Design and Synthesis of Novel 4-Phenoxyquinolines Bearing 3-Hydrosulfonylacrylamido or 1H-Imidazole-4-carboxamido Scaffolds as c-Met Kinase Inhibitors.

A series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing (E)-3-hydrosulfonylacrylamido or 1H-imidazole-4-carboxamido moieties were designed, synthesized and evaluated for their cytotoxicity against A549, MKN-45, and HT-29 cancer cell lines in vitro. All the target compounds showed moderate to significant cytotoxic activity against the tested cells with IC50 values ranging from 0.13 to 2.65 µM. Five of them were further examined for their inhibitory activity against c-Met kinase, which identified compound 30 as a promising agent (c-Met IC50 = 1.52 nM) with IC50 values of 0.24, 0.45, and 0.13 µM against HT-29, MKN-45, and A549 cells, respectively.

Expression of HIF-1α and MDR1/P-glycoprotein in refractory mesial temporal lobe epilepsy patients and pharmacoresistant temporal lobe epilepsy rat model kindled by coriaria lactone.

Hypoxia-inducible factor-1α (HIF-1α) is thought to mediate pharmacoresistance in tumor by inducing Pgp overexpression. We aimed to investigate the expression of HIF-1α and MDR1/P-glycoprotein in refractory epilepsy, to explore the correlation of HIF-1α with epilepsy multidrug resistance. We collected hippocampus and mesial temporal lobe (MTL) cortex of refractory mesial temporal lobe epilepsy (mTLE) patients that underwent surgery, and established a pharmacoresistant TLE rat model kindled by coriaria lactone. We used real-time quantitative PCR (RQ-PCR) and western blot to investigate expression of HIF-1α and MDR1 in hippocampus and MTL/entorhinal cortex. We found that the expression of HIF-1α and MDR1, at both mRNA and protein levels, were up-regulated in hippocampus and MTL cortex of mTLE patients compared with the control cortex (all P < 0.05), and increased in hippocampus and entorhinal cortex of kindled rat model versus the control group (all P < 0.05). These results demonstrated the overexpression of HIF-1α and MDR1/Pgp in hippocampus and MTL/entorhinal cortex of mTLE patients and the pharmacoresistant TLE rat model. HIF-1α may have a regulatory effect on MDR1 expression in refractory epilepsy, which is probably consistent with MDR mechanism in tumor.

Clinical Reasoning: A 26-Year-Old Woman With Recurrent Pain, Weakness, and Atrophy in Bilateral Upper Limbs During Pregnancy and Puerperium.

We present the case of a 26-year-old woman with recurrent episodes of severe pain, weakness, and atrophy in her bilateral upper extremities during pregnancy and puerperium. She reported 2 similar episodes at ages 5 and 10 years, after which she fully recovered. On examination, we observed significant atrophy in her bilateral upper extremity muscles with decreased strength. Needle electromyography (EMG) revealed neurogenic damage in her bilateral upper limbs. The patient's clinical manifestations and auxiliary examination suggested a brachial plexopathy. Metabolic and immune factors that may occur during pregnancy and puerperium were evaluated. We also screened for paraneoplastic, neoplastic, and genetic factors. Finally, a hereditary form of disease was considered. This case emphasizes the importance of early diagnosis and avoidance of triggers.

Elucidation of the Herbicidin Tailoring Pathway Offers Insights into Its Structural Diversity.

The biosynthetic gene clusters for herbicidins ( hbc) and aureonuclemycin ( anm) were identified in Streptomyces sp. KIB-027 and Streptomyces aureus, respectively. The roles of genes possibly involved in post-core-assembly steps in herbicidin biosynthesis in these clusters and a related her cluster were studied. Through systematic gene deletions, structural elucidation of the accumulated intermediates in the mutants, and in vitro verification of the encoded enzymes, the peripheral modification pathway for herbicidin biosynthesis is now fully established.

Discovery and Optimization of Novel 5-Indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrile Derivatives as Potent Antitubulin Agents Targeting Colchicine-binding Site.

Aiming at development of potent antitubulin agents targeting colchicine-binding site, a series of novel 5-indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrilederivatives (5a-5v and 7a-7h) were designed based on bioisosterism and hybridization strategies. All these compounds were concisely synthesized via a three-step process and examined against five human cancer cell lines (HT-29, A549, MKN-45, MDA-MB-231 and SMMC-7721) along with a normal human cell (L02) in vitro. A structure-activity relationships (SARs) study was carried out and optimization towards this series of compounds in cellular assay resulted in the discovery of 5k, which displayed similar or better antitumor potency against the tested cancer cells with IC50 value ranging from 0.02 to 1.22 µM superior to CA-4 and Crolibulin. Significantly, a cell cycle study disclosed the ability of 5k to arrest cell cycle at the G2/M phase, and immunofluorescence assay as well as a colchicine competition assay revealed that tubulin polymerization was disturbed by 5k by binding to the colchicine site. Moreover, the molecular modeling mode showed the posture of 5k and Crolibulin was similar in the colchcine-binding pocket of tubulin as identified with the SARs and pharmacological results. Together, all these results rationalized 5k might serve as a promising lead for a novel class of antitubulin agents for cancer treatments.

Synthesis and biological evaluation of 4-(2-fluorophenoxy)-3,3'-bipyridine derivatives as potential c-met inhibitors.

Six series of novel 4-(2-fluorophenoxy)-3,3'-bipyridine derivatives conjugated with aza-aryl formamide/amine scaffords were designed and synthesized through a structure-based molecular hybridization approach. The target compounds were evaluated for c-Met kinase inhibitory activities and cytotoxicity against four cancer cell lines (HT-29, A549, MKN-45 and MDA-MB-231) in vitro. Most compounds exhibited moderate to excellent potency, and the most promising candidate 26c (c-Met kinase IC50 = 8.2 nM) showed a 4.7-fold increase in cytotoxicity against c-Met-addicted MKN-45 cell line in vitro (IC50 = 3 nM), superior to that of Foretinib (IC50 = 23 nM). The preliminary structure-activity relationship indicated that a 1H-benzo [e] [1,3,4]thiadiazine-3-carboxamide-4,4-dioxide moiety as linker contributed to the antitumor potency.

Clinical features and outcome of super-refractory status epilepticus: a retrospective analysis in West China.

PURPOSE: Data about super-refractory status epilepticus (SRSE) are scarce. This study aimed to assess the clinical features and outcome of patients with SRSE. METHOD: Clinical features of all SRSE patients admitted to the Neurologic Intensive Care Unit (NICU)/Neurology Department of West China Hospital, Sichuan University, between January 2010 and August 2013, were retrospectively analyzed. Outcome at discharge, at the three-month and long-term follow-ups were evaluated using the Glasgow Outcome Scale (GOS). Possible predictors of mortality and outcome were also evaluated. RESULTS: Thirteen patients with SRSE were included. Young patients with encephalitis accounted for the majority of the series (61.5%). In-hospital mortality was 15.4% (2/13), and the three-month mortality was 36.4% (4/11; two patients ceasing therapy were excluded). At the long-term follow-up, 18.2% of patients improved and 45.5% of patients recovered. Patients of older age and those with multiple complications had higher mortality compared with those of younger age and those with fewer complications. For survivors, functional outcome had significantly improved at three-month follow-up (GOS score=4.1 ± 1.2) compared to that at discharge (GOS score=3.1 ± 1.2, P<0.05). Long duration of anesthesia, etiology of encephalitis and positive neuroimaging findings tended to be associated with poor functional outcome. CONCLUSION: We conclude that the typical patient susceptible to development of SRSE in West China is a young patient with encephalitis. Older age and multiple complications increase the risk of death. Most patients can survive with aggressive therapy, and their functional outcome improves over time.

Effectiveness of levetiracetam use following resective surgery in patients with refractory epilepsy: a prospective observational study.

PURPOSE: This study aimed to evaluate the effectiveness of levetiracetam (LEV) use for seizure control in patients who had undergone resective surgery for intractable epilepsy in routine clinical practice. METHODS: This was a prospective, observational study. Refractory epilepsy patients who underwent epilepsy surgery from January 2008 to December 2011 in the Department of Neurosurgery, West China Hospital were prospectively analyzed. Patients were divided into two groups according to antiepileptic drug (AED) treatment used immediately after epilepsy surgery (group A: therapy with LEV; group B: therapy without LEV). AED regimens were compared with regard to seizure-outcome for a period of more than 2 years. The International League Against Epilepsy (ILAE) classification was used to categorize seizure outcome. RESULTS: A total of 319 patients (184 male and 135 female patients; mean age 28.2±13.4 years) were studied. The mean postoperative follow-up period was 3.9±1.2 years. The two groups showed was no significant difference in preoperative baseline data. At the 6-month follow-up, the proportion of patients with seizure freedom was significantly higher in group A than in group B (78.8% vs. 67.5%, p=0.03). Seizure outcomes after 2 years were assessed using the ILAE classification. The proportion of patients under ILAE seizure-outcome classification I (seizure freedom) was significantly higher in group A than in group B (74.3% vs. 60.7%, p=0.01). Seizure recurrence rates at the final assessment, after planned reduction or withdrawal, were 26.3% for group A and 40.6% for group B (p=0.04). CONCLUSIONS: AED strategy after resective surgery may be a potentially modifiable prognostic indicator influencing seizure outcome in patients with intractable epilepsy. Compared to other AEDs, LEV appears to be more effective in controlling postoperative seizures in our long-term follow-up, and the advantage can be seen in early stage after surgery.

Tetramethylenedisulfotetramine intoxication presenting with de novo Status Epilepticus: a case series.

Tetramethylenedisulfotetramine (TETS), a neurotoxic rodenticide banned in China, has repeatedly been shown to kill healthy people. We report a series of nine people with TETS intoxication presenting with Convulsive Status Epilepticus (CSE) as the initial manifestation. Median duration of CSE after admission was 6h. All had normal neuro-imaging but inter-ictal EEG showed bilateral epileptic waves. Despite aggressive anti-convulsive treatment, attempts at reducing TETS levels and supportive therapy, outcomes were poor. Multiple organ dysfunction syndrome (MODS) occurred in six people, of whom three died. TETS exposure should be part of the differential diagnosis in people presenting with unexplained SE in rural China, particularly if this occurs in family clusters. Over 14,000 cases of TETS intoxication occurred in China between 1 January 1991 and 31 December 2010, and 932 of these died. Cases were widely distributed throughout the country, occurring primarily in rural areas. CSE seems to be a frequent symptom of severe intoxication. There is, however, still a lack of information about the hazards of TETS and it is imperative that both the public and physicians are made aware of its risks and complications.

Evaluation of different antiepileptic drug strategies in medically refractory epilepsy patients following epilepsy surgery.

PURPOSE: This study aimed to explore the most appropriate antiepileptic drug strategies after successful epilepsy surgery. METHODS: A total of 131 refractory epilepsy patients who underwent epilepsy surgery from January 2005 to December 2008 in the Department of Neurosurgery, West China Hospital, were retrospectively reviewed. Patients were divided into three groups (monotherapy, duotherapy, and polytherapy) according to drug combinations used immediately after epilepsy surgery. Seizure outcomes were followed up for more than 2 years. Engel classification was used to evaluate seizure outcomes. RESULTS: The mean postoperative follow-up period was 3.7±1.0 years. Preoperative baseline data among the three groups were comparable. Seizure recurrence rate in monotherapy was obviously higher than in other groups (34.1% vs. 15.1%, 7.1%) at 6-month follow-up, which showed a statistically significant difference (p=0.02). Seizure outcomes for 2 years were assessed using Engel classification. In the duotherapy group, the rate of Engel class I was definitely higher than in the other two groups (69.9% vs. 47.7%, 57.1%, p=0.02). Seizure relapse rates at the 2-year follow-up, after planned reduction or withdrawal, were 46.4% for monotherapy, 16.9% for duotherapy, and 25.0% for polytherapy (p=0.01). CONCLUSIONS: Monotherapy may be not sufficient enough to control seizures completely. It appears to have a higher risk for seizure relapse when considering drug reduction. It suggests that duotherapy may be more effective and safer than monotherapy. Even after successful epilepsy surgery, duotherapy seems preferable to monotherapy or polytherapy for control of residual seizures.