Small-molecule modulators of tumor necrosis factor signaling.

Tumor necrosis factor (TNF) is a pleiotropic cytokine with a major role in immune system homeostasis and is involved in many inflammatory and autoimmune diseases, such as rheumatoid arthritis (RA), psoriasis, Alzheimer's disease (AD), and multiple sclerosis (MS). Thus, TNF and its receptors, TNFR1 and TNFR2, are relevant pharmacological targets. Biologics have been developed to block TNF-dependent signaling cascades, but they display serious side effects, and their pharmacological effectiveness decreases over time because of their immunogenicity. In this review, we present recent discoveries in small molecules targeting TNF and its receptors and discuss alternative strategies for modulating TNF signaling.

A New Manganese Superoxide Dismutase Mimetic Improves Oxaliplatin-Induced Neuropathy and Global Tolerance in Mice.

Reactive oxygen species (ROS) are produced by every aerobic cell during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Superoxide Dismutases (SOD) are antioxidant proteins that convert superoxide anions (O2•-) to hydrogen peroxide (H2O2) and dioxygen. Using the differential in the level of oxidative stress between normal and cancer cells, SOD mimetics can show an antitumoral effect and prevent oxaliplatin-induced peripheral neuropathy. New Pt(IV) conjugate prodrugs (OxPt-x-Mn1C1A (x = 1, 1-OH, 2)), combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, were designed. Their stability in buffer and in the presence of sodium ascorbate was studied. In vitro, their antitumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3). In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells in Balb/c mice. Tumor size and volume were measured weekly in four groups: vehicle, oxaliplatin, and oxaliplatin associated with MnSODm Mn1C1A and the bis-conjugate OxPt-2-Mn1C1A. Oxaliplatin-induced peripheral neuropathy (OIPN) was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including four items: weight loss, weariness, alopecia, and diarrhea. In vitro, Mn1C1A associated with oxaliplatin and Pt(IV) conjugates treatment induced significantly higher production of H2O2 in all cell lines and showed a significant improvement of the antitumoral efficacy compared to oxaliplatin alone. In vivo, the association of Mn1C1A to oxaliplatin did not decrease its antitumoral activity, while OxPt-2-Mn1C1A had lower antitumoral activity than oxaliplatin alone. Mn1C1A associated with oxaliplatin significantly decreased OIPN and also improved global clinical tolerance of oxaliplatin. A neuroprotective effect was observed, associated with a significantly improved tolerance to oxaliplatin without impairing its antitumoral activity.

Rhodium(III)-Catalyzed C(sp2)-H Functionalization of Cyclobutenes. Access to Cyclobuta[c]pyridones and -pyridines.

O-(ω-Alkynyl) hydroxamates derived from cyclobutenyl carboxylic acids were identified as viable substrates in intramolecular rhodium(III)-catalyzed heteroannulations, which led to diversely substituted cyclobuta[c]pyridones. Further functionalization of the resulting cyclobutapyridones enabled the synthesis of cyclobuta[c]pyridines and other nitrogen heterocycles after electrocyclic ring opening of the four-membered ring.