Heterocyclyl tetracyclines. 2. 7-Methoxy-8-pyrrolidinyltetracyclines: discovery of TP-2758, a potent, orally efficacious antimicrobial against Gram-negative pathogens.

A convergent total synthesis platform led to the discovery of TP-2758 from a series of novel 7-methoxy-8-heterocyclyl tetracycline analogs. TP-2758 demonstrated high in vitro potency against key Gram-negative pathogens including extended spectrum ß-lactamases- and carbapenemase-producing Enterobacteriaceae and Acinetobacter spp. strains. This compound was efficacious when administered either intravenously or orally in multiple murine infection models and displayed a favorable preclinical pharmacological profile supporting its advancement into clinical development.

Heterocyclyl Tetracyclines. 1. 7-Trifluoromethyl-8-Pyrrolidinyltetracyclines: Potent, Broad Spectrum Antibacterial Agents with Enhanced Activity against Pseudomonas aeruginosa.

Utilizing a total synthesis approach, the first 8-heterocyclyltetracyclines were designed, synthesized, and evaluated against panels of tetracycline- and multidrug-resistant Gram-positive and Gram-negative pathogens. Several compounds with balanced, highly potent in vitro activity against a broad range of bacterial isolates were identified through structure-activity relationships (SAR) studies. One compound demonstrated the best antibacterial activity against Pseudomonas aeruginosa both in vitro and in vivo for tetracyclines reported to date.

Genome-wide screen of ovary-specific DNA methylation in polycystic ovary syndrome.

OBJECTIVE: To compare genome-wide DNA methylation profiles in ovary tissue from women with polycystic ovary syndrome (PCOS) and healthy controls. DESIGN: Case-control study matched for age and body mass index. SETTING: University-affiliated hospital. PATIENT(S): Ten women with PCOS who underwent ovarian drilling to induce ovulation and 10 healthy women who were undergoing laparoscopic sterilization, hysterectomy for benign conditions, diagnostic laparoscopy for pelvic pain, or oophorectomy for nonovarian indications. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genome-wide DNA methylation patterns determined by immunoprecipitation and microarray (MeDIP-chip) analysis. RESULT(S): The methylation levels were statistically significantly higher in CpG island shores (CGI shores), which lie outside of core promoter regions, and lower within gene bodies in women with PCOS relative to the controls. In addition, high CpG content promoters were the most frequently hypermethylated promoters in PCOS ovaries but were more often hypomethylated in controls. Second, 872 CGIs, specifically methylated in PCOS, represented 342 genes that could be associated with various molecular functions, including protein binding, hormone activity, and transcription regulator activity. Finally, methylation differences were validated in seven genes by methylation-specific polymerase chain reaction. These genes correlated to several functional families related to the pathogenesis of PCOS and may be potential biomarkers for this disease. CONCLUSION(S): Our results demonstrated that epigenetic modification differs between PCOS and normal ovaries, which may help to further understand the pathophysiology of this disease.

Design, Synthesis, and Biological Evaluation of Hexacyclic Tetracyclines as Potent, Broad Spectrum Antibacterial Agents.

A series of novel hexacyclic tetracycline analogues ("hexacyclines") was designed, synthesized, and evaluated for antibacterial activity against a wide range of clinically important bacteria isolates, including multidrug-resistant, Gram-negative pathogens. Valuable structure-activity relationships were identified, and several hexacyclines displayed potent, broad spectrum antibacterial activity, including promising anti-Pseudomonas aeruginosa activity in vitro and in vivo.

Lack of efficacy of Tai Chi in improving quality of life in breast cancer survivors: a systematic review and meta-analysis.

BACKGROUND: It is controversial whether Tai Chi (TC) benefits breast cancer survivors (BCS) on quality of life (QoL). We therefore undertook a meta-analysis to assess this question. MATERIALS AND METHODS: A computerized search through electronic databases was performed to identify relevant randomized controlled trials (RCTs). The primary outcome was QoL, while secondary outcomes included body mass index (BMI), bone mineral density (BMD), and muscle strength. RESULTS: Five RCTs involving 407 patients were included in the meta-analysis. The pooled standardized mean differences were 0.10 (95% confidence interval (CI): -0.35-0.54) for physical well- being, 0.03 (95%CI: -0.18-0.25) for social/family well-being, 0.24 (95%CI: 0.02-0.45) for emotional well-being, 0.23 (95%CI: -0.03-0.49) for functional well-being, and 0.09 (95%CI: -0.19-0.36) for additional concerns. TC failed to improve BMI, BMD, and muscle strength. CONCLUSIONS: There is currently lack of sufficient evidence to support TC improving QoL and other important clinical endpoints.

Characteristics, sources, and transport of tetrabromobisphenol A and bisphenol A in soils from a typical e-waste recycling area in South China.

We studied the tetrabromobisphenol A (TBBPA) and bisphenol A (BPA) patterns and their sources and transport in different land-use soils from Longtang, South China, a typical electronic waste recycling center. We also studied the reductive debromination of TBBPA in paddy soils. TBBPA and BPA concentrations (on a dry weight basis) were undetected-220 and 0.50-325 ng/g, respectively, and both increased, by similar factors, in the following order: pond sediments < paddy soils = vegetable soils < wasteland < dismantling sites < former open burning sites. BPA concentrations were higher than TBBPA concentrations in all six land-use soils, and they correlated significantly. TBBPA and BPA were transported through the soil profiles, being found at relatively high concentrations in soil 0-40 cm deep, but only at low concentrations in soil 40-80 cm deep. The surface soil concentrations appear to have been strongly affected by crude recycling activities, and former open burning and dismantling sites were the main point sources. The areas surrounding the open burning sites and dismantling sites have been contaminated not only by the dumping of waste residues but also by fly ash deposition, even though the agricultural soils are far from the point pollution sources. Some BPA in the soils is likely to be the reductive debromination product of TBBPA because the long rainy season promotes TBBPA transformation and because BPA can persist for a long time. Incubation experiments confirmed that TBBPA could be transformed into BPA and that BPA could accumulate in waterlogged paddy soils, and this may be why BPA concentrations were higher than TBBPA concentrations in the Longtang area.

Promoter methylation of CYP19A1 gene in Chinese polycystic ovary syndrome patients.

AIMS: This study aimed to examine the methylation status of the CYP19A1 promoter region in Chinese polycystic ovary syndrome (PCOS) patients. METHODS: A case-control study was designed that involved 10 PCOS patients and 10 controls. Ovary tissues obtained from 10 women with PCOS and 10 healthy controls were matched for body mass index and age. Methylation of CYP19A1 promoter was detected by methylation-specific PCR. CYP19A1 expression was measured by real-time PCR and Western blotting. RESULTS: The methylation level of CYP19A1 promoter in PCOS samples was significantly higher than in controls (0.698 ± 0.192 vs. 0.210 ± 0.064, p < 0.01). A significant downregulation of CYP19A1 mRNA and protein expression levels was observed in PCOS ovary tissues. Furthermore, the scatter plot revealed that promoter methylation was inversely correlated with CYP19A1 mRNA level (Pearson's correlation -0.820, p < 0.01). CONCLUSION: CYP19A1 expression is frequently repressed in PCOS ovaries due to the promoter hypermethylation. CYP19A1 promoter hypermethylation may play a key role in the pathogenesis of PCOS. © 2013 S. Karger AG, Basel.

Synthesis and biological evaluation of 8-aminomethyltetracycline derivatives as novel antibacterial agents.

The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models.

Data mining of spatial-temporal expression of genes in the human endometrium during the window of implantation.

Previous studies of microarrays have produced mass data that are far from fully applied. To make full use of the available mass data and to avoid redundancy and unnecessary waste, we employed bioinformatics tools GeneSifter and Ingenuity Pathway Analysis (IPA) to mine and annotate 45 microarrays related to endometrium receptivity from GEO (Gene Expression Omnibus) database. In total, 1543 gene sets were found to express differentially, of which 148 highly regulated genes were listed as potential biomarkers of the receptive endometrium. The function and pathway analysis identified the differentially expressed genes primarily involved in immune response and cell cycle. Two networks related to the cardiovascular system and cancers were generated within the genes which changed more than 10-fold. Nine genes were validated by real-time polymerase chain reaction. It was a meaningful exploration of the existing data to acquire useful and reliable information, and our results undoubtedly provided valuable clues for further studies.

Fluorocyclines. 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent.

This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

Synthesis and antibacterial activity of pentacyclines: a novel class of tetracycline analogs.

Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10. Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity. A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms. Several analogs have also shown promising oral bioavailability in rats and cynomolgus monkey.

Heterogeneous photodegradation of pentachlorophenol and iron cycling with goethite, hematite and oxalate under UVA illumination.

Heterogeneous photodegradation of pentachlorophenol (PCP) in the goethite (alpha-FeOOH) and hematite (alpha-Fe(2)O(3)) systems with oxalate under UVA illumination was investigated. The PCP degradation, dechlorination and detoxification, in terms of Microtox acute toxicity, were all achieved to the higher efficiency in the hematite suspension than in the goethite suspension. The optimal initial concentration of oxalic acid (C(ox)(0)) for the PCP degradation with goethite and hematite under the experimental conditions was found to be 1.2mM, since sufficient Fe(III) as Fe(C(2)O(4))(3)(3-) and Fe(II) as Fe(C(2)O(4))(2)(2-) can be formed at C(ox)(0)>or=1.2mM. The main intermediates of PCP degradation were identified by GC-MS, HPLC and IC analyses. It was found that the cycling process between Fe(III) and Fe(II) in both the goethite and hematite systems occurred more vigorously at the initial stage and gradually became gentle, while the rate of PCP photodegradation varied from fast to slow during the reaction time. Furthermore, the formation of H(2)O(2) during photoreaction was studied to explore its relationship with the photodegradation efficiency and the iron cycling process.

A robust platform for the synthesis of new tetracycline antibiotics.

Tetracyclines and tetracycline analogues are prepared by a convergent, single-step Michael-Claisen condensation of AB precursor 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at -78 degrees C, while Claisen cyclization of the enolate produced is rate-determining, typically occurring upon warming to 0 degrees C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semisynthetic methods (presently the only means of tetracycline production) and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.

Explorations on the total synthesis of the unusual marine alkaloid chartelline A.

In work directed toward a total synthesis of chartelline A (1a), a strategy was investigated to construct the 10-membered ring of this marine alkaloid via an intramolecular aldehyde/beta-lactam cyclocondensation to form the macrocyclic enamide functionality. Therefore, spiro-beta-lactam and imidazole fragments were first prepared. Tribromooxindole beta-lactam 24 was synthesized from commercially available 5-nitroisatin (18) in seven steps and 30% overall yield via a Staudinger ketene-imine [2 + 2]-cycloaddition strategy. The requisite 2-bromoimidazole subunit 40 bearing a terminal alkyne and a masked aldehyde was efficiently prepared from the readily available imidazole ester 25 in 10 steps. With both advanced intermediates available, the addition of the lithium acetylide generated from 2-bromoimidazole subunit 40 to the gamma-lactam carbonyl group of N-Boc-tribromooxindole 24 was investigated, affording the desired N-Boc-aminal 41. Hydrolysis of the acetonide moiety of 41, followed by oxidative cleavage of the resulting diol, gave the aldehyde 42. Unfortunately, treatment of aldehyde 42 with p-toluenesulfonic acid did not give the desired 10-membered macrocyclic (Z)-enamide 46, but rather the highly unsaturated seven-membered ring compound 44.

Construction of beta-haloenamides via direct copper-promoted coupling of lactams with 2-chloro and 2-bromo vinyliodides.

[reaction: see text] Cu(I)-catalyzed coupling of lactams with (E)-2-chlorovinyliodides or (E)-2-bromovinyliodides produces the corresponding beta-haloenamides in moderate to excellent yields.

[Clinical study of effect of laparoscopic diagnosis and treatment on pelvic endometriosis-associated infertility].

OBJECTIVE: To investigate the role of laparoscopy in diagnosis and treatment of infertile women with endometriosis. METHODS: Totally 314 infertile cases were diagnosed as having endometriosis by laparoscopy, and 58, 173, 68 and 15 cases were assigned to stage I, II, III and IV groups respectively according to the revised classification American Fertility Society (r-AFS). Laparoscopic treatment included excision of ovarian endometriosis lesions, lysis of adhesions, endocoagulation of pelvic endometriosis lesions with controlled heating (100 degrees C) and lavaging of the peritoneal cavity. The duration of follow-up after laparoscopic surgery was censored at 36 weeks. Women who became pregnant were followed up to 20 weeks' gestation. The U and chi(2) tests were used to determine significance of difference in the rate of pregnancy and spontaneous abortion between all clinical stages. RESULTS: Of all the 314 cases, 254 became pregnant within 36 weeks after surgery. The cumulative numbers of pregnancy were 50 (86.2%, 50/58), 141 (81.5%, 141/173), 52 (76.5%, 52/68) and 11 (73.3%, 11/15) in stage I-IV groups respectively. The accumulative pregnancy rates were, however, not significantly different among stages I-IV (P > 0.05). The accumulative pregnancy rate within 24 weeks after surgery (93.7%, 238/254) was higher than that within 25 - 36 weeks after surgery (6.3%, 16/254). Of 254 cases who were pregnant, 12 had miscarriage. There was no significant difference of miscarriage rate between all stages (P > 0.05). While the rate of miscarriage was higher within 12 weeks of gestation (83.3%, 10/12) than that of after 12 weeks of gestation (P < 0.05). CONCLUSIONS: Early lesions of endometriosis and pelvic factors for infertility can be found by laparoscopy. And pregnancy rate of endometriosis-associated infertility can be improved by laparoscopic surgery. To clean the menstrual blood pool and ablate peritoneal lesion with endocoagulation as completely as possible have significant importance for enhancement of fecundity in infertile women with endometriosis, especially for stage I-II cases.

[Comparative study of laparoscopically assisted myomectomy and mini- laparotomy for uterine intramural fibroids].

OBJECTIVE: To evaluate the feasibility and safety of laparoscopically assisted myomectomy (LAM) for uterine intramural fibroids. METHODS: Thirty-seven selected patients with uterine intramural fibroids with the diameters > 5 cm and < 9 cm were subjected to LAM technique, the intramural fibroid of 2 among which penetrated into the uterine cavity (< 50%). LAM was completed with a laparoscopically assisted enucleation. After the fibroid was half-scripped, the incision of puncture point at the middle of abdominal wall was expanded to 4 approximately 5 cm in length. The scripping of the fibroid and the suture of the uterine wound were completed outside the abdominal incision. The duration of operation, blood loss, intra- and post-operation complications and time to full recovery were evaluated and comparison with those in 630 patients with hysteromyoama who underwent myomectomy by laparotomy during the same period. RESULTS: The operative time in LAM group ranged from 50 min to 240 min (101 min +/- 56 min), without a significant difference in comparison with that in the group of myomectomy by laparotomy (89 min +/- 38 min, P > 0.05). However, the median of blood loss in LAM group was 50 ml, significantly less than that in the group of myomectomy by laparotomy (80 ml, P < 0.05). The incidence of pyrexia was lower and the time needed for recovery was shorter after LAM in comparison with those in the group of myomectomy by laparotomy (P < 0.001). Neither intra-operative nor post- operative complication was observed in the LAM group. Eight of the 11 cases with infertility in the LAM group were conceived at least one year after LAM. The pregnancy was uneventful and proceeded to cesarean section at the 37 approximately 38 th week. CONCLUSION: LAM operation is feasible and safe, and offers a easy-to-perform minimally invasive myomectomy technique for intramural fibroid removal with all the advantages of laparoscopic surgery and a good reconstructive outcome.

Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy.

Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper-catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid-catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (+/-)-lepadiformine (6). The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R),5(S),10(S),13(S).