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Undifferentiated endometrial carcinoma (UEC) is a rare and poorly recognized entity, associated with a poor outcome. The clinical, pathologic, and immunohistochemical features of 17 cases diagnosed at our center are described. The median age was 60 yr. Postmenopausal bleeding was the most common presenting symptom (76.9%). Most patients presented with advanced stage (64.7%). Total hysterectomy with bilateral salpingo-oophorectomy was the commonly offered surgical treatment (80.0%). Nine (52.9%) patients received adjuvant treatment. The median overall survival was 11 mo. Pure UEC was seen in 8 cases (47.0%), while dedifferentiated carcinoma in 5 cases (29.4%). The epithelial component was part of carcinosarcoma or was mixed with serous carcinoma in 2 cases (11.8%) each. Positivity for one or more of the cytokeratin cocktails, mostly as strong focal staining, was evident in 16 cases (94.1%). PAX-8 was negative in 13 cases (86.7%). BRG-1/SMARCA4 was lost in 3 cases (20.0%). Eleven cases (64.7%) were MLH1/PMS2 deficient. Ten cases (66.7%) were positive for programmed death ligand 1, with positivity in 10%, 20%, and 100% of tumor cells detected in a single case each. Only 2 of 11 (18.2%) referral cases were correctly diagnosed as UEC. UEC is a rare tumor that is frequently misdiagnosed. A panel of immunostains is necessary to make the correct diagnosis. The range of positivity for programmed death ligand 1 testing suggests that immunotherapy might be considered in the adjuvant setting, especially with the poor response of this tumor to traditional therapies.

Background: Oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has been highlighted as a therapeutic target for anticancer drug design. Objective: Target compounds were designed to address the effect of different substitution patterns at the N atom of the carboxamide moiety on the bioactivity of this series. Methods: Synthesis of the targeted compounds, crystallography, biological evaluation tests against human colon carcinoma (HCT-116), and Glide docking studies. Results: A new series of N-substituted- 4-hydroxy-2-quinolone-3-carboxamides was prepared and characterized by means of FT-IR, 1H and 13C NMR, and elemental analysis. In addition, the identity of the core nucleus 5 was successfully characterized with the aid of X-ray crystallography. Biological activity of prepared compounds was investigated in vitro against human colon carcinoma (HCT-116) cell line. Results revealed that these compounds inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA cellular content. Compounds 7, 14, and 17 which have H-bond acceptor moiety on p-position displayed promising PI3Kα inhibitory activity. On the other hand, derivatives tailored with bulky and hydrophobic motifs (16 and 18) on o- and m-positions exhibited moderate activity. Molecular docking studies against PI3Kα and caspase-3 showed an agreement between the predicted binding affinity (ΔGobsd) and IC50 values of the derivatives for the caspase-3 model. Furthermore, Glide docking studies against PI3Kα demonstrated that the newly synthesized compounds accommodate PI3Kα kinase catalytic domain and form H-bonding with key binding residues. Conclusion: The series exhibited a potential PI3Kα inhibitory activity in HCT-116 cell line.

Background: Elevated levels of serum LDL and total cholesterol are considered important risk factors for the development of atherosclerosis. Cholesteryl ester transfer protein inhibition raises HDL levels and reduces atherosclerotic lesions. Objective: Consequently, there is a great interest in developing new CETP inhibitors. Methods: Herein, synthesis of four chlorobenzyl benzamides 8a-d that aim at CETP inhibition was performed. Results: Benzamide 8a showed the best CETP inhibitory activity with an IC50 of 1.6 μM. In vitro biological data shows that the presence of p-trifluoromethoxy group enhances CETP inhibitory activity more than m-trifluoromethyl groups. QPLD docking shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by hydrophobic lining. The scaffold of 8a-d matches the pharmacophoric points of CETP inhibitors; particularly hydrophobic and aromatic functionalities. Conclusion: Future structural modification is needed to improve CETP inhibitory activity and to enhance understanding of the structure-activity relationship.

Background: Hyperlipidemia is one of the most common chronic diseases worldwide. Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that facilitates the transfer of cholesteryl ester from the atheroprotective high-density lipoprotein (HDL) to the proatherogenic low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). Methods: In this work, synthesis and characterization of five fluorinated 3-benzylamino benzamides 8a-8c, 13a and 13b that target CETP activity were carried out. Results: Benzamides 8b and 8a showed the highest CETP inhibitory activities with an IC50 of 0.75 μ M and 4.1 μ M respectively. It was found that the presence of p-OCF3 group (as in 8a-8c) enhances CETP inhibitory activity more than p-OCF2CHF2 (as in 13a and 13b) which could be attributed to the bulkiness of the tetrafluoroethoxy group hindering their proper orientation in the binding domain. Additionally m-F derivatives were found to have higher activity against CETP than p-F ones leaving the o-F analogues with the weakest anti-CETP bioactivity. Conclusion: Ligand-based and structure-based drug design strategies confirm that hydrophobic interaction mediates ligand/protein complex formation and explains the activity of our verified molecules.

Drugs comprising a heterocyclic system show widespread therapeutic impact such as antimicrobial, antidepressant, antihypertensive, and anticancer activity. We describe herein computational studies that support the promising biological activity of four new compounds (5, 6, 10 and 13). The wild-type and mutant phosphatidylinositol-4,5-bisphosphate 3-kinaseα (PI3Kα) proteins were used as models to explore the potential interaction of the designed molecules with this important kinase involved in the growth regulation of cancer cells. The results of our studies showed that the verified compounds ought to fit into the kinase domain of wild-type and mutant PI3Kαs. It is predicted that they interact with S774, K802, Y836, V851, S854, T856, Q859, and D933 that are known to be key binding residues for active inhibitors both in wild-type and mutant PI3Kαs. Docking scores infer the selectivity of compounds 5, 6 and 10 toward the mutant PI3Kα (H1047R), whereas compound 13 displayed a slightly higher affinity to the wild-type protein. The pharmacophore modeling of PI3Kα inhibitors showed that the explored compounds shared four out of five pharmacophoric points with such inhibitors. Thus, the recently developed four compounds might be recruited as lead structures for the design of new antitumor drugs targeting PI3Kα.

The heterocyclic system is a promising core nucleus in many bioactive compounds. This work describes our effort to synthesize and characterize a set of new biphenyl, benzofuran and benzothiophene carboxamide derivatives. Our biological studies showed that compounds 10 and 17 have antifungal activity against C. galabrate more potent than fluconazole compounds 9, 10, and 17 exerted cytotoxic activities in immortalized embryonic mouse fibroblast cells (3T3) and a human cervical cancer cell line (HeLa); in particular, the cyclic amidine derivative 17 showed selective toxicity against HeLa. This study showed that the tested compounds have the potential to be useful as antitumor drugs after further optimization.

Benzothiophene carboxamide derivatives of aminobenzophenone, aminopyridine, aminobenzimidazole, and aniline derivatives (compounds 1 - 9) were synthesized and compounds 3, 6, 7, 8, and 9 tested in vivo for their hypolipidemic activity. Compounds 1 - 8 were prepared adopting the fusion process at 130 - 150°C between benzothiophene-2-carbonyl chloride and aminobenzophenones, aminopyridine, and anilines, respectively, and were obtained in high yield, while compound 9 was obtained from the reaction of benzothiophene acyl chloride with aminobenzimidazole in DMF at 160°C. At a dose of 15 mg/kg body weight compounds 6, 7, and 9 significantly reduced plasma triglyceride levels in Triton WR-1339-induced hyperlipidemic rats in comparison to control rats. Furthermore, they significantly increased high-density lipoprotein levels. It is therefore reasonable to assume that compounds 6, 7, and 9 may have a promising potential in the treatment of hyperlipidemia and atherosclerosis

Background:Clostridium diffcile infection (CDI) is the most common nosocomial infection. Patients with heart failure (HF) are frequently hospitalized due to exacerbations or with common bacterial infections. It is unclear if patients with HF experience adverse outcomes from CDI compared to patients without HF. We performed a study to evaluate outcomes of CDI in HF patients using the National Inpatient Sample 2014.Methods:Using the National Inpatient Sample 2014, we identified patients with a diagnosis of CDI. These patients were stratified based on HF versus no HF. We calculated the rate of CDI in patients with and without CHF. Chi square test and Logistic regression were used to estimate difference in rates and Odd ratios. Our outcomes of interest included mortality and length of stay in the hospital. All statistics were performed using STATA version 15.Results:A total of 210,391 admission of adult patients (age >18 years) had a diagnosis of CDI. Among those, a total of 49,171 (23.4%) had HF and a total of 161,220 (76.6%) had no history of HF. On comparing CDI patients with HF to without HF, patients with HF were significantly older, had more comorbidities and had high charlson comorbidity index (median 4 vs 2, p<0.001). Patients with HF had a statistically significant increased risk of mortality (11% vs 6%) and had increased length of stay of more than 7 days (56.1% vs 42.3%, p<0.01). On multivariate regression analysis, after adjusting for age and other comorbidities, we found that CDI patients with HF had statistically significant increased risk for mortality with an Odds ratio (1.31, 95% CI, 1.26-1.37, p<0.01).Conclusion:HF is associated with increased mortality and length of stay among hospitalized patients with CDI, even after adjusting for known risk factors for CDI. These finding serve as an opportunity to improve outcomes of hospitalized patients who have HF, possibly through early C. difficilescreening, using narrow spectrum antibiotics whenever possible and treating other comorbidities.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.