Dithiocarbamation of spiro-aziridine oxindoles: a facile access to C3-functionalised 3-thiooxindoles as apoptosis inducing agents.

Herein, we report the first dithiocarbamation of spiro-aziridine oxindoles involving regiospecific ring-opening by using in situ generated nucleophilic dithiocarbamates as an instant source of sulfur. This approach afforded C3-functionalised-3-thiooxindoles in good to excellent yields with a wide substrate scope under catalyst-free and mild reaction conditions. These compounds were screened for their anticancer activity against a panel of human cancer cell lines, wherein compound 3u exhibited significant cytotoxic activity against human lung cancer cells with an IC50 value of 4.31 ± 1.88 µM. Phase contrast microscopy as well as different staining assays such as acridine orange/ethidium bromide (AO/EB), DAPI and DCFDA demonstrated the induction of apoptosis in A549 lung cancer cells after treatment with compound 3u. In addition, the clonogenic assay and migration assay demonstrated the ability of compound 3u to inhibit colony formation and cell migration, respectively, in A549 cells in a dose-dependent manner.

Development of quinoline-based hybrid as inhibitor of methionine aminopeptidase 1 from Leishmania donovani.

Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and a potential antileishmanial target for its role in N-terminal methionine processing. As an effort towards new inhibitor discovery against methionine aminopeptidase 1 from Leishmania donovani (LdMetAP1), we have synthesized a series of quinoline-based hybrids, that is (Z)-5-((Z)-benzylidine)-2-(quinolin-3-ylimino)thiazolidin-4-ones (QYT-4a-i) whose in vitro screening led to the discovery of a novel inhibitor molecule (QYT-4h) against LdMetAP1. The compound QYT-4h showed nearly 20-fold less potency for human MetAP1 and had drug-like features. Time-course kinetic assays suggested QYT-4h acting through a competitive mode by binding to the metal-activated catalytic site. Notably, QYT-4h was most potent against the physiologically relevant Mn(II) and Fe(II) supplemented forms of LdMetAP1 and less potent against Co(II) supplemented form. Surface plasmon resonance and fluorescence spectroscopy demonstrated high affinity of QYT-4h for LdMetAP1. Through molecular modelling and docking studies, we found QYT-4h binding at the LdMetAP1 catalytic pocket occupying both the catalytic and substrate binding sites mostly with hydrogen bonding and hydrophobic interactions which provide structural basis for its promising potency. These results demonstrate the feasibility of employing small-molecule inhibitors for selective targeting of LdMetAP1 which may find use to effectively eliminate leishmaniasis.

Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect.

The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 µM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310-920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.

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.

Altered glucose disposition and insulin sensitivity in peri-pubertal first-degree relatives of women with polycystic ovary syndrome.

BACKGROUND: First-degree relatives (FDRs) of women with PCOS are at increased risk for impaired insulin sensitivity and diabetes mellitus. Glucose tolerant FDR have evidence of insulin resistance and hyperinsulinemia prior to emergence of frank PCOS. AIM: To study insulin dynamics parameters in the early adolescent FDR of women with PCOS. METHODS: This is a cross-sectional study involving 18 adolescents whose mothers or sisters had been diagnosed with PCOS and 21 healthy, age-matched control adolescents without FDR. Subjects underwent anthropometric measurements, steroid profiling and frequently sampled Intravenous Glucose Tolerance Test (IVGTT), Homeostasis Model Assessment (HOMA) index, Glucose Disposal Index (GDI), Acute Insulin Response (AIR) and Quantitative insulin sensitivity check index (QUICKI) were derived from IVGTT results. RESULTS: FDRs showed significantly higher mean HOMA and lower GDI. There were no differences in mean age or BMI Z-score between the cohorts. No differences in sex steroids or AIR were identified between groups. CONCLUSION: Female adolescent FDR of women with PCOS have higher HOMA index and lower QUICKI, reflecting altered insulin sensitivity and lower GDI reflecting poorer beta-cell function. The presence of multiple risk factors for type 2 diabetes suggests that aggressive screening of the early adolescent FDR of women with PCOS is indicated.

Real-life utilization of real-time continuous glucose monitoring: the complete picture.

BACKGROUND: Very few studies to date have analyzed the reasons why some people do not use real-time continuous glucose monitoring (RT-CGM) continuously, especially given its positive glycemic outcomes, or choose not to wear it at all, even after learning about its benefits. METHODS: A questionnaire was designed to assess real-life use of and issues surrounding RT-CGM. Hemoglobin A1c (HbA1c) and duration of sensor use were also obtained from the patients' charts. RESULTS: Fifty-eight subjects with type 1 diabetes (T1DM), average age 15.0 ± 4.8 years, T1DM duration 5.7 ± 3.8 years, HbA1c 8.8 ± 2.1%, 50% with RT-CGM, were included in the analysis. Hemoglobin A1c was lower with increased RT-CGM use. Real-time continuous glucose monitoring was ordered to improve control. Users liked the continuous data. The most disliked part was pain and discomfort. Occasional users described RT-CGM as annoying, a hassle, and interfering with their lives. Reasons for discontinuing RT-CGM included problematic equipment and inaccuracy (64%), intrusion in life (36%), and insurance issues (29%). Twenty-one percent of nonusers reported RT-CGM to be inconvenient or a hassle or just did not want it. Fifty-two percent of subjects continue to use RT-CGM despite reported problems. CONCLUSION: Real-time continuous glucose monitoring is a beneficial tool for improving glycemic control, and many use it despite reported problems and hassles with current devices. However, this technology has not been wholeheartedly embraced by many individuals with T1DM, especially in youngsters, because of issues mentioned here. Based on the findings of this study, it is hoped that improvements will be made to RT-CGM technology so that more people with diabetes will embrace this beneficial tool.

Basal insulin requirements on continuous subcutaneous insulin infusion during the first 12 months after diagnosis of type 1 diabetes mellitus.

INTRODUCTION: While the endogenous first-phase insulin response has disappeared by the time of diagnosis of type 1 diabetes mellitus (T1DM), anecdotal evidence suggests that these patients can continue to have a second-phase insulin response during the first 12 months after diagnosis. We hypothesized that patients who are started on continuous subcutaneous insulin infusion (CSII) at the time of diagnosis of T1DM would have a lower basal insulin requirement than the 40-60% usually expected. METHODS: We analyzed 38 patients with T1DM, age 9.9 +/- 6.4 years, 71% male, who were started on CSII within the first month of diagnosis. RESULTS: Average basal insulin requirements were 47-49% of total daily dose during the first 12 months after diagnosis and decreased from 0.30 U/kg/day at diagnosis to 0.20 U/kg/day by 12 months. Baseline percentage of basal insulin was significantly correlated with hemoglobin A1c at baseline and at six months. The percentage of basal insulin requirement at 12 months after diagnosis was significantly correlated with baseline body mass index (BMI) and current BMI. No other correlations between percentage of basal insulin requirements and any other factors were seen. CONCLUSION: Our data suggest that, even though some endogenous insulin production remains during the first year after diagnosis of T1DM, the distribution of basal versus total daily insulin requirements remains the same as in the general population of people with diabetes. There may be benefits to starting patients on a higher basal rate at time of diagnosis for overall glycemic control during the first six months. Further research is needed to optimize starting insulin doses to maximize their potential in preserving beta-cell function.

Hypothyroidism after 131I-monoclonal antibody treatment of neuroblastoma.

BACKGROUND: To determine the prevalence of and risk factors for primary hypothyroidism following treatment with a radiolabeled monoclonal antibody ((131)I-3F8) in children with neuroblastoma. PROCEDURE: In the current study, we assessed thyroid function in 51 neuroblastoma patients who survived for > or =3 months after treatment with (131)I-3F8 (a murine IgG3 monoclonal antibody that reacts with the ganglioside GD2) at 4 mCi/kg/day x 5 days (total 20 mCi/kg). Prior therapy in all subjects included dose-intensive chemotherapy; 13 subjects also received external beam radiation to the neck. Oral iodide and liothyronine sodium (T3) were administered for protection of the thyroid gland. RESULTS: Thirty-two of 51 subjects (63%) developed hormonal evidence of primary hypothyroidism. The median time to hypothyroidism after treatment with (131)I-3F8 was 6.4 months. The probability of developing hypothyroidism was 56% at 2 years following treatment with (131)I-3F8. There was evidence for an association between thyroidal uptake of (131)I and development of hypothyroidism (hazard ratio 1.83, 95% confidence interval 0.91-3.30; P = 0.09). CONCLUSIONS: We conclude that hormonal evidence of primary hypothyroidism developed in a majority of subjects treated with (131)I-3F8, despite pretreatment with oral iodide plus liothyronine sodium. Alternative strategies for thyroid gland protection are needed.

Characteristics of children with premature pubarche in the new york metropolitan area.

BACKGROUND: Premature pubarche (PP) is defined as the appearance of pubic hair before 8 years in girls and 9 years in boys, without other signs of puberty. In the USA the prevalence of childhood overweight tripled between 1980 and 2000. An association between overweight and PP has been identified. METHODS: We conducted a chart review to identify patients with the diagnosis of PP who were evaluated from July 2000 to October 2005. 38 patients, 29 females and 9 males, were studied. 16 were Caucasian, 11 African-American, 10 Hispanic, and 1 Arab. Age range was 4.3-9.8 years. Auxological features were analyzed. RESULTS: Of the 38, 20 (52.6%) had a BMI >85th percentile. Increased weight was more common among females (62%) and Hispanics (80%). The study group was taller than expected Z = 1.11 +/- 0.95 (TH Z = 0.34 +/- 0.86). Among the 18 children who had bone age advancement >1.5 years, 10 (56%) had a predicted height <1 SD below the TH (p = 0.005). CONCLUSIONS: In this study we confirmed the correlation between weight gain and PP. We also found that when the bone age was advanced >1.5 years, the predicted adult height was affected.

Real-time continuous glucose monitoring in the clinical setting: the good, the bad, and the practical.

Real-time continuous glucose monitoring (RT-CGM) is the latest technological breakthrough in diabetes care. Despite its limitations of lag time between sensor and blood glucose, the need for calibration, false detection of and failure to detect hypoglycemia, and mild discomfort or skin irritation reported in some users, RT-CGM is a highly beneficial tool that can be used to detect nocturnal or unrecognized hypoglycemia and glycemic variability. This, in turn, can lead to better treatment decisions, which may improve metabolic control and decrease the incidence and progression of diabetes complications. The RT-CGM devices are fairly accurate and easy to use. It is not difficult to establish a clinical RT-CGM program in the office. However, it requires persistence and an understanding of the patient's perspective of using RT-CGM so it can be presented and taught appropriately. This article discusses the benefits and limitations of RT-CGM and establishment of a RT-CGM program in the clinical setting.