A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): The importance of halogen binding interactions.

The Forkhead boX M1 (FOXM1) protein is an essential transcription factor required for the normal activation of human cell cycle. However, increasing evidence supports a correlation between FOXM1 overexpression and the onset of several types of cancer. Based on a previously reported molecular modeling and molecular dynamics simulations (MD) study, we hypothesized the role of an essential halogen-bonding interaction between the 4-fluorophenyl group in the forkhead domain inhibitor-6 (FDI-6) and an Arg297 residue inside the FOXM1-DNA binding domain (DBD). To prove the importance of this binding interaction, we synthesized and screened ten FDI-6 derivatives possessing different groups at the 4-fluorophenyl position of the lead molecule. Briefly, we found that derivatives possessing a 4-chlorophenyl, 4-bromophenyl, or a 4-iodophenyl group, were equipotent to the original 4-fluorophenyl moiety present in FDI-6, whereas derivatives without this 4-halogen moiety were inactive. We also observed that positional isomers in which the halogen was relocated to positions 2- or 3- on the phenyl group were significantly less active. These results provide evidence to support the essential role of a 4-halophenyl bonding interaction, with the Arg297 residue in the FOXM1-DBD, to exert inhibition of transcriptional activity.

Dose-intense capecitabine, oxaliplatin and bevacizumab as first line treatment for metastatic, unresectable colorectal cancer: a multi-centre phase II study.

BACKGROUND: Dose intense chemotherapy may improve efficacy with acceptable toxicity. A phase II study was conducted to determine the feasibility of a dose-intense two weekly schedule of capecitabine, oxaliplatin, and bevacizumab in metastatic colorectal cancer (mCRC). METHODS: 49 patients with previously untreated mCRC were recruited. Nineteen received capecitabine (1750 mg/m(2) oral BD days 1-7)oxaliplatin (85 mg/m(2)i.v. day 1) and bevacizumab (5 mg/kg i.v. day 1) using a 14-day cycle (C1750). Following toxicity concerns capecitabine was reduced to 1500 mg/m2oral BD (C1500) and 30 further patients recruited. RESULTS: Over 80% of patients received at least 75% of planned chemotherapy doses over the first two cycles. At C1750 Grade 3 or higher toxicity occurred in 74% (95% CI 49% to 91%) and on C1500 in 70% (95% CI 51% to 85%). The median progression-free survival was 6.9 months (95% CI 4.7 to 8.7) for C1750 dose and 8.9 months (95% CI 4.1 to 12.4) for C1500. 3 treatment-related deaths occurred. CONCLUSIONS: Dose intense capecitabine and oxaliplatin with bevacizumab does not show additional efficacy and has potentially significant toxicity. Its use outside of clinical trials is not recommended. TRIAL REGISTRATION: ISRCTN41540878.

Nonbacterial thrombotic endocarditis with ST-elevation myocardial infarction treated with percutaneous coronary aspiration thrombectomy.

ST-elevation myocardial infarction from coronary embolus is a rare complication of nonbacterial thrombotic endocarditis, with little data on therapeutic management. We present a novel use of percutaneous coronary aspiration thrombectomy using an Export(®) catheter resulting in successful restoration of normal coronary blood flow. We also demonstrated complete resolution of the thrombotic valvular lesion with double antiplatelet and anticoagulation therapy alone. The clinical manifestations and management of coronary embolisation from nonbacterial thrombotic endocarditis are reviewed.

In silico Study on the Binding Interactions of SSTA and 18F-SSTA Towards Somatostatin Receptor Subtype 2.

BACKGROUND: Somatostatin analogs (SSTAs) are versatile drugs that target a group of proteins known as somatostatin receptors. SSTAs are used for the treatment and PET-molecular imaging of Neuro Endocrine Tumors (NET), for they are labeled with the radionuclide 18F, a positron emitter radionuclide. OBJECTIVE: The aim of this work was to theoretically study the binding interactions of SSTA labeled with 18F (half-life of 109.7 min) and somatostatin receptor subtype 2. As the labeling of SSTA with 18F required the use of a prosthetic group, a hydrophilicity enhancer, and a linker, the influence of these traits on the interactions of 18F-SSTA with the SSTR-2 binding site was studied. METHODS: The binding modes of 18F-labeled analogues with SSTR-2 were studied by using protein homology modelling, non-equilibrium molecular dynamics, and molecular docking calculations, by means of three docking software: MVD, MOE, and VINA. RESULTS: The results showed the main role of Asp122, Asn276, Phe272 and Phe294 from the SSTR-2 binding site, which form interactions with residues Lys, Trp, Tyr, and Thr from 18F-labeled somatostatin analogues. CONCLUSION: The interaction between Lys (from 18F-SSTA) and Asp122 (from SSTR-2) was identified as the most energetic and considered the one that drives the binding between 18F-SSTA and SSTR-2 (the anchor interaction). Despite the presence of prosthetic groups, linkers, and hydrophilicity enhancers, all the studied 18F-SSTA formed the anchor interaction. The trend in the results agreed with the experimental reports, identifying the main role of Asp122 in the binding of somatostatin-14 to SSTR-2.

Structure-Activity Relationship of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring.

We report synthesis, characterization, biological evaluation, and molecular-docking studies of 18 thieno[2,3-b]pyridines with a phenylacetamide moiety at position 2, which is disubstituted with F, Cl, Br, or I at position 4, and with electron-withdrawing and electron-donating groups (-CN, -NO2, -CF3, and -CH3) at position 2, to study how the electronic properties of the substituents affected the FOXM1-inhibitory activity. Among compounds 1-18, only those bearing a -CN (regardless of the halogen) decreased FOXM1 expression in a triple-negative breast cancer cell line (MDA-MB-231), as shown by Western blotting. However, only compounds 6 and 16 decreased the relative expression of FOXM1 to a level lower than 50%, and hence, we determined their anti-proliferative activity (IC50) in MDA-MB-231 cells using the MTT assay, which was comparable to that observed with FDI-6, in contrast to compound 1, which was inactive according to both Western blot and MTT assays. We employed molecular docking to calculate the binding interactions of compounds 1-18 in the FOXM1 DNA-binding site. The results suggest a key role for residues Val296 and Leu289 in this binding. Furthermore, we used molecular electrostatic potential maps showing the effects of different substituents on the overall electron density.

Semiautomatic assessment of whole-body tumor burden with 18F-PSMA-1007 in biochemical recurrent prostate cancer.

OBJECTIVE: The aim of the study was to evaluate the 18F-PSMA-1007 PET/computed tomography (CT) semiautomatic volumetric parameters to assess the whole-body tumor burden and its correlation with prostate-specific antigen (PSA) and Gleason score in patients with biochemically recurrent prostate cancer (PCa). MATERIALS AND METHODS: A total of 110 patients referred for 18F-PSMA-1007 PET/CT due to biochemical recurrence were retrospectively analyzed. Whole-body total lesion prostate-specific membrane antigen (wbTl-PSMA) and whole-body PSMA-derived tumor volume (wbPSMA-TV) metrics on 18F-PSMA-1007 were obtained semiautomatically in dedicated software. A Spearman test was performed to explore the correlation of volumetric imaging parameters with PSA levels and Gleason score. To analyze the association between volumetric measures and PSA subgroups, we used a Kruskal-Wallis test and a Dunn's test to identify each group causing an observed difference. RESULTS: A total of 492 metastatic lesions were analyzed, and a significant correlation was found between wbTL-PSMA (R = 0.63, P < 0.0001) and wbPSMA-TV (R = 0.49, P < 0.0001) with serum PSA. A statistically significant difference with wbTL-PSMA was found in patients with a PSA less than or equal 0.5 ng/ml and PSA in the range of 0.51-1.0 ng/ml. CONCLUSION: 18F-PSMA-1007 PSMA volumetric parameters can provide a quantitative imaging biomarker for whole-body tumor burden.

FOXM1 Inhibitors as Potential Diagnostic Agents: First Generation of a PET Probe Targeting FOXM1 To Detect Triple-Negative Breast Cancer in†vitro and in†vivo.

The FOXM1 protein controls the expression of essential genes related to cancer cell cycle progression, metastasis, and chemoresistance. We hypothesize that FOXM1 inhibitors could represent a novel approach to develop 18 F-based radiotracers for Positron Emission Tomography (PET). Therefore, in this report we describe the first attempt to use 18 F-labeled FOXM1 inhibitors to detect triple-negative breast cancer (TNBC). Briefly, we replaced the original amide group in the parent drug FDI-6 for a ketone group in the novel AF-FDI molecule, to carry out an aromatic nucleophilic (18 F)-fluorination. AF-FDI dissociated the FOXM1-DNA complex, decreased FOXM1 levels, and inhibited cell proliferation in a TNBC cell line (MDA-MB-231). [18 F]AF-FDI was internalized in MDA-MB-231 cells. Cell uptake inhibition experiments showed that AF-FDI and FDI-6 significantly decreased the maximum uptake of [18 F]AF-FDI, suggesting specificity towards FOXM1. [18 F]AF-FDI reached a tumor uptake of SUV=0.31 in MDA-MB-231 tumor-bearing mice and was metabolically stable 60 min post-injection. These results provide preliminary evidence supporting the potential role of FOXM1 to develop PET radiotracers.

SP1-independent inhibition of FOXM1 by modified thiazolidinediones.

This research article describes an approach to modify the thiazolidinedione scaffold to produce test drugs capable of binding to, and inhibit, the in vitro transcriptional activity of the oncogenic protein FOXM1. This approach allowed us to obtain FOXM1 inhibitors that bind directly to the FOXM1-DNA binding domain without targeting the expression levels of Sp1, an upstream transcription factor protein known to activate the expression of FOXM1. Briefly, we modified the chemical structure of the thiazolidinedione scaffold present in anti-diabetic medications such as pioglitazone, rosiglitazone and the former anti-diabetic drug troglitazone, because these drugs have been reported to exert inhibition of FOXM1 but hit other targets as well. After the chemical synthesis of 11 derivatives possessing a modified thiazolidinedione moiety, we screened all test compounds using in vitro protocols to measure their ability to (a) dissociate a FOXM1-DNA complex (EMSA assay); (b) decrease the expression of FOXM1 in triple negative-breast cancer cells (WB assay); (c) downregulate the expression of FOXM1 downstream targets (luciferase reporter assays and qPCR); and inhibit the formation of colonies of MDA-MB-231 cancer cells (colony formation assay). We also identified a potential binding mode associated with these compounds in which compound TFI-10, one of the most active molecules, exerts binding interactions with Arg289, Trp308, and His287. Unlike the parent drug, troglitazone, compound TFI-10 does not target the in vitro expression of Sp1, suggesting that it is possible to design FOXM1 inhibitors with a better selectivity profile.

Silicon containing ibuprofen derivatives with antioxidant and anti-inflammatory activities: An in vivo and in silico study.

There are many chronic diseases related with inflammation. The chronic inflammation can produce other problems as cancer. Therefore, it is necessary to design drugs with better anti-inflammatory activity than those in the clinic. Likewise, these could be used in chronic treatments with minimum adverse effects. The amide or ester functionality in combination with the insertion of a silyl alkyl moiety is able to improve some drug properties. In this context, the evaluation of a group of silicon containing ibuprofen derivatives (SCIDs) as antioxidants and anti-inflammatory agents is reported. Antioxidant activity was evaluated by the 2,2-Diphenyl-1-picrylhydrazyl (DPPH⨪), 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS•+) and the Fe(II) chelating ability methods. The anti-inflammatory activity was determined by using the carrageenan induced rat paw edema. The gastrotoxic profile of the SCIDs that displayed significant anti-inflammatory activity was determined by the indomethacin induced ulceration method. The SCIDs performed better than ibuprofen as chelating agents for Fe(II) and as scavengers for the free radicals DPPH• and ABTS•+. On the anti-inflammatory test, compound 4a inhibited the edema up to 87%, while 4d &10b achieved significant inflammation inhibition at a lower effective dose 50 (ED50) than ibuprofen´s. None of the SCIDs endowed with anti-inflammatory activity, showed significant gastrotoxic effects with respect to those displayed by ibuprofen. Based on the experimental results and aided by the theoretical docking approach, it was possible to rationalize how the SCIDs may bind to cyclooxygenase isoforms and helped to explain their reduced gastrotoxicity. The evaluated effects were improved in SCIDs with respect to ibuprofen.