Since the synthesis of 4,6-dinitrobenzofuroxan in 1899 by Drost, benzofuroxans have attracted particular attention. This peculiar series of compounds exhibit a broad spectrum of biological activity including antibacterial, antifungal, antileukemic, acaricide and immunodepressive properties. These works embrace a period of more than 50 years since the pioneering paper of Gosh and Whitehouse and papers in this major field of the heterocyclic chemistry are still published in 2013. The review has been built in two independent parts. The first one is directly dedicated to the structure of substituted benzofuroxans and will show many medicinal applications of these compounds such as nitric oxide-releasing abilities, induction of oxidative stress, potent anti-cancer agents, anti-chagas agent, target for antiamoebic agent, Ca2+ channel blockers or cytotoxic, mutagenic and genotoxic agent… The second part of this review will be in close connection with the use of benzofuroxans as synthetic precursors in the preparation of new biological compounds such as quinoxaline dioxide, benzimidazole and phenazine derivatives. The interaction of substituted benzofuroxans with electron rich heterocycles or carbanions is the key step in the synthesis of these new biological active compounds. These derivatives can be used as cytotoxic drugs, antimycobacterial agent and display anti-malarial, antileishmanial and antituberculosis activity. The nature of the substituent linked to the carbocyclic ring of benzofuroxan is of primary importance to understand the medicinal properties of this family of compounds. For example, when benzofuroxans are substituted by electron-releasing substituents, the chemical reactivity is transferred from the carbocyclic ring to the furoxan ring.

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

Hybrid drug strategy is based on the combination of two or more pharmacophores into a new chemical entity to improve the properties of the original compounds or to obtain double action of resulting molecule. Hybrid molecules, comprised of some pharmacophore and nitric oxide (NO) donor moiety, constitute one of the more promising approaches for the design of drugs. Furoxans and benzofuroxans are considered NO releasing prodrugs and are of great interest for researchers. In this review we will focus on furoxan and benzofuroxan hybrids described in literature during the last years (from 2005 to 2016).

A library of novel 2-(het)arylpyrrolidine-1-carboxamides were obtained via a modular approach based on the intramolecular cyclization/Mannich-type reaction of N-(4,4-diethoxybutyl)ureas. Their anti-cancer activities both in vitro and in vivo were tested. The in vitro activity of some compounds towards M-Hela tumor cell lines was twice that of the reference drug tamoxifen, whereas cytotoxicity towards normal Chang liver cell did not exceed the tamoxifen toxicity. In vivo studies showed that the number of surviving animals on day 60 of observation was up to 83% and increased life span (ILS) was up to 447%. Additionally, some pyrrolidine-1-carboxamides possessing a benzofuroxan moiety obtained were found to effectively suppress bacterial biofilm growth. Thus, these compounds are promising candidates for further development both as anti-cancer and anti-bacterial agents.