Since the approval of three hydroxamic acid-based HDAC inhibitors as anticancer drugs, such functional groups acquired even more notoriety in synthetic medicinal chemistry. The ability of hydroxamic ...acids (HAs) to chelate metal ions makes this moiety an attractive metal binding groupin particular, Fe(III) and Zn(II)so that HA derivatives find wide applications as metalloenzymes inhibitors. In this minireview, we will discuss the most relevant features concerning hydroxamic acid derivatives. In a first instance, the physicochemical characteristics of HAs will be summarized; then, an exhaustive description of the most relevant methods for the introduction of such moiety into organic substrates and an overview of their uses in medicinal chemistry will be presented.
Prostate cancer is the most common type of cancer in men. The disease presents good survival rates if treated at the early stages. However, the evolution of the disease in its most aggressive variant ...remains without effective therapeutic answers. Therefore, the identification of novel effective therapeutics is urgently needed. On these premises, we developed a series of machine learning models, based on compounds with reported highly homogeneous cell-based antiproliferative assay data, able to predict the activity of ligands towards the PC-3 and DU-145 prostate cancer cell lines. The data employed in the development of the computational models was finely-tuned according to a series of thresholds for the classification of active/inactive compounds, to the number of features to be implemented, and by using 10 different machine learning algorithms. Models’ evaluation allowed us to identify the best combination of activity thresholds and ML algorithms for the classification of active compounds, achieving prediction performances with MCC values above 0.60 for PC-3 and DU-145 cells. Moreover, in silico models based on the combination of PC-3 and DU-145 data were also developed, demonstrating excellent precision performances. Finally, an analysis of the activity annotations reported for the ligands in the curated datasets were conducted, suggesting associations between cellular activity and biological targets that might be explored in the future for the design of more effective prostate cancer antiproliferative agents.
The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date ...been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data.
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•New AKR1C3 inhibitors were obtained using hydroxybenzoisoxazoles scaffolds.•X-ray was used for experimentally identify the binding mode in the AKR1C3 active site.•Seven compounds were assayed for AKR1C3 selectivity and cell-based activities.•Cpd 6 was found more then 460 time more selective on C3 compared to C2 AKR1 isoform.
Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known ...to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings. Both compounds were found to target AKR1C3 in a selective manner. In particular, hydroxyfurazan derivative is highly selective for AKR1C3 over the 1C2 isoform (up to 90-times more) and inactive on COX enzymes. High-resolution crystal structure of its complex with AKR1C3 shed light onto the binding mode of the new inhibitors. In cell-based assays (on colorectal and prostate cancer cells), the two indomethacin analogues showed higher potency than indomethacin. Therefore, these two AKR1C3 inhibitors can be used to provide further insight into the role of AKR1C3 in cancer.
The design of multi-target drugs acting simultaneously on multiple signaling pathways is a growing field in medicinal chemistry, especially for the treatment of complex diseases, such as cancer. ...Histone deacetylase 6 (HDAC6) is an established anticancer drug target involved in tumor cells transformation. Being an epigenetic enzyme at the interplay of many biological processes, HDAC6 has become an attractive target for polypharmacology studies aimed at improving the therapeutic efficacy of anticancer drugs. For example, the molecular chaperone Heat shock protein 90 (Hsp90) is a substrate of HDAC6 deacetylation, and several lines of evidence demonstrate that simultaneous inhibition of HDAC6 and Hsp90 promotes synergistic antitumor effects on different cancer cell lines, highlighting the potential benefits of developing a single molecule endowed with multi-target activity. This review will summarize the complex interplay between HDAC6 and Hsp90, providing also useful hints for multi-target drug design and discovery approaches in this field. To this end, crystallographic structures of HDAC6 and Hsp90 complexes will be extensively reviewed in light of discussing binding pockets features and pharmacophore requirements and providing useful guidelines for the design of dual inhibitors. The few examples of multi-target inhibitors obtained so far, mostly based on chimeric approaches, will be summarized and put into context. Finally, the main features of HDAC6 and Hsp90 inhibitors will be compared, and ligand- and structure-based strategies potentially useful for the development of small molecular weight dual inhibitors will be proposed and discussed.
The development of drugs for the treatment of advanced prostate cancer (PCA) remains a challenging task. In this study we have designed, synthesized and tested twenty-nine novel HDAC inhibitors based ...on three different zinc binding groups (trifluoromethyloxadiazole, hydroxamic acid, and 2-mercaptoacetamide). These warheads were conveniently tethered to variously substituted phenyl linkers and decorated with differently substituted pyrrolo-pyrimidine and purine cap groups. Remarkably, most of the compounds showed nanomolar inhibitory activity against HDAC6. To provide structural insights into the Structure-Activity Relationships (SAR) of the investigated compounds, docking of representative inhibitors and molecular dynamics of HDAC6-inhibitor complexes were performed. Compounds of the trifluoromethyloxadiazole and hydroxamic acid series exhibited promising anti-proliferative activities, HDAC6 targeting in PCA cells, and in vitro tumor selectivity. Representative compounds of the two series were tested for solubility, cell permeability and metabolic stability, demonstrating favorable in vitro drug-like properties. The more interesting compounds were subjected to migration assays, which revealed that compound 13 and, to a lesser extent, compound 15 inhibited the invasive behaviour of androgen-sensitive and –insensitive advanced prostate cancer cells. Compound 13 was profiled against all HDACs and found to inhibit all members of class II HDACs (except for HDAC10) and to be selective with respect to class I and class IV HDACs. Overall, compound 13 combines potent inhibitory activity and class II selectivity with favorable drug-like properties, an excellent anti-proliferative activity and marked anti-migration properties on PCA cells, making it an excellent lead candidate for further optimization.
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•Three series of novel HDAC inhibitors were designed and synthesized.•Most of the compounds showed potent HDAC6 inhibitory activity.•Proliferation of aggressive prostate cancer cells, anti migration and in vitro drug-like properties were determined.•Compound 13 constitutes an excellent lead candidate.
Histone deacetylase (HDAC) inhibitors are highly involved in the regulation of many pharmacological responses, which results in anti-inflammatory and anti-cancer effects. In the present work, ...chemoinformatic analyses were performed to obtain two potent and selective aminotriazoloquinazoline-based HDAC6 inhibitors. We unexpectedly obtained an aminotriazole from a water-driven ring opening of the triazoloquinazoline scaffold. Both compounds were evaluated as HDAC6 inhibitors, resulting in subnanomolar inhibitory activity and high selectivity with respect to class I HDAC1 and HDAC8. Importantly, the compounds were about 3- and 15-fold more potent compared to the reference compound trichostatin A. Additionally, the predicted binding modes were investigated with docking. Considering that the aminotriazole scaffold has never been embedded into the chemical structure of HDAC6 inhibitors, the present study suggests that both the aminotriazoloquinazoline and aminotriazole classes of compounds could be excellent starting points for further optimization of potential anticancer compounds, introducing such novel groups into a relevant and new area of investigation.
Potent and selective inhibitors of HDAC6 have been designed, synthesized and tested. An unexpected opening of the quinazoline ring led to both aminotriazoloquinazoline and aminotriazole compounds with potent activity and isoform selectivity.
The identification of different compound series with corresponding structure–activity relationship (SAR) progression for a given target is referred to as SAR transfer, which is of interest in lead ...optimization. If difficulties are encountered during multiproperty optimization, the SAR transfer concept can be applied attempting to replace a lead compound with another candidate. For a systematic assessment of SAR transfer, computational approaches are required. So far, SAR transfer has been investigated at the level of compounds and analogue series. Herein, we introduce a new computational method for structure-guided exploration of SAR transfer. The approach relies on a three-dimensional molecular fragmentation and recombination scheme and the identification of analogues of crystallographic ligands. On the basis of spatially aligned X-ray ligands, alternative substituents and compound cores are identified, enabling the detection of multiple SAR transfer events. Application of the methodology across different targets identified SAR transfer events with high frequency.
In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 ...1.2 nM), we kept improving the structure–activity relationship of this class of compounds characterized by 2-hydroxypyrazolo1,5-apyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.
We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening ...procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (Ki = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC99 = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition.
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•A VS study identified new MbtI inhibitors bearing the furan ring as potential antitubercular agents.•1a exerts a slightly better in vitro inhibitory activity on MbtI, compared to the best inhibitor reported to date.•1a is the first potent MbtI inhibitor endowed with a promising activity against Mycobacterium tuberculosis.•Siderophore production assays suggest a correlation between the antimycobacterial effects of 1a and iron-uptake inhibition.
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