Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents.

In search of new compounds with strong antiproliferative activity and simple molecular structure, we designed a novel series of agents based on the 2-amino-3-alkoxycarbonyl/cyano-5-arylethylthiophene scaffold. The presence of the ethyl spacer between the 2',5'-dimethoxyphenyl and the 5-position of the thiophene ring, as well as the number and location of methoxy substitutents on the phenyl ring, played a profound role in affecting the antiproliferative activity. Among the synthesized compounds, we identified the 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 2c as the most promising derivative against a wide panel of cancer cell lines (IC50=17-130 nM). The antiproliferative activity of this compound appears to correlate well with its ability to inhibit tubulin assembly and the binding of colchicine to tubulin. Moreover 2c, as determined by flow cytometry, strongly induced arrest in the G2/M phase of the cell cycle, and annexin-V and propidium iodide staining indicate that cell death proceeds through an apoptotic mechanism that follows the intrinsic mitochondrial pathway.

Correlates of quality of life in China rural-urban female migrate workers.

BACKGROUND: Rural-urban female migrant workers living in factories are a special majority group in the city of Shenzhen, China. These female workers came from different provinces of mainland China. The health-related issues and quality of life (QOL) of this migrator have become serious public health and social problems, which have not been well characterized. This study aimed to explore the QOL and related factors of rural-urban female migrant workers living in factories in China. METHODS: In total, 3,622 rural-urban female migrant workers completed the Health Survey Short Form (SF-36). Sociodemographic characteristics, health status and job satisfaction during the past 6 months were also collected. RESULTS: Subjects had an average of 2.53 ± 1.93 (median = 2.00, quartile interval = 3.00) diseases. The two-week Morbidity Rate was 21.9%, and only 14.0% of the subjects were satisfied with their current job. Compared to Chinese female norms, the participants scored lower in seven concepts domains of SF-36 (role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health). Multiple stepwise linear regression analysis showed that after adjustment for age, education level, work duration and job satisfaction, two-week Morbidity Rate, anemia symptoms and muscular soreness proved to be significant predictors for all the 7 domains (except for physical functioning). Digestive system disease was a significant predictor in 5 out of 7 domains, while urinary system disease and gynecological disease were significant predictors in 4 out of 7 domains. CONCLUSIONS: In general, QOL in rural-urban female migrant workers was lower than Chinese female norms. Improving their job satisfaction and controlling job-related disease appears to be critical to improving their QOL.

[Survival status and prognostic factors of liver metastases from colorectal cancer].

OBJECTIVE: To analyze the survival status and prognostic factors of patients with liver metastases from colorectal cancer. METHODS: The survival rate and prognostic factors of 112 patients with liver metastases from colorectal cancer, who had complete follow-up data, were retrospectively assessed by Kaplan-Meier analysis and multivariate regression analysis. RESULTS: The median survival time of the 112 patients was 18.25 months. The 1-, 2-, 3- and 5-year overall survival rates were 60.8%, 35.0%, 20.3% and 4.8%, respectively. Univariate analysis demonstrated that gender, age, primary tumor site, chemotherapy and pathological types had no significant correlation with the overall survival. But the treatment of primary tumor, time of liver metastasis, gross type of tumor, resection of liver metastases and clinical stage status were all independently related with the prognosis of patients. Multivariate regression analysis showed that resection of liver metastases, gross type of tumor and clinical stage were key factors affecting the prognosis of patients with liver metastases from colorectal cancer. CONCLUSION: Patients with advanced stage, infiltrative gross type of colorectal cancer should be followed-up closely so that liver metastases from the cancer can be diagnosed and treated early. Resection of both the primary tumor and liver metastasis may improve survival of the patients.

TNM staging of colorectal cancer should be reconsidered by T stage weighting.

AIM: To verify that the T stage has greater weight than the N stage in the staging of colorectal cancer. METHODS: Open data from the Surveillance, Epidemiology, and End Results program were reviewed and analyzed according to the T stage, N stage, and patients' observed survival (OS). The relative weights of the T and N stages were calculated by multiple linear regressions based on their impact on survival. Risk scores for 25 TN categories were then calculated from the T and N stage relative weights, and a rearranged tumor node metastasis (TNM) staging system was proposed via a cluster analysis of the TN scores. RESULTS: Both T and N stages significantly affect the OS of patients with colorectal cancer. Moreover, the T stage has greater weight than the N stage in the TNM staging system of colorectal cancer. For colon cancer, the relative T and N stage weights were 0.58 and 0.42, respectively, and for rectal cancer, the relative T and N stage weights were 0.61 and 0.39, respectively. On the basis of cluster analysis of the TN scores, T1N1a was classified to stage I, and T2N1a-1b and T1N1b-2a were classified to stage II in our revised TNM staging system for both colon and rectal cancer. For colon cancer, T4bN0 was classified to stage IIIa, but for rectal cancer, it was classified to stage IIIb. CONCLUSION: As the T stage affects colorectal cancer survival more significantly than the N stage, the TNM staging should be revised by relative T stage weight.

[Effect of homoharringtonine on expression of NF-κB and BCL-2 proteins in K562 cells].

This study was aimed to investigate the effect of homoharringtonine (HHT) on K562 cell proliferation, apoptosis and expression of BCL-2 and NF-κB proteins. The cells proliferation was assayed with MTT method, the cell apoptosis, cell cycle and BCL-2 expression were analyzed with flow cytometry, NF-κB protein expression was detected with Western blot. The results showed that HHT concentration-dependently inhibited proliferation of K562 cells, the IC50 at 48 h was 43.89 ng/ml. Treated with HHT 10 ng/ml for 48 h, K562 cell apoptosis significantly increased, cell cycle was blocked at G0/G1, the expression level of BCL-2 and NF-κB proteins was lower than that in control group (P < 0.05). It is concluded that HHT may inhibit the proliferation of K562 cells, and down-regulating expression levels of BCL-2 and NF-κB may be one of its anti-CML mechanisms.

Concise synthesis and biological evaluation of 2-Aroyl-5-amino benzo[b]thiophene derivatives as a novel class of potent antimitotic agents.

The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2-(3',4',5'-trimethoxybenzoyl)-5-aminobenzo[b]thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure-activity relationship analysis established that the best activities were obtained with amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c-e showed more potent inhibition of tubulin polymerization than combretastatin A-4 and strong binding to the colchicine site. These compounds also demonstrated substantial antiproliferative activity, with IC50 values ranging from 2.6 to 18 nM in a variety of cancer cell lines. Importantly, compound 3c (50 mg/kg), significantly inhibited the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice.

Discovery and optimization of a series of 2-aryl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazoles as novel anticancer agents.

A new series of tubulin polymerization inhibitors based on the 2-aryl/heteroaryl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole scaffold was synthesized and evaluated for growth inhibition activity on a panel of cancer cell lines, cell cycle effects, and in vivo potency. Structure-activity relationships were elucidated with various substitutions at the 2-position of the thiazole skeleton. Hydrophobic moieties, such as phenyl and 3-thienyl, were well tolerated at this position, and variation of the phenyl substituents had remarkable effects on potency. The most active compound (3b) induced apoptosis through the mitochondrial pathway with activation of caspase-3. We also showed that it has potential antivascular activity since it reduced in vitro endothelial cell migration and disrupted capillary-like tube formation at noncytotoxic concentrations. Furthermore, compound 3b significantly reduced the growth of the HT-29 xenograft in a nude mouse model, suggesting that 3b is a promising new antimitotic agent with clinical potential.

Synthesis and evaluation of 1,5-disubstituted tetrazoles as rigid analogues of combretastatin A-4 with potent antiproliferative and antitumor activity.

Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 4l significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 4l is a promising new antimitotic agent with clinical potential.

Translational research of a novel humanized epidermal growth factor receptor-related protein: a putative inhibitor of pan-ErbB.

PURPOSE: The ErbB family members are protein tyrosine kinases, which play a crucial role in the signal transduction pathways that regulate key cellular functions. Overexpression of the ErbB family members is associated with oncogenicity, metastatic potential, cell proliferation, apoptosis, angiogenesis, and prognosis in cancer. Molecular-targeted therapies centered on the ErbB signaling pathway are the currently promising anti-cancer therapies. METHODS: We reviewed the literature to summarize the current knowledge of epidermal growth factor receptor (EGFR)-related protein (ERRP) and determine the potential of this protein to be translated into a molecular-targeting treatment for cancer. RESULTS: ERRP isolated from rat gastroduodenal mucosa is a pan-ErbB inhibitor that targets multiple members of the ErbB family both in vitro and in vivo. Sequestration of ErbB ligands by ERRP results in the formation of inactive ErbB heterodimers and subsequent attenuation of signaling pathways activated by ErbB. We suggest a strategy to develop a humanized ERRP protein based on activity of rat EERP in vitro. CONCLUSIONS: As rat ERRP protein is expected to generate an immune response in humans, we propose a hypothesis that a humanized version of ERRP has potential therapeutic value for cancer patients.

Endostar enhances the antineoplastic effects of combretastatin A4 phosphate in an osteosarcoma xenograft.

Vascular-targeting agents (VTAs) can be divided into two groups: anti-angiogenesis agents and vascular disrupting agents (VDAs). The purpose of this study was to evaluate the antineoplastic activity of a combination of the anti-angiogenesis agent, Endostar, and the VDA combretastatin, A4 phosphate (CA4P). This study is the first to evaluate the activity of this combination against tumors and the first to investigate the activity of the combination against osteosarcoma. Endostar combined with CA4P had a good anti-tumor effect with no significant toxicity, and was at least not inferior to adriamycin, which is the main drug for osteosarcoma. The use of VDAs combined with anti-angiogenic drugs can result in significantly enhanced anti-tumor effects, providing a novel approach to cancer treatment, which could effectively complement standard treatments. It is believed that this exciting new treatment has the potential to transform the management of cancer.

One-pot synthesis and biological evaluation of 2-pyrrolidinyl-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole: a unique, highly active antimicrotubule agent.

A wide variety of small molecules with diverse molecular scaffolds inhibit microtubule formation. In this article we report a one-pot procedure for the preparation of a novel 2-(N-pyrrolidinyl)-4-amino-5-(3',4',5'-trimethoxybenzoyl)thiazole in which the size of the substituent at the C-2 position of the thiazole ring plays an essential role in compound activity. The most active agent (3f) inhibited at submicromolar concentrations the growth of tumor cell lines. It also inhibited tubulin polymerization with an activity quantitatively similar to that of CA-4, and treatment of HeLa cells resulted in their arrest at the G2-M phase of the cell cycle. Furthermore, 3f was effective against multidrug resistant cancer cells and inhibited the growth of the HT-29 xenograft in a nude mouse model. This indicated that 3f is a promising new antimitotic agent with encouraging preclinical potential.