Search results for "Drug Design"
showing 10 items of 232 documents
Recent advances in computational design of potent aromatase inhibitors: open-eye on endocrine-resistant breast cancers.
2019
Introduction: The vast majority of breast cancers (BC) are estrogen receptor positive (ER+). The most effective treatments to fight this BC type rely on estrogen deprivation therapy, by inhibiting the aromatase enzyme, which performs estrogen biosynthesis, or on blocking the estrogens signaling path via modulating/degrading the estrogen's specific nuclear receptor (estrogen receptor-?, ER?). While being effective at early disease stage, patients treated with aromatase inhibitors (AIs) may acquire resistance and often relapse after prolonged therapies. Areas covered: In this compendium, after an overview of the historical development of the AIs currently in clinical use, and of the computati…
Toward a Rational Design of Polyamine-Based Zinc-Chelating Agents for Cancer Therapies.
2020
In vitro viability assays against a representative panel of human cancer cell lines revealed that polyamines L1a and L5a displayed remarkable activity with IC50 values in the micromolar range. Preliminary research indicated that both compounds promoted G1 cell cycle arrest followed by cellular senescence and apoptosis. The induction of apoptotic cell death involved loss of mitochondrial outer membrane permeability and activation of caspases 3/7. Interestingly, L1a and L5a failed to activate cellular DNA damage response. The high intracellular zinc-chelating capacity of both compounds, deduced from the metal-specific Zinquin assay and ZnL2+ stability constant values in solution, strongly sup…
Synthesis and evaluation of diverse thio avarol derivatives as potential UVB photoprotective candidates.
2007
Semisynthesis of 13 new thio avarol derivatives (4-16) and in vitro evaluation on the photodamage response induced by UVB irradiation are described. Their ability to inhibit NF-kappaB activation and TNF-alpha generation in HaCaT cells as well as their antioxidant capacity in human neutrophils has also been studied. Among them we have identified two monophenyl thio avarol derivatives (4-5) lacking cytotoxicity which can be considered promising UVB photoprotective agents through the potent inhibition of NF-kappaB activation with a mild antioxidant pharmacological profile.
De novo design of protein kinase inhibitors by in silico identification of hinge region-binding fragments.
2013
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible w…
Development of Polyamine‐Substituted Triphenylamine Ligands with High Affinity and Selectivity for G‐Quadruplex DNA
2019
Currently, significant efforts are devoted to designing small molecules able to bind selectively to guanine quadruplexes (G4s). These noncanonical DNA structures are implicated in various important biological processes and have been identified as potential targets for drug development. Previously, a series of triphenylamine (TPA)-based compounds, including macrocyclic polyamines, that displayed high affinity towards G4 DNA were reported. Following this initial work, herein a series of second-generation compounds, in which the central TPA has been functionalised with flexible and adaptive linear polyamines, are presented with the aim of maximising the selectivity towards G4 DNA. The acid-bas…
Cyclooxygenase-1/2 (COX-1/COX-2) and 5-lipoxygenase (5-LOX) inhibitors of the 6,7-diaryl-2,3-1H-dihydropyrrolizine type
2003
A series of 6,7-diaryl-2,3-1H-dihydropyrrolizines was prepared as COX-1/COX-2 and 5-LOX inhibitors. The inhibition of COX-1 was evaluated using intact bovine platelets as the enzyme source, whereas LPS-stimulated human monocytes served as the enzyme source for inducible COX-2. The determination of arachidonic metabolites was performed by HPLC for COX-1 and RIA for COX-2. The balance between COX-1/COX-2 and 5-LOX inhibition can be shifted by modifying the substitution pattern of the phenyl moiety at the 6- and 7-position of the pyrrolizine nucleus. Structure-activity relationships are discussed.
Inhibition of HSP70: a challenging anti-cancer strategy.
2012
HSP70 is a chaperone that accumulates in the cells after many different stresses promoting cell survival in response to the adverse conditions. In contrast to normal cells, most cancer cells abundantly express HSP70 at the basal level to resist to various insults at different stages of tumorigenesis and during anti-cancer treatment. This cancer cells addiction for HSP70 is the rational for its targeting in cancer therapy. Much effort has been dedicated in the last years for the active search of HSP70 inhibitors. Additionally, the recent clinical trials on highly promising inhibitors of another stress protein, HSP90, showed compensatory increase in HSP70 levels and raised the question of nec…
From a Better Understanding of the Mechanisms of Action of Histone Deacetylases Inhibitors to the Progress of the Treatment of Malignant Lymphomas an…
2017
Background Notable progress has been made in chemo- and immunotherapy of B-cell lymphomas, but less in the treatment of T-cell lymphomas. Objective Histone deacetylases inhibitors are a potentially useful therapeutic mean, as an epigenetic dysregulation is present in lymphomas, and especially in T-cell types. We aimed to study the progress made in this area. Method A mini-review was achieved using the articles published in PubMed in the last two years and the new patents made in this field. Results Histone deacetylases inhibitors are involved in the derepression of tumor suppressor genes through a histone deacetylase-mediated transcriptional process. Their inhibition is followed by cell cyc…
Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications.
2004
Cathepsin D is a lysosomal acid proteinase which is involved in the malignant progression of breast cancer and other gynecological tumors. Clinical investigations have shown that in breast cancer patients cathepsin D overexpression was significantly correlated with a shorter free-time disease and overall survival, whereas in patients with ovarian or endometrial cancer this phenomenon was associated with tumor aggressiveness and a degree of chemoresistance to various antitumor drugs such as anthracyclines, cis-platinum and vinca alkaloids. Therefore, a lot of research has been undertaken to evaluate the role and the prognostic value of cathepsin D also in other solid neoplasms. However, conf…
A bioactive designer cytokine for human hematopoietic progenitor cell expansion
1997
Efficient expansion of hematopoietic progenitor cells requires, at least, the simultaneous stimulation of the receptors c-kit and gp130. While c-kit is activated by SCF; gp130, in cells which do not express sufficient amounts of IL-6R, can be activated by the complex of soluble IL-6R (sIL-6R) and IL-6. The therapeutic use of IL-6/sIL-6R, however, has been hampered by the high concentrations of the sIL-6R protein required. We have designed a fusion protein of sIL-6R and IL-6, linked by a flexible peptide chain, that was expressed to high levels. On gp130 expressing cells the fusion protein turned out to be fully active at 100 to 1,000-fold lower concentration than the combination of unlinked…