No abstract

Human health in the current medical era is facing numerous challenges, especially cancer. So, the therapeutic arsenal for cancer should be unremittingly enriched with novel small molecules that selectively target tumour cells with minimal toxicity towards normal cells. In this context, herein a new series of 3,6disubstituted pyridazines 11a-r has been synthesised and evaluated for in vitro anticancer activity. They possessed good anti-proliferative action towards human breast cancer T-47D (IC 50 range: 0.43 ± 0.01 À 35.9 ± 1.18 mM) and MDA-MB-231 (IC 50 range: 0.99 ± 0.03 À 34.59 ± 1.13 mM) cell lines, whereas they displayed weak activity against the tested ovarian cancer cell line SKOV-3. Among the studied compounds, the methyltetrahydropyran-bearing pyridazine 11m emerged as the unique submicromolar growth inhibitor herein reported towards both T-47D (IC 50 ¼ 0.43 ± 0.01 mM) and MDA-MB-231 (IC 50 ¼ 0.99 ± 0.03 mM) cell lines. In addition, the biological results indicated that pyridazines 11l and 11m exerted an efficient alteration within the cell cycle progression as well as induction of apoptosis in both T-47D and MDA-MB-231 cells. Moreover, pyridazines 11l and 11m displayed good mean tumour S. I. values of 13.7 and 16.1 upon assessment of their cytotoxicity towards non-tumorigenic breast MCF-10A cells. Furthermore, an in silico study proposed CDK2 as a probable enzymatic target for pyridazines 11, and explored their binding interactions within the vicinity of CDK2 binding site. Subsequently, pyridazines 11e, 11h, 11l, and 11m were selected to be evaluated for their ability to inhibit CDK2, where they exerted good inhibitory activity (IC 50 ¼ 151, 43.8, 55.6 and 20.1 nM, respectively). Finally, the in silico study implied that target pyridazines 11 exhibited not only an efficient anticancer activity but also an acceptable ADME, physicochemical and druglikeness properties, specifically pyridazines 11l and 11m. Overall the obtained results from this study quite sustained our strategy and gave us a robust opportunity for further development and optimisation of 3,6-disubstituted pyridazine scaffold to enrich therapeutic arsenal with efficient and safe anticancer CDK inhibitors.

Acute painful crisis is the most frequent complication of sickle cell disease (SCD) in children. Recurrent vaso-occlusion may be associated with cardiac injury. The study aimed to assess silent myocardial injuries for sickle cell children during acute painful crisis by measuring serum level of troponin I and galectin-3. The study included 87 participates; study group (n = 44) sickle cell children presented at Jeddah hospitals in Saudi Arabia by painful crisis or acute illness as fever or cough (2017-2018). The controls were healthy children (n = 43). Demographic and history data were collected from the cases. Troponin I and galectin-3 were measured. Galectin-3 values were higher among cases with significant difference when compared to controls (7.5 ± 3.1 versus 3.2 ± 1.6, < 0.001). Galectin-3 at a cutoff > 5.1 ng/ml, the sensitivity was 88.64 and specificity was 88.37. Galectin-3 levels were higher for the pain crisis subgroup in comparison to acute illness group with significant difference (r 0.551*, p < 0.001*. Galectin-3 values were higher among troponin-positive cases with significant difference (p = 0.046) to troponin-negative cases.Conclusion: Positive results of troponin I and high levels of galectin-3 in sickle cell children during acute painful crisis were potent indicators for subclinical myocardial injury. What is Known: • The hallmark of sickle cell disease is recurrent episodes of vaso-occlusive crisis which had deleterious effects on many organs. • Cardiac changes in pediatric sickle cell disease whether structural or functional are mainly attributed to chronic anemia and or pulmonary hypertension. What is New: • The observed positive results of cardiac troponin I and high values of galectin-3 in sickle cell children during vaso-occlusive crisis are strong indicator of myocardial ischemia and ongoing cardiac fibrosis respectively. • The observed correlation between biological markers (positive troponin and high galectin-3) could be an indication of subclinical cardiac injury.

Introduction recent studies show a good relationship between breast cancer (BC) and human papillomaviruses (HPV) wich is responsible for about 18% of BC cases. This study aimed to assess the relationship between different genotypes of HPV and the expression of P53 and retinoblastoma (RB) genes and estrogen and progesterone receptors in BC among Sudanese women. Methods one hundred and fifty tissue blocks were obtained from females diagnosed with BC. Positive samples were used to determine genotypes with an applied biosystem (ABI 3730XL) genetic analyzer for sequencing and immunohistochemistry. Results 13/150 samples showed HPV DNA. High-risk HPV-16 was detected in 5 cases, high-risk-HPV-58 was found in four cases, and HPV-18 was detected in three cases. Low-risk-HPV-11 was detected in a single invasive lobular carcinoma (ILC) case. P53 and RB gene mutations were detected in 35 and 30 BC cases, respectively. P53 gene mutation was frequently identified in grade (III) BC while RB gene mutation was positive in grade (II). Grade (II) BC had a higher incidence of HPV-16 and 58. On the other hand, HPV-18 had a higher incidence in grade (III). Estrogen and progesterone receptors were expressed in 94 and 79 HPV cases among the study group, respectively. Conclusion this study elucidates the associations between HPV genotypes and BC. A statistically significant association was observed among p53 and RB gene mutations and different BC histological types. On the other hand, there was a statistically insignificant association between HPV genotyping and different BC gradings, BC histological types, P53 and RB genes mutations, and estrogen and progesterone receptor expression. Also, there was a statistically insignificant association among estrogen and progesterone receptors expression and BC grading. RB gene mutation was significantly associated with different BC grades. On the other hand, there was a statistically insignificant association between progesterone receptor expression and BC.

Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells,