The nitro group is considered to be a versatile and unique functional group in medicinal chemistry. Despite a long history of use in therapeutics, the nitro group has toxicity issues and is often categorized as a structural alert or a toxicophore, and evidence related to drugs containing nitro groups is rather contradictory. In general, drugs containing nitro groups have been extensively associated with mutagenicity and genotoxicity. In this context, efforts toward the structure–mutagenicity or structure–genotoxicity relationships have been undertaken. The current Perspective covers various aspects of agents that contain nitro groups, their bioreductive activation mechanisms, their toxicities, and approaches to combat their toxicity issues. In addition, recent advances in the field of anticancer, antitubercular and antiparasitic agents containing nitro groups, along with a patent survey on hypoxia-activated prodrugs containing nitro groups, are also covered.

This article arranges the microtubule-targeting agents that have published in patent in recent years. It may help in the investigation of new tubulin binding site and development of novel drug candidate in the future.

This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1 H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future.

A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC value of 0.29 nM, which is 4,000-43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.

Countless clinical trials evaluating the efficacy, safety and pharmacokinetics of novel tubulin inhibitors highlights the scientific efforts being paid to establish their candidature as cancer therapeutics. Colchicine binding site inhibitors as vascular disrupting agents (VDAs) and new taxanes appear to be the most likely agents for future clinical interest. Numerous agents have demonstrated clinical benefits in terms of efficacy and survival in phase I and II studies. However conclusive benefits can only be ascertained on the basis of phase III studies.

Recently, histone deacetylase (HDAC) inhibitors have emerged as a promising class of drugs for treatment of cancers, especially subcutaneous T-cell lymphoma. In this study, we demonstrated that MPT0E028, a novel N-hydroxyacrylamide-derived HDAC inhibitor, inhibited human colorectal cancer HCT116 cell growth in vitro and in vivo. The results of NCI-60 screening showed that MPT0E028 inhibited proliferation in both solid and hematological tumor cell lines at micromolar concentrations, and was especially potent in HCT116 cells. MPT0E028 had a stronger apoptotic activity and inhibited HDACs activity more potently than SAHA, the first therapeutic HDAC inhibitor proved by FDA. In vivo murine model, the growth of HCT116 tumor xenograft was delayed and inhibited after treatment with MPT0E028 in a dose-dependent manner. Based on in vivo study, MPT0E028 showed stronger anti-cancer efficacy than SAHA. No significant body weight difference or other adverse effects were observed in both MPT0E028-and SAHA-treated groups. Taken together, our results demonstrate that MPT0E028 has several properties and is potential as a promising anti-cancer therapeutic drug.

A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 μM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N'-phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.

Denbinobin inhibited IL-1β-induced ICAM-1/VCAM-1 expression and monocyte adhesion to OA-FLS. It was due to denbinobin increased miR-146a level, which in turn inhibited NF-κB signaling. Our overall findings suggest that denbinobin can be used as a potent anti-inflammatory agent.