RESUMEN
Vanillin (vanH) is the major component of vanilla and one of the most widely used flavoring agents. In this work the complex [Cu(phen)(van)2] was prepared and characterized by structural (X-ray), spectroscopic (IR, UV-Vis, EPR) and electrochemical techniques. This compound showed an octahedral geometry with an unusual arrangement of the vanillin ligands, where the methoxy groups of the vanillinate ions are coordinated opposite to each other. The compound promoted DNA cleavage in the presence of glutathione (GSH) and H2O2. At 40 µmol L-1 of complex with GSH (10 mmol L-1), there is a complete cleavage of DNA to nicked form II, while only at 10 µmol L-1 of this complex with H2O2 (1 mmol L-1) an extensive cleavage leading to form III took place. Additionally, we have evidences of superoxide generation upon reaction with GSH. Therefore, DNA fragmentation occurs likely through an oxidative pathway. MTT assays indicated that the complex is highly cytotoxic against three distinct cell lines: B16-F10 (IC50 = 3.39 ± 0.61 µmol L-1), HUH-7 (IC50 = 4.22 ± 0.31 µmol L-1) and 786-0 (IC50 = 10.38 ± 0.91 µmol L-1). Flow cytometry studies conducted with 786-0 cell line indicated cell death might occur by apoptosis. Cell cycle progression evaluated at 5 and 10 µmol L-1 resulted in a clear increase of 786-0 cells at G1 phase and depletion of G2/M, while higher doses showed an expressive increase of sub-G1 phase. Altogether, these results pointed out to a promising biological activity and potential as an anti-cancer agent.
RESUMEN
Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant strains have created a need for the development of new antimycobacterial agents. Mycolic acids, the hallmark of mycobacteria, are high-molecular-weight alpha-alkyl, beta-hydroxy fatty acids, which appear mostly as bound esters in the mycobacterial cell wall. The product of the M. tuberculosis inhA structural gene (InhA) has been shown to be the primary target for isoniazid (INH), the most prescribed drug for active TB and prophylaxis. InhA was identified as an NADH-dependent enoyl-ACP reductase specific for long-chain enoyl thioesters. InhA is a member of the mycobacterial Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. Although the history of chemotherapeutic agent development demonstrates the remarkably successful tinkering of a few structural scaffolds, it also emphasizes the ongoing, cyclical need for innovation. The main focus of our contribution is on new data describing the rationale for the design of a pentacyano(isoniazid)ferrateII compound that requires no KatG-activation, its chemical characterization, in vitro activity studies against WT and INH-resistant I21V M. tuberculosis enoyl reductases, the slow-onset inhibition mechanism of WT InhA by the inorganic complex, and molecular modeling of its interaction with WT InhA. This inorganic complex represents a new class of lead compounds to the development of anti-tubercular agents aiming at inhibition of a validated target.
