolide B (1) starting from a common, inexpensive chiral-pool precursor, L-Malic acid. Key stereocenters and structural motifs were established using Sharpless asymmetric epoxidation, regioselective nucleophilic epoxide opening, Mannich reaction for exo-methylene introduction, and a tandem iodination–zinc elimination cascade. This unified precursor approach offers a streamlined tactical route toward the core macrolide framework.
A series of five novel 3-methyl-1-phenyl-4-(4-thioaroyl)-pyrazol-5-ones is obtained in excellent yields by thionation of the corresponding O-analogues with Lawesson’s reagent. The products are characterized in solution and solid phase. It is found that only mono-thionation occurs and that the products exist in enol-thione forms. Atypical side products are isolated and characterized. The preferred solid state forms are analyzed and compared with those of the corresponding O-analogues.
Catalysis has been recognized as a key science in contemporary chemistry, owing to the significant potential of nanocatalysts and organic–inorganic hybrid materials, due to their high surface area and tunability properties, as well as the possibility of conducting green syntheses. Multicomponent reactions (MCRs) constitute an efficient one-pot sustainable manufacturing approach for the synthesis of a variety of heterocycles in reduced number of steps, reagents and hazardous waste. Si-based hybrid nanocatalysts and functionalized silica materials have been shown to be effective catalysts with a high catalytic activity, selectivity, and recyclability, whose mechanisms have been studied extensively and related to substrate activation and reaction acceleration. In this review, recent developments in heterogeneous Si-based hybrid nanocatalysts and functionalized silica supported materials for the MCR preparation of pyridines, pyrimidines, imidazoles, quinolines, quinoxalines, thiazoles, chromenes, pyrans, and pyrazoles are highlighted. The review particularly focuses on acid/base-functionalized silica, immobilized metals, ionic-liquid/silica hybrids, magnetic silica, and hierarchical silica. The mechanisms of these catalysts are also considered in this work, particularly substrate activation, acid–base cooperation, and adsorption and stabilization of the reactive intermediates. Sustainable catalysis strategies include ones that are solvent-free and ones that use water as a solvent, catalyst recovery and recycling, energy-efficient processes, and strategies that have a high atom economy and reaction mass efficiency and low E-factor. These advances illustrate the feasibility of functionalized silica-based MCRs as environmentally friendly materials for heterocycle production.
The influence of the counter anion and solvent on the N-heterocyclic carbene (NHC)-catalyzed nucleophilic aroylation of electron-deficient aromatic compounds was investigated using iodide, bis(trifluoromethanesulfonyl)imide (TFSA), and tetrafluoroborate (BF4−) precatalysts. For quinazoline substrates, the relative efficiency of the precatalysts depended strongly on the solvent. The iodide precatalyst showed higher reactivity in MeCN, whereas the TFSA and BF4− precatalysts were more effective under some conditions in THF/DMF. Additive experiments using NaI, NaNTf2, and AgOTs suggested that free iodide plays an active role in promoting the reaction in MeCN. Halogen-exchange experiments and time-course 1H NMR analysis supported a pathway involving iodide-mediated substitution of the quinazoline substrate followed by aroylation of the resulting iodo intermediate. The magnitude of the counter-anion effect varied with the structure of the aromatic substrate, whereas nitrobenzene derivatives showed little dependence on the counter anion. The iodide/MeCN conditions were also successfully applied to the synthesis of a precursor of termicalcicolanone A.
