Ring-opening cyclization of activated spiro-aziridine oxindoles with heteroarenes: a facile synthetic approach to spiro-oxindole-fused pyrroloindolines

Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrroloindolines and benzofurano-pyrrolidines via a Lewis acid-catalyzed domino ring-opening with concomitant ring annulation using activated spiro-aziridines and heteroarenes. This method offers a new class of novel spiro-fused polycyclic pyrrolidines in a one-pot and sustainable manner with good yields and high diastereoselectivity. In addition, the structure of 3d was confirmed by single X-ray crystallography analysis.

Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrroloindolines and benzofurano-pyrrolidines via a Lewis acid-catalyzed domino ring-opening annulation using activated spiro-aziridines and heteroarenes.     

Risk of renal cell carcinoma and polymorphism in phase I xenobiotic metabolizing CYP1A1 and CYP2D6 enzymes

The progressive increase in sporadic renal cell carcinoma (RCC) observed in industrialized countries supports the opinion that certain carcinogens present in the environment (tobacco smoke, drugs, pollutants, and dietary constituents) may affect the occurrence and progression of this disease in developing countries like India. The polymorphism of the enzymes involved in metabolism of such environmental factors may, therefore, confer variable propensity to RCC. The possible association between RCC and a polymorphism of the CYP1A1 and CYP2D6 genes specific to the Indian population was examined using peripheral blood DNA from 196 RCC cases and 250 population controls with detailed data of clinicopathologic characteristics for the disease. The CYP1A1 (val) “variant” genotype, which contains at least 1 copy of the CYP1A1 variant alleles, was found to be associated with a 2.03-fold [GG ver. AA/AG, unadjusted OR = 2.03; 95%CI = 1.233–3.342; P = 0.005] increase in the risk of RCC. There was also a significant association (p^trend = 0.034) between higher frequency of RCC subjects containing at least of copy of the CYP1A1 (val) “variant” genotype with III or IV Fuhrman's grade. Whereas, the CYP2D6 polymorphism did not show any association with RCC risk [TT ver. CT/CC, unadjusted OR = 95%CI = 1.233–3.342; P = 0.005]. There was a significant association (p^trend = 0.001) between the poor metabolizer CYP2D6 (TT) and progression towards higher pathological stage of RCC. Our data demonstrate for the first time a significant association between pharmacogenetic polymorphisms of CYP1A1 and risk of RCC development in the Indian population. The findings suggest that inter-individual variation in the phase I metabolic enzymes involved in the fictionalization and detoxification of specific xenobiotics is an important susceptibility factor for development and progression of RCC in Indians.     

A Double-blind Clinical Evaluation of the Effect of Nizofenone (Y-9179) on Delayed Ischemic Neurological Deficits Following Aneurysmal Rupture

The effect of Nizofenone (Y-9179), a verebral protective agent, on delayed ischemic neurological deficits following subarachnoid hemorrhage (SAH) due to aneurysmal rupture was investigated by a cooperative double-blind clinical trial. Delayed ischemic neurological deficits following SAH are closely associated with the occurrence of vasospasm, and the effectiveness of any cerebral protective agent depends on sufficient coverage by the drug over the period around the onset of ischemic insult. Therefore, the study was designed so that the effect of Nizofenone could be analyzed in terms of these two factors.

In patients admitted within day 9 of SAH, drug administration was immediately initiated and continued for 5 days. When delayed ischemic neurological deficits occurred, angiography was carried out to confirm the presence of vasospasm, and then drug administration was extended for an additional 5 days. Ten of the 100 cases enlisted in the study were excluded prior to code-breaking because of the occurrence of severe complications not related to vasospasm.

Out of the 42 cases of the Nizofenone group and 48 of the placebo group, 25 and 29 developed vasospasm, respectively. Thus Nizofenone did not prevent vasospasm. Of the 25 cases of the Nizofenone group with vasospasm, 13 cases received sufficient drug coverage around the onset of vasospasm. The placebo group, the total Nizofenone group, and the Nizofenone group with sufficient drug coverage were stratified according to the occurrence of vasospasm. The disability status index one month after admission and the neurological functions, such as motor and speech functions, of each group were then compared. In patients who developed vasospasm, only the Nizofenone group with sufficient drug coverage had a significantly better outcome than the placebo group (p < 0.05). No particular side effect of Nizofenone was observed.

Thus, the results indicate that Nizofenone may be useful in the therapy of delayed ischemic neurological deficits following SAH, although the effect of the drug may be considerably influenced by the timing of its administration.     

Motor and Tactile-Perceptual Skill Differences Between Individuals with High-Functioning Autism and Typically Developing Individuals Ages 5–21

We examined motor and tactile-perceptual skills in individuals with high-functioning autism (IHFA) and matched typically developing individuals (TDI) ages 5–21 years. Grip strength, motor speed and coordination were impaired in IHFA compared to matched TDI, and the differences between groups varied with age. Although tactile-perceptual skills of IHFA were impaired compared to TDI on several measures, impairments were significant only for stereognosis. Motor and tactile-perceptual skills should be assessed in children with IHFA and intervention should begin early because these skills are essential to school performance. Impairments in coordination and stereognosis suggest a broad though selective under-development of the circuitry for higher order abilities regardless of domain that is important in the search for the underlying disturbances in neurological development.     

Efficacy of metformin in the management of periodontitis: A systematic review and meta-analysis

Periodontitis is characterized by inflammation of the periodontium and leads to loss of teeth if untreated. Although a number of surgical and pharmacological options are available for the management of periodontitis, it still affects a large proportion of population. Recently, metformin (MF), an oral hypoglycemic, has been used to treat periodontitis. The aim of this review is to systematically evaluate the efficacy of MF in the treatment of periodontitis. An electronic search was carried out using the keywords ‘metformin’, ‘periodontal’ and ‘periodontitis’ via the PubMed/Medline, ISI Web of Science and Google Scholar databases for relevant articles published from 1949 to 2016. The addressed focused question was: ‘Is metformin effective in reducing bone loss in periodontitis? Critical review and meta-analysis were conducted of the results obtained in the selected studies. Following the removal of the duplicate results, the primary search resulted in 17 articles and seven articles were excluded based on title and abstract. Hence, 10 articles were read completely for eligibility. After exclusion of four irrelevant studies, six articles were included. The topical application of MF resulted in improved histological, clinical and radiographic outcomes. Additionally, results from the meta-analysis indicated that application of metformin improved the clinical and radiographic outcomes of scaling and root-planing, but at the same time heterogeneity was evident among the results. However, because of a lack of histological and bacterial studies, in addition to short follow-up periods and risk of bias, the long-term efficacy of MF in the treatment of bony defects is not yet ascertained. Further studies are needed to envisage the long-term efficacy of MF in the management of periodontitis.     

Nano in nano: Biosynthesized gold and iron nanoclusters cargo neoplastic exosomes for cancer status biomarking

Timely detection is crucial for successful treatment of cancer. The current study describes a new approach that involves utilization of the tumor cell environment for bioimaging with in-situ biosynthesized nanoscale gold and iron probes and subsequent dissemination of Au-Fe nanoclusters from cargo exosomes within the circulatory system. We have isolated the Au-Fe cargo exosomes from the blood of the treated murine models after in situ biosyntheses from their respective pre-ionic solutions (HAuCl₄, FeCl₂), whereas Na₂SeO₃ supplementation added into Au lethal effect. The microarray data of various differentially expressed genes revealed the up-regulated tumor ablation and metal binding genes in SGC-7901 cell lines after treatment with Au-Fe-Se triplet ionic solution. The isolation of Au-Fe nanoclusters cargo exosomes (nano in nano) after secretion from deeply seated tumors may help in early diagnosis and reveal the tumor ablation status during and after the relevant treatment like radio-chemo therapies et al.     

Unsymmetrical 1,3-disubstituted urea derivatives as α-chymotrypsin inhibitors

The objective of this study was to synthesize potent and/or novel inhibitors for α-chymotrypsin activity. Eighteen derivatives of N-methylphenyl-N′-(alkyl/aryl) urea (1–18) were synthesized, and their inhibitory effects on α-chymotrypsin enzyme were evaluated. Two compounds exhibited potent inhibitory activities. The most potent, N-(2-methylphenyl)-2-oxo-1-pyrrolidinecarboxamide (15) having a methyl group at ortho position was the most active inhibitor with an IC₅₀ value of 8.10 ± 0.14 μM, which was comparable to standard chymostatin (IC₅₀ = 8.24 ± 0.11 μM). A slightly less potent, N-(2-acetylphenyl)-N′-(3-methylphenyl) urea (10), exhibited an IC₅₀ of 13.6 ± 0.23 μM. Compounds 3, 4, 7, 11, and 13 exhibited moderate activities. The results demonstrated that α-chymotrypsin inhibition is related to the position of the methyl group and the presence of substituent at the nitrogen of the urea bridge. The inhibitory trend suggests that α-chymotrypsin inhibitory activity declines with ortho > meta > para substitution order. In conclusion, our data suggest that the compound 15 may serve as a lead compound for further designing of other potent or novel α-chymotrypsin inhibitors.