Synthesis and biological evaluation of aminobenzamides containing purine moiety as class I histone deacetylases inhibitors.

The aminobenzamide is selective to class I histone deacetylases (HDACs) and displays unique tight-binding/slow-off HDAC-binding mechanism. Herein, we report a series of 9-substituted purine aminobenzamides that selectively inhibit class I HDACs. The activities in vitro showed compound 9d exhibited 12 folds more potent than MS-275 against HDAC1 isoform and showed excellent inhibitory activity on cancer cells, including HCT-116, MDA-MB-231, K562 cell lines. The metabolic stability of 9d was much better than that of the well-known HDAC inhibitor SAHA. Pulse exposure test of western blot assay demonstrated that 9a, 9d induced histone acetylation in a similar manner to MS-275. Further biological validation demonstrated that 9d prevented cell transition from G1 phase to S phase by reducing Cyclin D1, CDK2 and lifting p21, induced early apoptosis by upregulating BAX and downregulating Bcl-2 in HCT-116 cells.

Artopithecins A-D, Prenylated 2-Arylbenzofurans from the Twigs of Artocarpus pithecogallus and Their Tyrosinase Inhibitory Activities.

Four new prenylated 2-arylbenzofurans, namely artopithecins A-D (1-4), together with five known compounds (5-9) were isolated from the twigs of Artocarpus pithecogallus for the first time. Their structures were elucidated based on extensive spectroscopic analysis and in comparison with literature data. All isolates were evaluated for their inhibitory activities against mushroom tyrosinase. Compounds 3 and 4 displayed significant tyrosinase inhibitory activities with IC50 values of 37.09±0.33 and 38.14±0.21 µM, respectively.

Prenylflavonoids from the Twigs of Artocarpus nigrifolius.

Two new prenylated flavones, artocarnin A (2) and carpachromenol (12), together with 13 known prenylflavonoids (1, 3-11, 13-15) were isolated from the twigs of Artocarpus nigrifolius for the first time. Their structures were elucidated by high resolution-electrospray ionization (HR-ESI)-MS, NMR spectroscopic analysis, and in comparison with the reported data. Compounds 1-15 were evaluated for their antiproliferative effects against SiHa and SGC-7901 human cancer cell lines in vitro. The most active compound, eleocharin A (10), showed significant cytotoxicity on SiHa cells (IC50=0.7±0.1 µM) and inhibitory activity against SGC-7901 cells (IC50=8.3±0.2 µM) and could be considered as potential lead compound for further development of novel anti-tumor agents.

[Study on HPLC Fingerprint of Kanggongyan Series].

OBJECTIVE: To establish analysis methods for fingerprint of Kanggongyan series by HPLC. METHODS: A Shiseido CAP-CELL PAK C18(250 mm x 4. 6 mm, 3 µm) column was used with acetonitrile-0. 5% phosphoric acid as the mobile phase by gradient elution. The flow rate was 0. 8 mL/min, the column temperature was 30 °C, and the detection wavelength was set at 280 nm during 0 ~ 44 min and at 332 nm during 44 ~ 115 min. RESULTS: Ten common peaks were selected as characteristic peaks in the chromatogram of Kanggongyan particles, eleven common peaks were selected as characteristic peaks in the chromatogram of Kanggongyan tablets and capsules ,the similarities were greater than 0. 9 among all batches. CONCLUSION: The method is simple, steady and repeatable. It provides a basis for the quality control of Kanggongyan series.

Different Kinds of Paraneoplastic Syndromes in Childhood Neuroblastoma.

BACKGROUND: Clinical presentations of paraneoplastic syndromes in neuroblastoma may multiply. Review of the clinical data and the literature on this syndrome may help in the diagnosis of neuroblastoma. OBJECTIVES: In order to make more accurate diagnosis, we reviewed the clinical data and the literature on this syndrome. PATIENTS AND METHODS: Between April 2007 and April 2012, 68 children were diagnosed with neuroblastoma or ganglioneuroblastoma in our institution, 9 of which presented exclusively with paraneoplastic syndromes and were not treated with chemotherapy prior to diagnosis. After the diagnosis, all patients received chemotherapy and operation on NB97 protocol. RESULTS: Among 68 pediatric patients with neuroblastoma or ganglioneuroblastoma, 4 (5.9%) patients suffered from neurological complications at diagnosis, 2 (2.9%) patients had digestive tract disorders, 2 (2.9%) patients had immune diseases, and 1 (1.5%) suffered from hematological disorder (without bone marrow involvement). All paraneoplastic syndrome patients achieved complete remission on paraneoplastic syndrome before completion of chemotherapy. CONCLUSIONS: Neuroblastoma may present with a range of non-specific neurologic symptoms in addition to the well-known opsoclonus-myoclonus syndrome and cerebellar ataxia. In any case, the presence of unexplained neurologic manifestations and other common clinical presentations such as rash, constipation, diarrhea, and especially immune disorders in an otherwise healthy child had raised the possibility of paraneoplastic syndrome due to the presence of an undiagnosed tumor.

Vincristine and irinotecan in children with relapsed hepatoblastoma: a single-institution experience.

PURPOSE: This study was to determine the efficacy of vincristine and irinotecan in children with relapsed hepatoblastoma (HB). METHODS: A total of 10 patients with relapsed HB were enrolled. Three patients were excluded. Patients received irinotecan 50 mg/m(2)/day, day 1-5 and vincristine 1.5 mg/m(2)/day, day 1, repeated every 3 weeks. The maximum cycles were eight. Reevaluation of tumor was performed every two cycles. The primary outcome was the rate of complete resection. Secondary outcomes were event-free survival (EFS) and overall survival (OS). RESULTS: Of the seven patients assessable for response, one patient with normal AFP level showed a progressive disease and withdrew. He finally died 6 months later. Four had PR, all of them underwent a second surgery and achieved complete resection. Two patients had SD, one patient relapsed 6 months after orthotopic liver transplantation and died, the other one undergoing surgery had micro margin positive, he relapsed again but alive. The rate of complete resection was 71.4% (including orthotopic liver transplantation). The 2-year EFS and OS for the whole group were 57.1% (95% CI, 12.7% to 34.2%) and 71.4% (95% CI, 16.39% to 37.4%), respectively. CONCLUSIONS: The combination of irinotecan and vincristine has a significant antitumor activity and acceptable toxicity in children with relapsed HB.

Synthesis and anticancer evaluation of benzyloxyurea derivatives.

A series of novel benzyloxyurea derivatives was designed, synthesized by substituting different benzyls or phenyls on N,N'-positions of the hydroxyurea (HU). These target compounds were evaluated for their anticancer activity in vitro against human leukemia cell line K562 and murine leukemia cell line L1210 in comparison with HU by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Some of the compounds showed promising anticancer activity against the cells. Molecular docking experiments with Saccharomyces cerevisiae R1 domain indicated that 4a and 4f' have stronger affinity than 4m and 4n. Flow cytometry study showed that compound 4g exerted greater apoptotic activity against K562 cells line than HU.

A seco-laurane sesquiterpene and related laurane derivatives from the red alga Laurencia okamurai Yamada.

A ring-cleaved sesquiterpene, named seco-laurokamurone, four laurane-type sesquiterpenes, laurepoxyene, 3ß-hydroperoxyaplysin, 3α-hydroperoxy-3-epiaplysin, and 8,10-dibromoisoaplysin, one laurokamurane-type sesquiterpene, laurokamurene D, and one bisabolane-type sesquiterpene, (5S)-5-acetoxy-ß-bisabolene, have been isolated from a re-collection of the red alga Laurencia okamurai Yamada, together with six other known sesquiterpenes. Their structures, including relative configuration, were elucidated by detailed analysis of spectroscopic data, and by comparison with data for related known compounds. In addition, on the basis of chemical conversions, degradation results, and biogenetic considerations, the absolute configurations of several of these compounds were also tentatively proposed. seco-Laurokamurone possesses an unprecedented carbon skeleton, formed from an oxidative cleavage of the laurokamurane skeleton, and laurokamurene D represents the fourth example of a laurokamurane-type sesquiterpene from a natural source. The in vitro antifungal activity of many of these compounds was evaluated against four fungi (Cryptococcus neoformans, Candida glabrata, Trichophyton rubrum, and Aspergillus fumigatus), as well as assessing cytotoxicity against HL-60 and A-549 human cancer cell lines. The compounds studied displayed moderate activities, relative to controls.

Single-agent cisplatin treatment of children with high-risk hepatoblastoma.

PURPOSE: The use of neoadjuvant chemotherapy has improved the survival of patients with hepatoblastoma (HB). However, an increased number of treatment complications and toxic deaths, particularly from heart failure, have been observed with doxorubicin treatment. We have applied cisplatin as a single agent to treat children with high-risk HB to improve event-free survival (EFS). METHODS: Between 2007 and 2009, 14 patients with untreated high-risk HB were enrolled in this study. All the patients received a single-agent treatment of cisplatin. The initial cisplatin cycle was administered in a continuous intravenous 24-hour infusion of 80 mg/m/24 h. The primary outcome was the rate of complete resection. Secondary outcomes were EFS and overall survival (OS). RESULTS: Eleven patients (78.6%) had an overall partial response. Two patients (14.3%) had stable disease. One patient experienced (7.1%) progression. Of the 4 patients who presented with lung metastases initially, 1 patient achieved complete response, 2 patients achieved partial response, and 1 patient experienced progression during preoperative chemotherapy. The complete resection rate was 78.6% (95% CI, 49%-95%). The Kaplan-Meier estimates of 2-year EFS and OS for the whole group were 64.3% (95% CI, 35%-87%) and 85.7% (95% CI, 57%-98%), respectively. The 2-year EFS and OS rates of patients who achieved complete resection were 81.8% (95% CI, 48%-98%) and 100% (95% CI, 62%-100%), respectively. CONCLUSIONS: The single-agent cisplatin had less toxicity than cisplatin plus doxorubicin and achieved an equal rate of complete resection in high-risk HB compared with conventional multiagent chemotherapy.

Racemosins A and B, two novel bisindole alkaloids from the green alga Caulerpa racemosa.

Racemosin A (1), a structurally unique bisindole alkaloid possessing the seco-indolo[3,2-a]carbazole skeleton with two uncommon indolinenone units both conjugated with a methyl propenoate moiety, and its unusual cyclized derivative, racemosin B (2), were isolated from the green alga Caulerpa racemosa, together with the most commonly encountered pigment in the genus Caulerpa, caulerpin (3). Their structures were elucidated by extensive spectroscopic analysis and by comparison with data for related known compounds. A plausible biosynthetic pathway of 1 and 2 was proposed. In a neuro-protective assay, compound 1 significantly attenuated the Aß2(5-35)-induced SH-SY5Y cell damage with a 14.6% increase in cell viability at the concentration of 10µM when compared to epigallocatechin gallate (EGCG, 16.57% increase at 10 µM) as the positive control.

Caulerprenylols A and B, two rare antifungal prenylated para-xylenes from the green alga Caulerpa racemosa.

Two new prenylated para-xylenes, named caulerprenylols A (1) and B (2), were isolated from the green alga Caulerpa racemosa, collected from the Zhanjiang coastline, China. The structures of the two metabolites were elucidated on the basis of detailed spectroscopic analysis. This is the first report of prenylated para-xylenes from marine algae and from marine organisms as well. Moreover, caulerprenylol B (2) is also characterized by an uncommon indane ring system. In in vitro bioassays, the new compounds exhibited a broad spectrum of antifungal activity against Candida glabrata (537), Trichophyton rubrum (Cmccftla), and Cryptococcus neoformans (32609) with MIC80 values between 4 and 64 µg/mL when compared to amphotericin B (MIC80 values of 2.0, 1.0, and 4.0 µg/mL, respectively) as a positive control and showed no growth inhibition activity against the tumor cells HL60 and A549.

Detection of human papillomavirus genotypes associated with mucopurulent cervicitis and cervical cancer in Changchun, China.

OBJECTIVE: To determine the prevalence and genotype distribution of human papillomavirus (HPV) infection among Chinese patients with mucopurulent cervicitis (MPC) or cervical cancer (CC). METHODS: In total, 191 cases of CC (n=66), acute MPC (n=84), and healthy cervix controls (n=41) were initially included; samples were collected between May 21, 2008, and October 9, 2011. Cervical specimens were screened for HPV using a nested polymerase chain reaction assay and DNA sequencing. RESULTS: Overall prevalence of HPV infection was 20.0% in the control group, 53.3% in the MPC group, and 93.8% in the CC group. The predominant genotype detected in all 3 groups was the oncogenic variant HPV 16 (87.7%, 18.7%, and 10.0% in the CC, MPC and control specimens, respectively). The second most frequent genotype among patients with MPC was HPV 58. This variant is also oncogenic and was detected at a higher rate in the MPC group (9.3%) than in the control (2.5%) and CC (1.5%) groups. CONCLUSION: Infection with HPV was prevalent among Chinese women with MPC or CC. Furthermore, the high prevalence of oncogenic genotypes observed among HPV-positive patients with MPC suggests that this group is at increased risk of developing CC.

Directed shift of vaginal flora after topical application of sucrose gel in a phase III clinical trial: a novel treatment for bacterial vaginosis.

BACKGROUND: Bacterial vaginosis (BV) is one of the most common infectious diseases among sexually active women and is associated with the increased acquisition of a variety of sexually transmitted diseases. This study aimed to compare the efficacy of a non-antibiotic sucrose gel against an antibiotic metronidazole gel for the treatment of BV. METHODS: A randomized, double-blinded, multi-center, parallel-group, placebo-controlled phase III clinical trial was conducted at eight hospitals in China. A total of 560 subjects with clinically diagnosed BV were randomly assigned into three groups for vaginally receiving sucrose, metronidazole, and placebo gels, respectively, twice daily for five consecutive days. The efficacy of therapeutic cure, defined as an achievement of both microbiologic cure (a Nugent score of 3 or less) and clinical cure (a resolution of the clinical findings from the baseline visit), was evaluated at the 1st and 2nd test-of-cure (TOC) visits at 7-10 and 21-35 days after the start of treatment, respectively. RESULTS: Therapeutic cure rates for sucrose, metronidazole, and placebo gel groups were 83.13%, 71.30% and 0.92%, at the 1st TOC, and 61.04%, 66.67% and 7.34%, at the 2nd TOC, respectively. While there was no significant difference between the sucrose and metronidazole gel groups at the 2nd TOC (P = 0.305), and sucrose gel was more effective than metronidazole gel at the 1st TOC (P = 0.009). CONCLUSION: These findings suggest that sucrose gel restores normal vaginal flora more rapidly than metronidazole gel and can be used as a novel treatment for BV.

[Treatment of nonneoplastic epithelial disorders of skin and mucosa of vulva with focused ultrasound].

OBJECTIVE: To explore the clinical efficacy of focused ultrasound for patients with white lesions of the vulva, as well as its safety and feasibility. METHODS: Clinical data of 941 patients with white lesions of the vulva treated with focused ultrasound from June 2003 to December 2005 were retrospectively reviewed. The mean age of the patients was 40.8 years (18 - 70 years) and the median course of the disease was 6.2 years (3 months - 45 years). Meanwhile, pathological diagnosis was performed in all the patients before treatment, in which 498 cases were squamous hyperplasia, 342 cases were lichen sclerosus and 101 cases were lichen sclerosus with squamous hyperplasia. Patients were followed up and therapeutic effects of focused ultrasound was evaluated at 6 and 12 months after the treatment, respectively. The symptoms of pruritus in the vulva and the changes in the color and elasticity of the vulvar lesions were observed. RESULTS: Of all the patients, 900 were followed up after the treatment, and the ratio of effectiveness was 94.9%. Only 46 patients (5.1%) had no response to the therapy. Of the effective patients, 434 cases were completely cured (48.2%), and 420 cases were improved (46.7%). Pruritus of vulva recurred in 101 patients (11.2%) one year after treatment; however, these patients still had a response to the second or third treatment. CONCLUSIONS: Focused ultrasound therapy is a highly effective instrument in treatment of white lesions of the vulva. It can not only relieve the symptoms of itching, but is also helpful in recovering the color and elasticity of the vulva.