Targeting Colon Cancer Cells with Pyrazino-Imidazolinone Derivatives: Synthesis, Molecular Docking, and in Vitro Evaluation of Anti-Proliferative and Pro-Apoptotic Activities.

We report the synthesis, spectroscopic characterization, molecular docking and biological evaluation of nine pyrazino-imidazolinone derivatives. These derivatives were evaluated for their anticancer activity against three cancer cell lines: 518A2 melanoma, HCT-116, and HCT-116 p53 knockout mutant colon carcinoma. The MTT assay was employed to assess their effectiveness. Among the nine compounds tested, four compounds (5 a, 5 d, 5 g, and 5 h) exhibited promising antiproliferative activity specifically against HCT-116 p53-negative cells (IC50 0.23, 0.20, 2.07 and 58.75 µM, respectively). Interestingly, treatment with the 3,4-dimethoxyphenyl derivative 5a resulted in a significant increase (199 %) in caspase activity in HCT-116 p53-negative cells compared to untreated cells while the bromo-pyrazine derivative 5d demonstrated (190 %) increase. These findings suggest that compounds 5a and 5 d induce p53-independent apoptotic cell death. Additionally, in silico molecular docking studies with EGFR and tyrosinase proteins indicated that compounds 5 d and 5 e have the potential to bind to important anticancer drug targets.

New Pyrano-4H-benzo[g]chromene-5,10-diones with Antiparasitic and Antioxidant Activities.

New pyranonaphthoquinone derivatives were synthesized and investigated for their activity against Trypanosoma brucei, Leishmania major, and Toxoplasma gondii parasites. The pentafluorophenyl derivative was efficacious against T. brucei with single digit micromolar EC50 values and against T. gondii with even sub-micromolar values. The 3-chloro-4,5-dimethoxyphenyl derivative showed an activity against amastigotes of Leishmania major parasites comparable to that of amphotericin B. In addition, antioxidant activities were observed for the bromophenyl derivatives, and their redox behavior was studied by cyclovoltammetry. Anti-parasitic and antioxidative activities of the new naphthoquinone derivatives appear uncorrelated.

Anti-cancer potential of natural products containing (6H-dibenzo[b,d]pyran-6-one) framework using docking tools.

To explore complex biological and chemical systems, pharmaceutical research has effectively included several molecular modeling tools into a range of drug development initiatives. Molecular docking methods are widely employed in current drug design to investigate ligand conformations within macromolecular targets' binding sites. This method also estimates the ligand-receptor binding free energy by assessing critical phenomena involved in the intermolecular recognition process. In an attempt, several natural products have been synthesized in our laboratory. All the synthesized compounds containing (6H-Dibenzo[b,d]pyran-6-one) framework were subjected to molecular docking studies for the inhibition of CYP1B1 and BCL2 proteins using Auto Dock Vina software and the interacting amino acid residues were visualized using Discovery Studio, to look into the binding modalities that might influence their anticancer properties. The in silico molecular docking study outcomes showed that all the synthesized compounds having optimum binding energy and have a decent affinity to the active pocket, thus, they may be considered as a respectable inhibitor of CYP1B1 and BCL2 proteins.

A new 4-(pyridinyl)-4H-benzo[g]chromene-5,10-dione ruthenium(II) complex inducing senescence in 518A2 melanoma cells.

2-Amino-5,10-dihydro-5,10-dioxo-4(pyridine-3-yl)-4H-benzo[g]chromene-3-carbonitrile 5, a cytotoxic lawsone derivative, was reacted with [Ru(p-cymene)Cl2]2 to afford a new Ru(II) 'piano-stool' complex 6 which differed from its ligand 5 by a greater selectivity for highly invasive 518A2 melanoma cells over human dermal fibroblasts in MTT cytotoxicity assays, and by inducing senescence rather than apoptosis in the former. DNA is a likely cellular target of complex 6 as it bound, presumably non-covalently, to linear and circular double-stranded DNA in vitro and as ruthenium was found in the lysate of nuclei of treated 518A2 melanoma cells. It also caused a fivefold increase of reactive oxygen species in these cells, originating from a more persistent redox cycling as visualised by cyclic voltammetry.

Changing pattern in the risk factors for diabetes in young adults from the rural area of Baluchistan.

OBJECTIVE: To observe changing pattern in the risk factors for diabetes as overweight, obesity, smoking, hypertension and family history of diabetes in young adults in the rural area of Baluchistan. METHODS: A community based observational study was carried out in the rural area of Baluchistan by conducting two surveys, in the years 2002 and 2009 respectively. The survey was further subdivided into two groups i.e. young adults (15-25 years) and adults (> or = 25 years). In this study, data of young adults was analyzed. Data obtained in 2002 was also analyzed according to the current guidelines and compared with 2009 survey. RESULTS: A total of 230 and 197 young adults participated in 2002 and 2009 surveys respectively. Obesity increased significantly (p < 0.001) from 20 (10.15%) young adults in the year 2002 to 64 (27.82%) in 2009. Similarly 15 (7.61%) young adults were overweight in 2002 which increased to 24 (10.43%) in 2009 (p < 0.317). Smoking increased from 8 (4.06%) to 49 (21.3%) in 2009 (p < 0.001). Family history of diabetes mellitus also showed a significant increase (p < 0.005). Hypertension increased from 13 (6.6%) young adults in 2002 survey to 17 (7.39%) in 2009, the increase was not statistically significant (p < 0.749). CONCLUSION: The present study showed that risk factors for diabetes such as overweight, obesity, smoking, hypertension and family history of diabetes increased over time in the young adults of rural Baluchistan.

Synthesis and biological evaluation of coumarin-quinone hybrids as multifunctional bioactive agents.

We report the synthesis, structural characterization and pharmaceutical activity of four coumarin-quinone hybrids. The compounds were significantly active against Staphylococcus aureus, Pseudomonas aeoginosa and Candida albicans. Promising antioxidant activity was observed when compared to ascorbic acid. Two compounds, DTBSB and DTBSN, also showed commendable in vitro antiproliferative activities against the cells of human cancer cell lines MCF-7, MDA-MB-231, COLO-205, HT-29 and A549 along with appreciable tumor selectivity with distinct selectivity index. Molecular docking studies using cyclooxygenase-2 (PDB ID: 6COX) revealed strong binding affinities for the COX-2 active site. Moreover, ADMET properties of the synthesized compounds were determined using the pKCSM and SwissADME online tools and all the compounds had accurate pharmacokinetic profiles. Hence, the new coumarin-quinone hybrids DTBSB and DTBSN can be considered for optimization and lead development.

A New Naphthopyran Derivative Combines c-Myb Inhibition, Microtubule-Targeting Effects, and Antiangiogenic Properties.

Based on the promising c-Myb inhibitor 1b, a series of 2-amino-4-aryl-4H-naphtho[1,2-b]pyran-3-carbonitriles (1a, 2a-q, 3a-g) were repurposed or newly synthesized via a three-component reaction of 1-naphthol, and various aryl aldehydes and malononitrile and screened for their c-Myb inhibitory activities. 1b also served as a lead compound for seven new naphthopyran derivatives (3a-f), which were cytotoxic with nanomolar IC50 values, to inhibit the polymerization of tubulin, and to destabilize microtubules in living cells. Especially, the alkyne 3f, originally made for intracellular localization studies using click chemistry, showed an overall high activity in all assays performed. A strong G2/M cell cycle arrest was detected, which resulted in a distinct increase in sub-G1 cells through the induction of effector caspases 3 and 7. Inhibition of angiogenesis was confirmed in vitro and in vivo. In summary, 3f was found to be a pleiotropic compound with high selectivity for cancer cells, combining c-Myb inhibitory, microtubule destabilizing, and antiangiogenic effects.

Coordination of Oral Anticoagulant Care at Hospital Discharge (COACHeD): protocol for a pilot randomised controlled trial.

BACKGROUND: Oral anticoagulants (OACs) are commonly prescribed, have well-documented benefits for important clinical outcomes but have serious harms as well. Rates of OAC-related adverse events including thromboembolic and hemorrhagic events are especially high shortly after hospital discharge. Expert OAC management involving virtual care is a research priority given its potential to reach remote communities in a more feasible, timely, and less costly way than in-person care. Our objective is to test whether a focused, expert medication management intervention using a mix of in-person consultation and virtual care follow-up, is feasible and effective in preventing anticoagulation-related adverse events, for patients transitioning from hospital to home. METHODS AND ANALYSIS: A randomized, parallel, multicenter design enrolling consenting adult patients or the caregivers of cognitively impaired patients about to be discharged from medical wards with a discharge prescription for an OAC. The interdisciplinary multimodal intervention is led by a clinical pharmacologist and includes a detailed discharge medication reconciliation and management plan focused on oral anticoagulants at hospital discharge; a circle of care handover and coordination with patient, hospital team and community providers; and early post-discharge follow-up virtual medication check-up visits at 24 h, 1 week, and 1 month. The control group will receive usual care plus encouragement to use the Thrombosis Canada website. The primary feasibility outcomes include recruitment rate, participant retention rates, trial resources management, and the secondary clinical outcomes include adverse anticoagulant safety events composite (AASE), coordination and continuity of care, medication-related problems, quality of life, and healthcare resource utilization. Follow-up is 3 months. DISCUSSION: This pilot RCT tests whether there is sufficient feasibility and merit in coordinating oral anticoagulant care early post-hospital discharge to warrant a full sized RCT. TRIAL REGISTRATION: NCT02777047.

Anticancer Active Heterocyclic Chalcones: Recent Developments.

BACKGROUND: Chalcones are structurally simple compounds that are easily accessible by synthetic methods. Heterocyclic chalcones have gained the interest of scientists due to their diverse biological activities. The anti-tumor activities of heterocyclic chalcones are especially remarkable and the growing number of publications dealing with this topic warrants an up-to-date compilation. METHODS: Search for antitumor active heterocyclic chalcones was carried out using Pubmed and Scifinder as common web-based literature searching tools. Pertinent and current literature was covered from 2015/2016 to 2019. Chemical structures, biological activities and modes of action of anti-tumor active heterocyclic chalcones are summarized. RESULTS: Simply prepared chalcones have emerged over the last years with promising antitumor activities. Among them, there are a considerable number of tubulin polymerization inhibitors. But there are also new chalcones targeting special enzymes such as histone deacetylases or with DNA-binding properties. CONCLUSION: This review provides a summary of recent heterocyclic chalcone derivatives with distinct antitumor activities.

Curcumin: reclaiming the lost ground against cancer resistance.

Curcumin, a polyphenol, has a wide range of biological properties such as anticancer, antibacterial, antitubercular, cardioprotective and neuroprotective. Moreover, the anti-proliferative activities of Curcumin have been widely studied against several types of cancers due to its ability to target multiple pathways in cancer. Although Curcumin exhibited potent anticancer activity, its clinical use is limited due to its poor water solubility and faster metabolism. Hence, there is an immense interest among researchers to develop potent, water-soluble, and metabolically stable Curcumin analogs for cancer treatment. While drug resistance remains a major problem in cancer therapy that renders current chemotherapy ineffective, curcumin has shown promise to overcome the resistance and re-sensitize cancer to chemotherapeutic drugs in many studies. In the present review, we are summarizing the role of curcumin in controlling the proliferation of drug-resistant cancers and development of curcumin-based therapeutic applications from cell culture studies up to clinical trials.

Metastatic 4S neuroblastoma with excellent outcome in Saudi cancer center.

OBJECTIVES: To retrospectively review a small series of infant neuroblastoma (NBL) in a single Saudi medical institution over 10 years, including their presentation, management, and outcomes. METHODS: Fifty-three subjects aged 0 to 14 years with previously untreated NBL who were diagnosed and treated at Princess Nora Oncology Center, King Abdulaziz Medical City (KAMC), Jeddah, Saudi Arabia, between 2010 and 2019. Six infants (11.3%) had stage 4S characteristics. RESULTS: The median age at diagnosis was 3 months (range 52 days - 4 months). Biopsies confirmed that the adrenal gland was the primary tumor site for 3 patients, while the other 2 had retroperitoneal sites. Four patients had favorable histology, and one had unfavorable histology. All patients had liver metastasis, and no bone marrow or skin metastasis was recorded. All patients received chemotherapy except one, and all survived with no disease progression at a median follow up to 5 years. CONCLUSION: Our data confirm that NBL-4S is a curable cancer, especially with early recognition and intervention. Chemotherapy is the first-line treatment for symptomatic patients. Unless the condition is life threatening, radiotherapy is not indicated. Surgical resection may be indicated in younger infants with localized tumors and favorable biology, but otherwise, it is not usually indicated for residual cases.

Thrombolysis in Myocardial Infarction (TIMI) Risk Score Assessment for Complications in Acute Anterior Wall ST Elevation Myocardial Infarction.

Introduction and objective Effective risk stratification is integral to the management of acute coronary syndromes. The Thrombolysis in Myocardial Infarction (TIMI) risk score for ST-segment elevation myocardial infarction (STEMI) is based on eight high-risk parameters that can be used at the bedside for risk stratification of patients presenting with STEMI. This study was designed to determine the frequency of cardiac complications of anterior wall STEMI assessed on TIMI risk score and to compare the rate of cardiac complications according to the TIMI score. Materials and methods An observational case series study was conducted in the Department of Cardiology at Sandeman Provincial Hospital in Quetta, Pakistan. The study duration was six months, from September 22, 2016 to March 23, 2017. A total of 369 patients were selected who had anterior wall myocardial infarction and received thrombolytic therapy, according to the inclusion and exclusion criteria. The TIMI score was calculated by proforma at the time of admission. Patients were divided into three groups: low-risk, moderate-risk, and high-risk TIMI groups. The frequency of complications of anterior wall myocardial infarction at the time of discharge was compared among these groups. Results The study included 285 male patients (77.2%) and 84 (22.8%) female patients. A total of 174 (47.2%) patients were smokers, 79 (21.4%) were obese, and 93 (25.2%) had hyperlipidemia. Of the 369 patients, 205 (55.6%) were included in the low-risk group, 150 (40.7%) in the moderate-risk group, and 14 (3.8%) in the high-risk group. Post-myocardial infarction arrhythmias were noted in 33 (16.09%) patients in the low-risk group and six (4%) patients in the moderate-risk group. Left ventricular dysfunction was noted in 158 (77.07%) patients in the low-risk group, 78 (52%) patients in the moderate-risk group, and seven (50%) patients in the high-risk group. Cardiogenic shock occurred in seven (3.41%) patients in the low-risk group, 47 (31.33%) patients in the moderate-risk group, and 0 (0%) patient in the high-risk group. Death occurred in seven (3.41%) patients in the low-risk group, 19 (12.66%) patients in the moderate-risk group, and seven (50%) patients in the high-risk group. Conclusion TIMI scoring provides a better assessment in terms of complications caused by STEMI. The complications include the mechanical and electrophysiology of the heart.

Recent developments concerning the application of the Mannich reaction for drug design.

INTRODUCTION: The versatile multicomponent Mannich reaction occupies a salient position in organic chemistry and drug design. Sound knowledge of its scope and variations and of the biological activities of Mannich bases is crucial for the development and improvement of drugs for various diseases. Areas covered: The following article provides an overview of the latest developments in the field of drugs based on the Mannich reaction. Web-based literature searching tools such as PubMed and SciFinder were applied to obtain useful articles. In addition, pertinent literature that was recently published by the authors is discussed in this manuscript. The chemical structures of bioactive Mannich bases are also given. Expert opinion: The Mannich reaction represents a feasible and cost-effective procedure with great potential for drug development. Several newly discovered Mannich bases exhibit sound activities against various human diseases as well as favorable pharmacokinetics. Thus, scientific research about Mannich bases is prospering and appears very attractive both for chemists and for clinicians.

Chemical and Biological Aspects of the Natural 1,4-Benzoquinone Embelin and its (semi-)Synthetic Derivatives.

BACKGROUND: Like the impressive biological properties of embelin, its chemical aspects have raised the interest of scientists in the field as well. A detailed understanding of the chemistry of embelin is necessary to fully exploit it medicinally. METHODS: Search for embelin isolation and its chemical modifications was carried out using web-based literature searching tools such as Pubmed and Scifinder. Pertinent literature is covered up to 2016. Structures of bioactive embelin derivatives are provided. RESULTS: Pure embelin, obtained from Embelia ribes berries extraction or by total synthesis, was applied for a number of biological assays. Semi-synthetic and total synthetic approaches led to new high affinity embelin-derived inhibitors of crucial protein targets and to new embelin derivatives with improved pharmacological properties (e.g., with better water-solubility or as applications for drug carrier systems). CONCLUSION: This review provides a summary of the rich chemistry of embelin and the latest developments in the field of optimized (semi-)synthetic embelin derivatives including their biological activities.

Temporal changes in the prevalence of diabetes, impaired fasting glucose and its associated risk factors in the rural area of Baluchistan.

AIMS: To observe temporal changes in the prevalence of diabetes, impaired fasting glucose and its associated risk factors in the rural area of Baluchistan province of Pakistan according to American Diabetes Association criteria by comparing the two surveys done in 2002 and 2009. METHODOLOGY: This community based survey of 1264 subjects aged 25 years and above was conducted from February 2009 to February 2010 in sixteen villages of southern Baluchistan. The temporal changes were assessed in comparison with a similar survey conducted seven years previously. Data from 2002 survey was also re-analyzed according to the latest ADA criteria. RESULTS: A two-fold increase in the prevalence of diabetes (from 7.2% to 14.2%) was seen in 2009 survey and the prevalence of impaired fasting glucose also increased significantly (6.5-11.0%). An important finding was the number of hypertensives and subjects with positive family history of diabetes also increased significantly (p<0.000) from the previous survey. CONCLUSION: Coordinated National Programs for primary prevention to counteract the increasing prevalence of diabetes are the need of time. Further large scale studies with proper risk factor assessment are needed to ascertain the reasons of rising prevalence of glucose intolerance.