Novel daidzein molecules exhibited anti-prostate cancer activity through nuclear receptor ERß modulation, in vitro and in vivo studies.

Eight novel ERß selective daidzein analogues (NCE1-8) were synthesized and their anti-cancer activity was evaluated by in vitro and in vivo methods. Cytotoxicity study, Receptor binding studies, Luciferase assay, cMYC & Cyclin D1 expression and Caspase 3, 8 & 9 activities were measured to ascertain the anticancer activity and mechanism. Uterotropic, anti-androgenic and anti-tumour activities were performed in rodents. The results revealed that NCEs produced anti-prostate cancer activity in DU145, LNCaP and PC3 cell lines and 50% more active than genistein. NCEs was significantly down-regulated cMYC & Cyclin D1 genes and elevated caspase 3 & 9 levels and did not show any difference in uterotropic, anti-androgenic activities. The tumour weight was also reduced. The NCE 1 and 2 have shown ERß selectivity in receptor binding studies. Daidzein with methyl substitution at R or R1 position exhibited more ERß selectivity and could be considered as lead molecules for anti-prostate cancer activity.

Crystal structure, DFT and Hirshfeld surface analysis of (E)-N'-[(1-chloro-3,4-di-hydro-naph-thal-en-2-yl)methyl-idene]benzohydrazide monohydrate.

In the title compound, C18H15ClN2O·H2O, a benzohydrazide derivative, the dihedral angle between the mean plane of the di-hydro-naphthalene ring system and the phenyl ring is 17.1 (2)°. In the crystal, O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds link the benzohydrazide and water mol-ecules, forming a layer parallel to the bc plane. Hirshfeld surface analysis and two-dimensional fingerprint plots indicate that the most important contributions to the crystal packing are from H⋯H (45.7%) and H⋯C/C⋯H (20.2%) contacts.

Procedural and follow-up clinical outcomes after chronic total occlusion revascularization: Data from an Indian public hospital.

BACKGROUND: Chronic total occlusion (CTO) continues to be challenging lesion subset for percutaneous intervention. Last decade has seen tremendous increase in percutaneous coronary intervention (PCI) in this subset owing to improved understanding of the anatomy and enhanced skillset with availability of dedicated hardware. We sought to study the outcomes of CTO PCI in an Indian public hospital. METHODS: This was a single-center non-randomized descriptive follow-up study on CTO PCI. The end-points were procedural success, immediate, and late adverse cardiovascular events [major adverse cardiac event (MACE)] and change in angina and left ventricular function at follow-up. RESULTS: A total 389 CTO lesions were treated with a success rate of 87% (339/389). The mean Japanese chronic total occlusion (J-CTO) score was 1.78 ± 0.12 (mean ± standard deviation). Multivariate analysis of different angiographic components of J-CTO score identified tortuosity (p = 0.001), calcifications (p ≤ 0.001), and blunt stump (p = 0.007) as independent predictors of procedural failure. The periprocedural mortality was less than 1%, and the non-life threatening complications were about 4%. The MACE rate was significantly higher in the procedural failure group (60%) than in the procedural success group (5.3%, p < 0.001). An increase in left ventricular ejection fraction (LVEF) was noted following successful CTO PCI after complete revascularization. CONCLUSIONS: The success rates for CTO PCI in this registry were about 87%. Immediate and long-term clinical outcomes were better with lower MACE (5%) after a successful procedure. A key outcome variable included an increase in LVEF among patients after a successful CTO PCI. The overall periprocedural complications were about 5.5%, but majority were non-life threatening.

Design, synthesis and biological evaluation of 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazole derivatives as anti-breast cancer agents.

Structural based molecular docking approach revealed the findings of 2-(phenoxymethyl) -5-phenyl-1,3,4-oxadiazole derivatives. The compounds (7a-o) were synthesized and characterized well by using conventional methods. The compounds, 7b and 7m were reconfirmed through single crystal XRD analysis. The synthesized compounds (7a-o) were evaluated their antiproliferative activities against MCF-7 and MDA-MB-453. Furthermore, Lipinski's rule of five and pharmacokinetic properties were predicted for the test compounds. These results demonstrate that the compounds 7b and 7d exhibit more potent cytotoxicity and 7d exhibits dose-dependent activity and reduced cell viability. Further, the mechanism of action for the induced apoptosis was observed through morphological changes and western blotting analysis. These findings may furnish the lead for further development.

In silico Molecular Modelling of Selected Natural Ligands and their Binding Features with Estrogen Receptor Alpha.

BACKGROUND: Breast cancer is one of the most common cancers diagnosed among women. It is now recognized that two receptors mediate estrogen action and the presence of estrogen receptor alpha (ERα) correlates with better prognosis and the likelihood of response to hormonal therapy. ERα is an attractive target for the treatment of breast cancer. Most of the drugs currently used for the breast cancer treatment have numerous side effects and they are often unsuccessful in removing the tumour completely. Hence, we focused on natural compounds like flavonoids, polyphenols, etc. which do not exhibit any high toxic effects against normal cells. OBJECTIVES: To identify the potential natural inhibitors for BCa through an optimised in silico approach. METHODS: Structural modification and molecular docking-based screening approaches were imposed to identify the novel natural compounds by using Schrödinger (Maestro 9.5). The Qikprop v3.5 was used for the evaluation of important ADME parameters and its permissible ranges. Cytotoxicity of the compounds was evaluated by MTT assay against MCF-7 Cell lines. RESULTS: From the docking studies, we found that the compounds, Myricetin, Quercetin, Apigenin, Luteolin and Baicalein showed the highest Glide Scores -10.78, -9.48, -8.92, -8.87 and -8.82 kcal mol-1 respectively. Of these, Luteolin and Baicalein showed the significant IC50 values (25 ± 4.0 and 58.3 ± 4.4 µM, respectively) against MCF-7 cell line. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. CONCLUSION: We mainly focused on in silico study to dock the compounds into the human estrogen receptor ligand binding domain (hERLBD) and compare their predicted binding affinity with known antiestrogens. Myricetin, Quercetin, Apigenin, Luteolin and Baicalein were identified as the most promising among all. Of these, Luteolin and Baicalein showed significant anticancer activities against MCF-7 cell line. These findings may provide basic information for the development of anti-breast cancer agents.

Spectrum of morphological abnormalities and treatment outcomes in ostium secundum type of atrial septal defects: Single center experience in >500 cases.

BACKGROUND: Transcatheter closure (TCC) has emerged as the first line treatment option for secundum type of atrial septal defects (ASD). Outcomes of TCC depend upon proper delineation of defect anatomy by transesophageal echocardiography (TEE). Stability and proper placement of the device mandates adequate rims and proper alignment to the septum. Failed or unfavorable morphology for TCC requires referral for surgical repair. METHODS: We prospectively analyzed the ASD patients who were referred for treatment. The morphological features of the defect were evaluated and the outcomes of TCC studied. Patients who undergo TCC and surgical repair were followed for immediate and long-term outcome comparison. RESULTS: Of the 512 patients who underwent treatment, TCC was attempted in 430/512 (83.2%) patients. It was successful in 393/430 (91.3%) patients. The remaining 119 patients underwent surgical patch closure. Twenty patients had failure of device alignment and device embolization occurred in 17 patients. Very large defect size ≥35 mm, absent or deficient posterior rim, absent/deficient inferior naval rim showed high chances for failure and formed major reasons for surgical referral. The surgical group had higher success (100%) across all anatomic variables. However, they had longer intensive care unit (ICU) and hospital stay (p < 0.001). CONCLUSION: TCC offered a success rate of 91% in complex defects after TEE selection. Very large size and deficient inferior, posterior rims predicted failure of TCC. Surgery offered 100% success and it involved a longer hospital and ICU stay. The long-term clinical results were identical with both treatment modalities.

Crystal structures of 3-meth-oxy-4-{[5-(4-meth-oxy-phen-yl)-1,3,4-oxa-diazol-2-yl]meth-oxy}benzo-nitrile and N-(4-{[5-(4-chloro-phen-yl)-1,3,4-oxa-diazol-2-yl]meth-oxy}phen-yl)acetamide.

The title compounds, C18H15N3O4 and C17H14ClN3O3, are heterocyclic 1,3,4-oxa-diazole derivatives which differ from each other in the groups attached to the carbon atoms: a meth-oxy-phenyl ring and a benzo-nitrile group in (I) and a chloro-phenyl ring and an acetamide group in (II). Short intra-molecular C-H⋯O hydrogen bonds occur in both mol-ecules. The crystal structure of (I) features C-H⋯N hydrogen bonds, while in the crystal structure of (II), N-H⋯N, C-H⋯N and C-H⋯O hydrogen bonds are observed.

Design, 3D QSAR modeling and docking of TGF-ß type I inhibitors to target cancer.

Transforming growth factor-ß (TGF-ß) family members plays a vital role in regulating hormonal function, bone formation, tissue remodeling, and erythropoiesis, cell growth and apoptosis. TGF-ß super-family members mediate signal transduction via serine/threonine kinase receptors located on the cell membrane. Variation in expression of the TGF-ß type I and II receptors in the cancer cells compromise its tumor suppressor activities which direct to oncogenic functions. The present study was aimed to screen the potent TGF-ß type I inhibitors through atom based 3D-QSAR and pharmacophore modelling. For this purpose, we have chosen known TGF-ß type I inhibitors from the binding database. The PHASE module of Schrodinger identified the best Pharmacophore model which includes three hydrogen bond acceptors (A), one hydrophobic region (H), and one ring (R) as the structural features. The top pharmacophore model AAAHR.27 was chosen with the R2 value of 0.94 and validated externally using molecules of the test set. Moreover the AAAHR.27 model underwent virtual screening using the molecules from the NCI, ZINC and Maybridge database. The screened molecules were further filtered using molecular docking and ADME properties prediction. Additionally, the 7 lead molecules were compared with a newly identified compound "SB431542" (well known TGF-ß type I receptor inhibitor) and Galunisertib, a small molecule inhibitor of TGF-ß type I, under clinical development (phase II trials) using the docking score and other binding properties. Also a top scored screened molecule from our study has been compared and confirmed using molecular dynamic simulation studies. By this way, we have obtained 7 distinct drug-like TGF-ß type I inhibitors which can be beneficial in suppressing cancers reported with up-regulation of TGF-ß type I. This result highlights the guidelines for designing molecules with TGF-ß Type I inhibitory properties.

Low power ablation for left coronary cusp ventricular tachycardia-Efficacy and long-term outcome.

BACKGROUND: The left coronary cusp is an uncommon but well-known site for the ablation of idiopathic ventricular tachycardia (VT). Proximity to the left coronary ostium makes ablation of this arrhythmia challenging. Different power settings have been described by various operators. Our objective was to describe the outcomes with low power ablation. METHODS: Once mapping confirmed origin from the left coronary cusp, ablation was performed if the best site was situated at least 5 mm from the left coronary ostium. Ablation was started at 15 W and, if successful, was stopped after 30 s. When required, higher powers were used up to 30 W. RESULTS: Ten patients with VT or premature ventricular beats mapped to the left coronary cusp were included in the study. No ablation was performed in one patient because of proximity to the left coronary ostium. Successful ablation was performed in eight of the other nine patients with a mean power of 18.1 ± 5.3 W and duration of 42.2 ± 13.5 s. There were no complications. All the eight patients remained free of recurrence at 16.8 ± 16.5 months of follow-up. CONCLUSIONS: VT can be ablated from the left coronary cusp close to the left coronary ostium. Ablation with low power is effective in achieving immediate success which is also durable with time while avoiding complications.

Iminoenamine based novel androgen receptor antagonist exhibited anti-prostate cancer activity in androgen independent prostate cancer cells through inhibition of AKT pathway.

Treatment by androgen receptor (AR) antagonists is one of the regimens for prostate cancer. The prolonged treatment with AR antagonist leads to the expression of point mutation in the ligand binding domain of the AR. This point mutation causes resistance to AR antagonist by converting them into an agonist. The T887A mutated AR was frequently expressed in androgen independent prostate cancer (AIPC) patients. Through literature survey and molecular modelling, we have identified a novel AR antagonist having a bulky ß-iminoenamine BF2 complex scaffold. The tested and standard ligands were screened in AR positive (LNCaP, MCF-7 and MDA-MB-453), AR negative (PC3), and non-cancerous (3T3) cell lines through anti-proliferation assay. The ligand, ARA3 was the most potent molecule among all the tested ligands and was 7.6 folds selective for AR positive cell lines. The mechanism of anti-prostate cancer activity of ARA3 was confirmed by western blot, qPCR, and apoptotic assays in LNCaP (T887A positive AR) cells. Structural activity relationship was derived by correlating the in-vitro and in-silico data. Consequently, we have identified the essential functional groups that could prevent the resistance concerning mutant AR. The ARA3 induces the apoptosis in AIPC cells by preventing the AR mediated activation of AKT pathway. The bicalutamide did not induce the apoptosis because it failed to prevent the AR mediated activation of AKT.

Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents.

The structural modification and molecular docking-based screening approaches on thiazole-based isoindolinediones were imposed to find the novel 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives. The best fit compounds (6a-n) were synthesized and evaluated their antiproliferative activities on the prostate cancer cell lines (PC-3 & LNCaP). Among them, the compound, 6m exhibited good activity, particularly on LNCaP (IC50=5.96±1.6µM), moderately active against PC-3 cell lines as compared to bicalutamide. The compound, 6m decreased the androgen-mediated transcription of ARE-mRNA in PSA, TMPRSS2, c-myc and cyclin D1 than R-bicalutamide. The compounds, 6e and 6f were reconfirmed through single crystal XRD analysis. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. These findings may provide vital information for the development of anti-prostate cancer agents.

Recent development of targeted approaches for the treatment of breast cancer.

Breast cancer is the most prominent cause of cancer death in women worldwide. The highlights of this review are to provide an overview of the targeted therapeutic agents, challenges with metastatic breast cancer (MBCa), mechanisms of action through Hedgehog/Gli 1 signaling pathway and future prospective. Over a decade of success, several drugs have been approved and are in the advanced stages of clinical trials that target the receptors such as estrogen receptor, growth factor receptor, receptor activator of nuclear factor kappa-B, etc. Currently, several monoclonal antibodies are also used for the treatment of breast cancer. Advances in understanding tumor biology, particularly signaling pathways such as Notch signaling pathway, Hedgehog/Gli 1 signaling pathway, and inhibitors are considered to be important for bone metastasis. These studies may provide vital information for the design and development of new strategies with respect to efficacy, reduction of the side effects, and treatment strategies.

Computational fluid dynamics modeling of Bacillus anthracis spore deposition in rabbit and human respiratory airways.

Three-dimensional computational fluid dynamics and Lagrangian particle deposition models were developed to compare the deposition of aerosolized Bacillus anthracis spores in the respiratory airways of a human with that of the rabbit, a species commonly used in the study of anthrax disease. The respiratory airway geometries for each species were derived respectively from computed tomography (CT) and µCT images. Both models encompassed airways that extended from the external nose to the lung with a total of 272 outlets in the human model and 2878 outlets in the rabbit model. All simulations of spore deposition were conducted under transient, inhalation-exhalation breathing conditions using average species-specific minute volumes. Two different exposure scenarios were modeled in the rabbit based upon experimental inhalation studies. For comparison, human simulations were conducted at the highest exposure concentration used during the rabbit experimental exposures. Results demonstrated that regional spore deposition patterns were sensitive to airway geometry and ventilation profiles. Due to the complex airway geometries in the rabbit nose, higher spore deposition efficiency was predicted in the nasal sinus compared to the human at the same air concentration of anthrax spores. In contrast, higher spore deposition was predicted in the lower conducting airways of the human compared to the rabbit lung due to differences in airway branching pattern. This information can be used to refine published and ongoing biokinetic models of inhalation anthrax spore exposures, which currently estimate deposited spore concentrations based solely upon exposure concentrations and inhaled doses that do not factor in species-specific anatomy and physiology for deposition.

Crystal structure of 2-(2,4-diphenyl-3-aza-bicyclo-[3.3.1]nonan-9-yl-idene)aceto-nitrile.

In the title 3-aza-bicyclo-nonane derivative, C22H22N2, both the fused piperidine and cyclo-hexane rings adopt a chair conformation. The phenyl rings attached to the central aza-bicylononane fragment in an equatorial orientation are inclined to each other at 23.7 (1)°. The amino group is not involved in any hydrogen bonding, so the crystal packing is stabilized only by van der Waals forces.

Crystal structure of 2-[4(E)-2,6-bis-(4-chloro-phen-yl)-3-ethyl-piperidin-4-yl-idene]acetamide.

In the title piperidine derivative, C21H22Cl2N2O, the piperidine ring adopts a chair conformation. The chloro-phenyl rings are oriented at an angle of 45.59 (14)° with respect to each other. In the crystal, mol-ecules are linked via N-H⋯O hydrogen bonds, forming C(4) chains along [100]. The chains are linked by C-H⋯O hydrogen bonds, forming sheets parallel to the ab plane. Within the sheets, there are N-H⋯π inter-actions present. The crystal studied was refined as an inversion twin.

Crystal structure of 1-(2-chloro-acet-yl)-3,3-dimethyl-2,6-di-p-tolyl-piperidin-4-one.

In the title compound, C23H26ClNO2, the piperidin-4-one ring adopts a distorted boat conformation. The two p-tolyl rings are nearly normal to each other, making a dihedral angle of 83.33 (10)°. They are inclined to the mean plane of the piperidine ring by 73.2 (1) and 87.22 (9)°. In the crystal, there are no significant inter-molecular inter-actions present.

Crystal structure of 1-(2-chloro-acet-yl)-2,6-bis-(4-fluoro-phen-yl)-3,3-di-methyl-piperidin-4-one.

In the title mol-ecule, C21H20ClF2NO2, the piperidine ring adopts a slightly distorted boat conformation. The two benzene rings form a dihedral angle of 87.43 (1)°. A weak intra-molecular C-H⋯π inter-action is observed. In the crystal, weak C-H⋯O hydrogen bonds and weak C-H⋯π inter-actions connect the mol-ecules, forming a three-dimensional network.

Incidence of bone metastases and survival after a diagnosis of bone metastases in breast cancer patients.

BACKGROUND: Bone is the most common metastatic site associated with breast cancer. Using a database of women with breast cancer treated at Guy's Hospital, London 1976-2006 and followed until end 2010, we determined incidence of and survival after bone metastases. METHODS: We calculated cumulative incidence of bone metastases considering death without prior bone metastases as a competing risk. Risk of bone metastases was modelled through Cox-regression. Survival after bone metastases diagnosis was calculated using Kaplan-Meier methodology. RESULTS: Of the 7064 women, 589 (22%) developed bone metastases during 8.4 years (mean). Incidence of bone metastases was significantly higher in younger women, tumour size >5 cm, higher tumour grade, lobular carcinoma and ≥ four positive nodes, but was not affected by hormone receptor status. Median survival after bone metastases diagnosis was 2.3 years in women with bone-only metastases compared with <1 year in women with visceral and bone metastases. There was a trend for decreased survival for patients who developed visceral metastases early, and proportionately fewer patients in this group. INTERPRETATION: Incidence of bone metastases has decreased but bone metastases remain a highly relevant clinical problem due to the large number of patients being diagnosed with breast cancer.

Ethyl 2-[2-(2,4-diphenyl-3-aza-bicyclo-[3.3.1]nonan-9-yl-idene)hydrazin-1-yl]-4-methyl-1,3-thia-zole-5-carboxyl-ate di-methyl-formamide monosolvate.

In the title mol-ecule, C27H30N4O2S·C3H7NO, the fused piperidine and cyclo-hexane rings adopt a twin chair conformation and the phenyl groups occupy equatorial sites. The phenyl rings make a dihedral angle of 40.74 (2)°. In the crystal, the di-methyl-formamide solvent mol-ecule is connected to the main mol-ecule by an N-H⋯O hydrogen bond. An additional N-H⋯O hydrogen bond connects mol-ecules into chains along [100]. Pairs of weak C-H⋯O hydrogen bonds connect inversion-related chains. The ethyl group was refined as disordered over two sets of sites with an occupancy ratio of 0.660 (17):0.340 (17).