naphthoquinones and nor-beta-lapachone

A series of novel 3-(1-benzotriazole)-nor-β-lapachones 5a-5l were synthesized as the NQO1-targeted anticancer agents. Most of these compounds displayed good antiproliferative activity against the breast cancer MCF-7, lung cancer A549 and hepatocellular carcinoma HepG2 cells in agreements with their NQO1 activity. Among them, compound 5k was identified as a favorable NQO1 substrate. It could activate the ROS production in a NQO1-dependent manner, arrest tumor cell cycle at G0/G1 phase, promote tumor cell apoptosis, and decrease the mitochondrial membrane potential. In HepG2 xenograft models, 5k significantly suppressed the tumor growth with no influences on animal body weights. Therefore, 5k could be a good lead for further anticancer drug developments.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Liver Neoplasms, Experimental; Mice; Mice, Nude; Models, Molecular; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Structure-Activity Relationship; Triazoles; Tumor Cells, Cultured

Prostate cancer is one of the most common malignant tumors in males and it has become a major worldwide public health problem. This study characterizes the encapsulation of Nor-β-lapachone (NβL) in poly(d,l-lactide-co-glycolide) (PLGA) microcapsules and evaluates the cytotoxicity of the resulting drug-loaded system against metastatic prostate cancer cells. The microcapsules presented appropriate morphological features and the presence of drug molecules in the microcapsules was confirmed by different methods. Spherical microcapsules with a size range of 1.03 ± 0.46 μm were produced with an encapsulation efficiency of approximately 19%. Classical molecular dynamics calculations provided an estimate of the typical adsorption energies of NβL on PLGA. Finally, the cytotoxic activity of NβL against PC3M human prostate cancer cells was demonstrated to be significantly enhanced when delivered by PLGA microcapsules in comparison with the free drug.

Topics: Antineoplastic Agents; Benzofurans; Capsules; Cell Line, Tumor; Cell Survival; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Humans; Inhibitory Concentration 50; Lactic Acid; Male; Models, Molecular; Molecular Conformation; Molecular Structure; Naphthoquinones; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostatic Neoplasms; Spectrum Analysis, Raman

We report herein a straightforward and efficient one-step reaction to prepare new nor-β-lapachone derivatives tethered with phenylthio groups at position 3 of the furan ring. We have screened the compounds on bloodstream trypomastigotes of Trypanosoma cruzi, the causative agent of Chagas disease, aimed at finding a new prototype with high trypanocidal activity. The new compounds possess a broad range of activity (IC50/24h from 9.2 to 182.7 μM), higher than the original quinone (391.5 μM) and four of them higher than standard drug benznidazole (103.6 μM). The most active was compound 13b (9.2 μM), being 11 times active than benznidazole and the less toxic derivative to heart muscle cells.

Topics: Animals; Benzofurans; Cell Survival; Cells, Cultured; Chagas Disease; Embryo, Mammalian; Heart; Humans; Mice; Myocardium; Naphthoquinones; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

Electrochemical, spectroelectrochemical, and theoretical studies of the reduction reactions in nor-β-lapachone derivatives including a nitro redox center showed that reduction of the compounds involves the formation of several radical intermediates, including a biradical dianion resultant from the separate reduction of the quinone and nitro groups in the molecules. Theoretical descriptions of the corresponding Fukui functions f(αα)⁺ and f(ββ)⁺(r) and LUMO densities considering finite differences and frozen core approximations for describing the changes in electron and spin densities of the system allowed us to confirm these results. A description of the potential relationship with the obtained results and biological activity selectivity indexes suggests that both the formation of stable biradical dianion species and the stability of the semiquinone intermediates during further reduction are determining factors in the description of their biological activity.

Topics: Anions; Benzofurans; Benzoquinones; Electrochemistry; Free Radicals; Naphthoquinones; Nitro Compounds; Oxidation-Reduction; Quantum Theory

In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO(2)) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF(4)) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO(2). QPhNO(2) caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO(2) treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Cell Survival; Comet Assay; DNA Damage; HL-60 Cells; Humans; Naphthoquinones; Oxidation-Reduction; Reactive Oxygen Species