Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors.

The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02-99.13 against 15 cancer cell lines at 10 µM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib.

Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells.

Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off-target side effects. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and to improve target tissue specificity. In this work, several bioreductive prodrugs for class I HDACs were designed based on known selective HDAC inhibitors. The zinc-binding group of the HDAC inhibitors was masked with various nitroarylmethyl residues to make them substrates of nitroreductase (NTR). The developed prodrugs showed weak HDAC inhibitory activity compared to their parent inhibitors. The prodrugs were tested against wild-type and NTR-transfected THP1 cells. Cellular assays showed that both 2-nitroimidazole-based prodrugs 5 and 6 were best activated by the NTR and exhibited potent activity against NTR-THP1 cells. Compound 6 showed the highest cellular activity (GI50 = 77 nM) and exhibited moderate selectivity. Moreover, activation of prodrug 6 by NTR was confirmed by liquid chromatography-mass spectrometry analysis, which showed the release of the parent inhibitor after incubation with Escherichia coli NTR. Thus, compound 6 can be considered a novel prodrug selective for class I HDACs, which could be used as a good starting point for increasing selectivity and for further optimization.

Histone Acetyltransferase and Deacetylase Inhibitors-New Aspects and Developments.

Epigenetic processes modulate gene transcription and genomic stability, ensuring proper cell development and differentiation [...].

Fragment merging approach for design, synthesis, and biological assessment of urea/acetyl hydrazide clubbed thienopyrimidine derivatives as GSK-3ß inhibitors.

New thienopyrimidine derivatives were designed and synthesized as GSK-3ß inhibitors based on the structure of active binding site of GSK-3ß enzyme. In this study, compounds 6b and 6a were found to be moderate GSK-3ß inhibitors with IC50s 10.2 and 17.3 µM, respectively. Molecular docking study was carried out by docking the targeted compounds in the binding site of the GSK-3ß enzyme using the MOE program. Moreover, ADME study was performed to predict certain pharmacokinetic properties. The results showed that all synthesized compounds may not be able to penetrate the blood brain barrier; so, the chances of CNS side effects are predicted to be low. CYP1D6 is predicted to be inhibited by compounds (5a, 5d, 6a, 9a and 9b), So drug-drug interactions are expected upon administration of these compounds.

Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells.

INTRODUCTION: Posttranslational modification of proteins by reversible acetylation regulates key biological processes. Histone deacetylases (HDACs) catalyze protein deacetylation and are frequently dysregulated in tumors. This has spurred the development of HDAC inhibitors (HDACi). Such epigenetic drugs modulate protein acetylation, eliminate tumor cells, and are approved for the treatment of blood cancers. OBJECTIVES: We aimed to identify novel, nanomolar HDACi with increased potency over existing agents and selectivity for the cancer-relevant class I HDACs (HDAC1,-2,-3,-8). Moreover, we wanted to define how such drugs control the apoptosis-autophagy interplay. As test systems, we used human leukemic cells and embryonic kidney-derived cells. METHODS: We synthesized novel pyrimidine-hydroxamic acid HDACi (KH9/KH16/KH29) and performed in vitro activity assays and molecular modeling of their direct binding to HDACs. We analyzed how these HDACi affect leukemic cell fate, acetylation, and protein expression with flow cytometry and immunoblot. The publicly available DepMap database of CRISPR-Cas9 screenings was used to determine sensitivity factors across human leukemic cells. RESULTS: Novel HDACi show nanomolar activity against class I HDACs. These agents are superior to the clinically used hydroxamic acid HDACi SAHA (vorinostat). Within the KH-series of compounds, KH16 (yanostat) is the most effective inhibitor of HDAC3 (IC50 = 6 nM) and the most potent inducer of apoptosis (IC50 = 110 nM; p < 0.0001) in leukemic cells. KH16 though spares embryonic kidney-derived cells. Global data analyses of knockout screenings verify that HDAC3 is a dependency factor in 115 human blood cancer cells of different lineages, independent of mutations in the tumor suppressor p53. KH16 alters pro- and anti-apoptotic protein expression, stalls cell cycle progression, and induces caspase-dependent processing of the autophagy proteins ULK1 and p62. CONCLUSION: These data reveal that HDACs are required to stabilize autophagy proteins through suppression of apoptosis in leukemic cells. HDAC3 appears as a valid anti-cancer target for pharmacological intervention.

Effect of hydrophobic extension of aryl enaminones and pyrazole-linked compounds combined with sulphonamide, sulfaguanidine, or carboxylic acid functionalities on carbonic anhydrase inhibitory potency and selectivity.

Design and synthesis of three novel series of aryl enaminones (3a-f and 5a-c) and pyrazole (4a-c) linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO2 hydrase assay. Enaminone sulphonamide derivatives (3a-c) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2-63.7 nM) and hence compounds 3a and 3c were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative 3c showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC50 = 4.918 and 12.27 µM, respectively) and hypoxic (IC50 = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC50 = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC50 = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that 3c may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.

Arylidine extensions of 3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-benzenesulfonamide derivatives: Synthesis, computational simulations and biological evaluation as tumor-associated carbonic anhydrase inhibitors.

Several pyrazole-benzene sulfonamides were reported as human carbonic anhydrase inhibitors. In this research work, a design of Arylidine-extented 5-oxo-pyrazole benzenesulfonamides (4a-i), (8a-d) and (10a-e) were reported based on tail-approach design. Beside the reported synthetic procedures and confirmation by different analytical procedures, a DFT study was employed to confirm the Z- conformer of the synthesized compounds. In vitro biological assay against four different human carbonic anhydrases took place and based on the results, SAR study was illustrated and selectivity indexes were discussed. Compounds 4g and 8a exhibited the best inhibitory activity among the target compounds with values (hCAIX: KI = 71.2 nM, hCAXII: KI = 22.5 nM), (hCAIX: KI = 34.3 nM, hCAXII: KI = 74.3 nM); respectively. Both of them were subjected to cellular assay against two different cancer cell lines with expressing nature to hCA isoforms under both normoxic and hypoxic conditions. Compound 4g showed the highest cytotoxic activity against MCF-7 cancer cell line (IC50 = 4.15 µM under hypoxic conditions and IC50 = 8.59 µM under normoxic conditions) compared to the reference drug doxorubicin under normoxic, (IC50 = 4.34 µM), and hypoxic, (IC50 = 2.23 µM), conditions. Further cellular investigations were employed to study the effect of this compound on the cell cycle of the affected cell line. Finally, molecular docking supported by molecular dynamic simulation was utilized to understand the mechanism of the inhibitory activity of two of these compounds - as representative examples- based on the designed rational.

Development of Pyrazine-Anilinobenzamides as Histone Deacetylase HDAC1-3 Selective Inhibitors and Biological Testing Against Pancreas Cancer Cell Lines.

Class I histone deacetylase (HDAC) enzymes are key regulators of cell proliferation and are frequently dysregulated in cancer cells. Here we describe the synthesis of a novel series of class-I selective HDAC inhibitors containing anilinobenzamide moieties as ZBG connected with a central (piperazin-1-yl)pyrazine moiety. Compounds were tested in vitro against class-I HDAC1, 2, and 3 isoforms. Some highly potent HDAC inhibitors were obtained and were tested in pancreatic cancer cells and showed promising activity. Moreover, we summarize how the growth-inhibitory effects of these compounds can be determined in murine pancreatic cancer cell lines.

Insights into the effect of elaborating coumarin-based aryl enaminones with sulfonamide or carboxylic acid functionality on carbonic anhydrase inhibitory potency and selectivity.

Recently, different mechanisms for inhibition of carbonic anhydrases (CAs) have been reported, such as the classical zinc-binding (exerted by sulfonamides and carboxylic acids) as well as occluding the entrance of the CA active site (exerted by coumarins). In this manuscript, we studied the effect of combining the pharmacopheric parts responsible for these two mechanisms on CA inhibitory potency and selectivity through the design and synthesis of novel coumarins tethered with the zinc-binding sulfonamide (5a-f, 11a-b and 13a-b) or carboxylic acid (7a-f) groups. In addition, another set of coumarin derivatives (9a-b) with no zinc-binding group (ZBG) was designed to act as non-classical CA inhibitors. The synthesized coumarins were examined for their inhibitory activities towards four hCA isoforms I, II, IX and XII. Coumarin sulfonamides (5a-f, 11a-b and 13a-b) effectively inhibited both tumor-associated hCA IX (KIs: 8.9-133.5 nM) and hCA XII (KIs: 3.4-42.9 nM) isoforms, whereas coumarin carboxylic acids (7a-f) weakly affected hCA IX (KIs: 0.49-11.2 µM) and hCA XII (KIs: 0.51-10.1 µM) isoforms. The coumarin based inhibitors featuring zinc-binding sulfonamide or carboxylic acid group achieved low to moderate hCA IX/XII selectivity. Interestingly, the ZBG-free coumarin derivatives (9a-b) emerged not only as effective hCA IX (KIs = 93.3 and 63.8 nM, respectively) and hCA XII (KIs = 85.7 and 72.1 nM, respectively) inhibitors, but also as a highly hCA IX/XII selective inhibitors over the off-target hCA I/II isoforms (SIs > 1000). Coumarin 9a was further evaluated for its anti-proliferative effect on MCF-7 and PANC-1 cancer cell lines, as well as its effect on the cell cycle and apoptosis towards MCF-7 cell line.

Docking, Binding Free Energy Calculations and In Vitro Characterization of Pyrazine Linked 2-Aminobenzamides as Novel Class I Histone Deacetylase (HDAC) Inhibitors.

Class I histone deacetylases, HDAC1, HDAC2, and HDAC3, represent potential targets for cancer treatment. However, the development of isoform-selective drugs for these enzymes remains challenging due to their high sequence and structural similarity. In the current study, we applied a computational approach to predict the selectivity profile of developed inhibitors. Molecular docking followed by MD simulation and calculation of binding free energy was performed for a dataset of 2-aminobenzamides comprising 30 previously developed inhibitors. For each HDAC isoform, a significant correlation was found between the binding free energy values and in vitro inhibitory activities. The predictive accuracy and reliability of the best preforming models were assessed on an external test set of newly designed and synthesized inhibitors. The developed binding free-energy models are cost-effective methods and help to reduce the time required to prioritize compounds for further studies.

Egyptian dermatologists attitude toward telemedicine amidst the COVID19 pandemic: a cross-sectional study.

BACKGROUND: Telemedicine involves distant exchange of medical information between health providers and patients via a telecommunication device with/without the aid of an audiovisual interactive assistance. The current COVID 19 pandemic impact on health services mandated an utmost readiness to implement telemedicine which in part is dependent on health care providers willingness to adopt such platforms. AIM: The aim of this cross sectional study was to assess knowledge and attitude toward telemedicine Egyptian dermatologists amidst the COVID 19 pandemic. PATIENTS AND METHODS: A cross sectional study was designed and data were collected using structured self-administered online questionnaires. RESULTS: Dermatologists had a good knowledge about telemedicine (mean 4.17 ± 1.63; p < .05). Of those completing the questionnaire, 193 (68.9%) were familiar with the term 'telemedicine' and 164 (58.6%) were familiar with tools like teleconferencing. The majority of responding dermatologists 227 (81.1%) were confident that the COVID 19 pandemic is a good opportunity to start applying telemedicine protocols however the majority 234 (83.6%) preferred using it on trial basis at first before full implementation. CONCLUSION: In conclusion an overall good attitude toward telemedicine was reported with a mean of 3.39 (p < .05). Further large scale studies are required to verify such findings.

Conservative Management of Suspected Emphysematous Gastritis.

Emphysematous gastritis is a rare surgical condition. Although there is a lack of a common definition, the key features of its presentation include gastric emphysema on imaging and the presence of gas-forming organisms in the gastric mucosa. In this study, we report the case of an 80-year-old Caucasian male who presented with abdominal pain; a computed tomography scan demonstrated gastric emphysema (intra-mural air within the stomach). After upper gastrointestinal endoscopy excluded gross perforation, ulcer, and malignancy, the patient recovered to baseline with conservative management consisting of gastric rest (nil by mouth and nasogastric tube decompression), intravenous antibiotics, and intravenous proton pump inhibitor. Given the wide pathogenic mechanisms for gastric emphysema, we recommend a conservative but cautious approach if the patient does not demonstrate clinical features of hemodynamic instability, sepsis, and peritonitis.

Design and synthesis of novel pyridopyrimidine derivatives with anchoring non-coplanar aromatic extensions of EGFR inhibitory activity.

The present study describes the synthesis of three series of 4-substituted pyridopyrimidin derivatives 4a-h, 5a-d. 6a-d, starting from 2-amino-6-(4-methoxyphenyl)-4-(4-(substituted) phenyl)nicotinonitrile 2a-d via the reaction with N,N-dimethyl-N-' substituted phenyl formimidamide to obtain 4a-h or with either phenyl isothiocyanate 1:1 and 1:2 to obtain 5a-d, 6a-d respectively. The synthesized compounds were evaluated for their effectiveness as EGFR inhibitors against Gefitinib. Six compounds; 4b,g,h, 5c and 6a,d prompted significantly higher EGFR inhibitory activity relative to that of Gefitinib. While two compounds 4d and 4f showed IC50 values non-significantly different from that of the reference drug. Furthermore, compounds 4a, 4 h, 6a and 6d were chosen to be assessed in vitro for their cytotoxicity against two EGFR-overexpressing cell lines; two human cancer cell lines namely: MCF7 and MDA-MB-361. Moreover, cell cycle analysis and apoptotic assay was applied for compound 4b that showed most potent inhibitory activity on EGFR, and the highest cytotoxicity against MCF7 and MDA-MB-361, where cell cycle arrest was achieved at pre G and S phases with increased apoptosis. Additionally, a molecular docking study was achieved to inspect the interaction of this compound with the active site of EGFR-TK.

Importance of glutamine 189 flexibility in SARS-CoV-2 main protease: Lesson learned from in silico virtual screening of ChEMBL database and molecular dynamics.

The current global pandemic outbreak of COVID-19, caused by the SARS-CoV-2, strikes an invincible damage to both daily life and the global economy. WHO guidelines for COVID-19 clinical management includes infection control and prevention, social distancing and supportive care using supplemental oxygen and mechanical ventilator support. Currently, evolving researches and clinical reports regarding infected patients with SARS-CoV-2 suggest a potential list of repurposed drugs that may produce appropriate pharmacological therapeutic efficacies in treating COVID-19 infected patients. In this study, we performed virtual screening and evaluated the obtained results of US-FDA approved small molecular database library (302 drug molecule) against two important different protein targets in COVID-19. Best compounds in molecular docking were used as a training set for generation of two different pharmacophores. The obtained pharmacophores were employed for virtual screening of ChEMBL database. The filtered compounds were clustered using Finger print model to obtain two compounds that will be subjected to molecular docking simulations against the two targets. Compounds complexes with SARS-CoV-2 main protease and S-protein were studied using molecular dynamics (MD) simulation. MD simulation studies suggest the potential inhibitory activity of ChEMBL398869 against SARS-CoV-2 main protease and restress the importance of Gln189 flexibility in inhibitors recognition through increasing S2 subsite plasticity.

Novel 3-substituted coumarins as selective human carbonic anhydrase IX and XII inhibitors: Synthesis, biological and molecular dynamics analysis.

In this study, diverse series of coumarin derivatives were developed as potential carbonic anhydrase inhibitors (CAIs). A "tail" approach was adopted by selecting the coumarin motif as a tail that is connected to the ZBG benzenesulfonamide moiety via a hydrazine (4a,b) or hydrazide (5a,b) linker. Thereafter, an aryl sulfone tail was incorporated to afford the dual tailed coumarin-sulfonamide arylsulfonehydrazones (13a-d) and hydrazides (14a,b). Then, the ZBG were removed from compounds 13 and 14 to furnish coumarin arylsulfonehydrazones (11a-d) and hydrazides (12a,b). Coumarin-sulfonamides 4 and 5 emerged as non-selective CAIs as they displayed good inhibitory activities toward all the examined CA isozymes (I, II, IX and XII) in the nanomolar ranges. Interestingly, the "dual-tail" approach (compounds 13 and 14) succeeded in achieving a good activity and selectivity toward CA IX/XII over the physiologically dominant CA I/II. In particular, compounds 13d and 14a were the most selective coumarin-sulfonamide counterparts. Concerning non-sulfonamide coumarin derivatives, coumarins 8 exhibited excellent activity and selectivity profiles against the target hCA IX/XII, whereas, coumarins 11 and 12 reported excellent selectivity profile, but they barely inhibited hCA IX/XII with KIs spanning in the micromolar ranges. Furthermore, molecular modelling studies were applied to get a deep focus about the feasible affinities and binding interactions for target coumarin-sulfonamides 4, 5, 13 and 14 with the active site for CA II, IX and XII isoforms.

Comparative study of intralesional tuberculin protein purified derivative (PPD) and intralesional measles, mumps, rubella (MMR) vaccine for multiple resistant warts.

BACKGROUND: Cutaneous warts are frequent conditions that possess much challenge to treat. OBJECTIVE: To evaluate safety and efficacy of intralesional injection of tuberculin purified protein derivative (PPD) antigen injection vs MMR (mumps, measles, rubella) antigen for the treatment of multiple warts. METHODS: The study included 90 Patients who were divided into three groups (A, B, and C). Each group consisted of (30) patients. Group (A) subjects received intralesional PPD injections. Group (B) subjects received intralesional MMR antigen injection and Group (C) received intralesional saline injection. RESULTS: Full clearance of warts was observed in 18 (60%) of patients in group (A) (70%) vs 24 patients (80%) in group (B). Distal warts completely disappeared in 18 (60%) of patients in group A and 12 (40%) of patients in group B. Infrequent side effects including pain, erythema, and minimal induration were reported in both groups. CONCLUSION: We established a good safety and efficacy profile for tuberculin PPD and MMR antigens in resistant wart treatment.

Implications of cigarette smoking on early-onset androgenetic alopecia: A cross-sectional Study.

BACKGROUND: Androgenetic alopecia (AGA) is a condition affecting both males and females. Aims We aimed to assess the demographic and clinical features of early-onset AGA among smokers and nonsmokers and to evaluate whether prevalence of AGA was affected by smoking. PAATIENTS/METHODS: One thousand (1000) healthy males aged between 20 and 35 years not complaining of any local scalp condition and free of any mental illness were recruited for this study and divided into two groups of 500 each based on their smoking attitudes. Androgenetic alopecia was classified according to the Hamilton baldness scale, and trichoscopy was used to confirm the diagnosis of AGA. A designed questionnaire to determine basic physical and smoking habits completed and results was interpreted and analyzed. RESULTS: The majority of smokers (425) had a form of AGA, while only (200) nonsmokers had a degree of AGA (P < .01). Of the smokers group, 235 (47%) had grade III AGA and 120 subjects (24%) had grade IV AGA. In the nonsmokers group, 100 subjects (20%) had grade II AGA and 50 subjects (10%) had either grade III or IV AGA. CONCLUSION: The prevalence of AGA among smokers was statistically higher than among nonsmokers, while severity of AGA was not associated with the intensity of smoking. Nicotine and its derivative cotinine might be responsible for accelerating AGA progress pending further validation.

Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity.

Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.