BackgroundTriple negative breast cancer (TNBC) is a heterogeneous subgroup (ER-, PR-, and HER2-) of invasive breast cancer, associated to poor prognosis, partially due to its resistance to available drugs. Therefore, it is imperative to discover new treatment options for the disease. In this context, we have synthesized and screened novel naphtoquinone-derived drugs (patent-protected), rationally designed to act through multiple pathways to avoid tumor chemoresistance. MethodsDrugs antineoplastic efficacy (AE) was accessed in the claudin-low TNBC cell line, MDA-MB231, by cellular metabolic viability (CMV) and IC 50 calculation (MTT method; GraphPad Prism version 5.1). Drugs toxicity was studied in healthy mice, following the Guideline 423 (for test of chemicals) of OECD; blood cells and tissues were analyzed by a Pathologist. Computational molecular dock studies were conducted to investigate the molecules tridimensional conformation and bounding energy to topoisomerase 2 (TOPO) and PI3K (Autodock Vina software). Results and conclusionsWe screened the AE of 43 novel drugs in MDA-MB231 (CMV ≤ 50% with 7 drugs). Of these, the most promising drugs PIC 20 (IC 50 1.38x10 -5 M; CMV = 10%) and PIC21 (IC 50 5.00x10 -5 M; CMV = 30%) showed significantly higher AE than cisplatin (IC 50 1.56x10 -4 M; CMV>90%), doxorubicin (IC 50 1.76x10 -4 M; CMV = 62%), and paclitaxel (IC 50 5.05x10 -7 M; CMV = 80%). None of the treated mice died, neither demonstrated symptoms of toxicity, following 14-days treatment with PIC. Indeed, there was no significant change in the animals' weight and general activity/behavior. Major organs showed no significant morphological changes, congestion, edema, necrosis, degeneration or inflammation. On the other hand, there was a 48.98% decrease in their hematocrit count. Finally, based on the crystalline structure of proteins deposited on PDB (1QZR, TOPO; 1E7U, PI3K), and PIC20 and PIC21 tridimensional structures, we concluded that the novel molecules bind to the ATP domain of the proteins with similar interaction energy (E) than the TOPO -Doxorubicin (E = -5.6) and Etoposide (E = -5.7) -or PI3K inhibitors -LY294002 (E = -9.5) and Wortmannin (E = -8.8): PIC20: E = -5.3 and -8.9; PIC21: E = -5.7 and -8.2, for TOPO and PI3K, respectively. In conclusion, we present novel and potentially safe drugs to treat TNBC, in an innovative and economically viable approach.
APPLICATION OF PAPER SPRAY IONIZATION MASS SPECTROMETRY AND RELATED TECHNIQUES IN THE DIRECT ANALYSIS OF BIOLOGICAL MATRICES FOR DETECTION OF DRUGS - A REVIEW. In recent years, technological development in analytical instrumentation has progressed vigorously, which has allowed the evolution of analytical techniques that play an indispensable role within society, highlighting mass spectrometry. Parallel to the technological advance of this technique, the development of new ionization methods that are simpler, faster, and allow direct analysis without the need for prior treatment or sample processing is underway. The methods of ambient ionization derived from paper spray have been developing rapidly in current days, mainly in the forensic field, due to the chemical modifications made in the paper substrate and the introduction of new types of organic materials that function as a probe/substrate to collect, store, and ionize the sample, then enabling more efficient and selective analyzes. This review highlights direct analyzes by applying paper spray ionization in the forensic field and some variations of this technique, including Thread Spray Ionization (TSI) when a fabric thread is used; Touch Spray Ionization (TSI), which uses materials such as metallic needles, medical swabs, and wooden sticks; Fiber Spray Ionization (FSI), which applies polymeric fibers as substrates.
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