Synthesis and biological evaluation of phosphoinositide 3-kinase (PI3K) inhibitors based on a quinoxaline scaffold / 药学学报

Based on the structure of inhibitors XL765 and WR23, the quinoxaline scaffold was selected as an attractive structure for drug design. In this protocol, the 2-position of quinoxaline was modified with a substituted phenoxy fragment. Meanwhile, the linking chain at the 3-position was changed to a sulfonyl hydrazine or was removed. A series of substituent groups were added at the 6-position of the quinoxaline scaffold. Twenty-two quinoline derivatives were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR, and ESI-MS. All compounds were screened for anti-tumor activity in vitro in A549, MCF-7, HCT-116 and HepG2 cancer cells. The results showed that P6b was effective, P6e and P6f had better activity against HCT116 (IC50 = 3.24, 4.78 and 4.50 μmol·L-1), and P6d had strong inhibitory effect on MCF-7 (IC50 = 0.228 7 μmol·L-1).

Anti-Tumour Activity Of Bromopyrrole Alkaloids Against Human Breast Tumour (MCF-7) Through Apoptosis Induction

Objective: The present study was conducted to screen the cytotoxicity and initiation of apoptosis in MCF-7 human breast tumour cells using the Indian sponge Acanthostylotela cornuta of the Gulf of Mannar. Methods: The crude methanol extract of A. cornuta was fractionated using a reversed phase silica gel column chromatography. The purity of the active fraction of bromopyrrole alkaloids was confirmed with Gas Chromatography-Mass Spectrometry (GCMS). The bromopyrrole alkaloids induce apoptotic changes in MCF-7 cells were studied with electrophoresis, caspase assay, and different staining analysis. The MCF-7 cells were analyzed by Flow cytometry to determine their DNA content. Results: Bromopyrrole alkaloids of A. cornuta showed cytotoxicity against MCF-7 human breast tumour cells with the IC50 value of 8.0μg/ml. The bromopyrrole compounds induced cells exhibited scatted red fluorescence, showing the presence of several residual bodies and condensation of chromatin. Caspase-3, pro-caspase-9, caspase-9 and Poly-ADP-Ribose-Polymerase (PARP) activity were occurred in bromopyrrole alkaloids treated tumour cell. The cell cycle arrest is conceivable that the compound prevented the progression of cell cycle through the G phase resulting from inhibition of survival, leading them to undergo apoptosis. Conclusion: Bromopyrrole alkaloids of A. cornuta possess antitumor activity which was arrested the G phase in cell cycle that clearly indicated its nature as that of antitumour drugs.

Synthesis and Physiological Activity of Novel Berberine Derivatives / 中国实验方剂学杂志

Objective: TO synthesize novel berberine derivatives with a variety of physiological activities,and study their antitumor activity and acetylcholinesterase inhibitory activity. Method: Berberines with a variety of physiological activities were pieced together isohydroxamic acid,o-phenylenediamine,and sulfhydryl pharmacophore with effects in inhibiting histones and removing acetylases. Totally 7 novel berberine derivatives were obtained by means of organic synthesis. The structures of these derivatives were characterized and confirmed by 1H-NMR,13 C-NMR and MS spectral data.Thiazolyl blue tetrazolium bromide(MTT) method was used in the determination of the cytotoxic activity of HCT116,HepG2,HeLa and CCRF-CEM human cancer cell lines in vitro. Ellman method was used to reveal the inhibitory activities of acetylcholinesterase and butyrylcholinesterase. Result: The results showed that the berberine derivatives containing methyl ketone had good antitumor and acetylcholinesterase inhibitory activities. The results demonstrated that compound 5b had the highest anti-proliferative activity against CCRF-CEM cell line and the acetylcholinesterase inhibitory activities, with IC50=1.48 μmol · L-1 and IC50=0.38 μmol · L-1,respectivly. Conclusion: This paper provides a reference for the synthesis and biological evaluation of this kind of alkaloid derivatives. Compound 5b is a promising candidate drug and worth further study.

The research progress in antitumor mechansim of Inonotus obliquus / 实用肿瘤学杂志

Since the tumor has become one of the most deadly diseases to human life ,it is of great impor-tance to explore a new effective antitumor medicine .This paper summarizes the chemical constituents and the mechanism of Inonotus obliquus .The mechanism includes the details of the inhibition of tumor cell proliferation , inducing tumor cell apoptosis ,influence tumor cell cycle etc .Meanwhile,it describes Inonotus obliquus to the ad-juvant chemotherapy of tumor .

An approach on microbial biosynthesis of L-glutaminase: a tumour inhibitor.

L-Glutaminase, an amidohydrolase enzyme has been a choice of interest in the treatment of lymphoblastic leukemia. This study investigates the production of extracellular L-glutaminase synthesis were carried out by using Aspergillus oryzae was evaluated under different fermentation parameters by employing submerged fermentation method. The L-glutaminase producers detected by the pink zone around the colony by simple plate assay method. Aspergillus oryzae S2 is the potential strain among the fungal isolates. The L-glutaminase synthesis were increased their yield after the optimization of fermentation parameters. The optimum pH 5.0, temperature 350C and inoculum size 1.0 ml and it showed 217.65 IU.

The Safety and Effectiveness of Single and Repeat Dosing of Intra-Articular Anti-Tumour Necrosis Factor Treatment after Failure of Intra-Articular Steroids.

Objectives: To determine if intra-articular (ia) anti-tumour necrosis factor (TNF) yielded benefit in patients failing ia steroid injections and determine the safety and durability of single and repeated ia anti-TNF treatment in inflammatory arthritis. Methods: Patients with inflammatory arthritis having one or two active joints, and having failed previous ia steroids were injected with ia adalimumab or ia etanercept mixed with triamcinolone and lidocaine via a retrospective chart audit. Results: Twenty-six patients were followed: 18 received ia adalimumab, 12 received ia etanercept and 4 received both. Twenty-five knees, 17 ankles, 1 wrist and 1 PIP were injected of whom 6 had repeated injections to a joint. Nine were on concomitant systemic anti-TNF therapy. Fifteen had RA, 4 had a seronegativearthropathy, 3 had psoriatic arthritis, and 4 had other arthritis. When determining a response to ia anti-TNF for > 2 months in patients with sufficient follow up 13 of 18 receiving iaadalimumab and 6/7 with ia etanercept had benefit. There were no serious adverse events (SAEs) and only one AE in a wrist post ia adalimumab, with rebound inflammation after 6 weeks of marked relief. Two were able to cancel or postpone joint surgery(knee and ankle)and one cancelled an yttrium injection. Conclusions: There were no SAEs and prolonged benefit was found with ia anti-TNF and steroids and lidocaine compared to previous ia steroids with lidocaine in the majority (20/27). Although not approved for ia administration, ia anti-TNFs may be cost effective in persistent synovitis of one or two joints recalcitrant to ia steroids.

Advances in immunotherapy using dendritic cells

The immune system is the host natural defence against cancer. Cancers are caused by progressive growth of the progeny of a single transformed host cell. The immune system is generally not able to mount immune responses to “self-antigens”, due to various mechanisms of immunological tolerance that are in place. This means that despite possessing a natural defence against tumours, many of the cancer patients may not be able to mount an effective immune response to fight the tumours. Dendritic cells (DC) are highly specialised in antigen presenting that can initiate and stimulate immune responses. These cells have the ability to stimulate naïve T cell proliferation and perform specific stimulatory and tolerogenic functions respectively. When the DC are activated by antigens, these cells undergoes further maturation and migrate to secondary lymphoid tissues, present antigen to T cells and finally induce an immune response. The ability of the DC to activate naïve and primed T-lymphocytes makes these cells a good candidate to be explored as a potential immunotherapeutic agent that can modulate antitumour immune responses in the affected host.

Inhibition of Ehrlich ascites carcinoma by Manilkara zapota L. stem bark in Swiss albino mice

<p><b>OBJECTIVE</b>To evaluate the antitumor activity of Manilkara zapota (M. zapota) L. stem bark against Ehrlich ascites carcinoma (EAC) in Swiss albino mice.</p><p><b>METHODS</b>The in vivo antitumour activity of the ethyl acetate extract of stem bark of M. zapota L. (EASM) was evaluated at 50, 100 and 200 mg/kg bw against EAC using mean survival time. After administration of the extract of M. zapota, viable EAC cell count and body weight in the EAC tumour hosts were observed. The animal was also observed for improvement in the haematological parameters (e.g., heamoglobin content, red and white blood cells count and differential cell count) after EASM treatment.</p><p><b>RESULTS</b>Intraperitoneal administration of EASM reduced viable EAC cells, increased the survival time, and restored altered haematological parameters. Significant efficacy was observed for EASM at 100 mg/kg dose (P<0.05).</p><p><b>CONCLUSIONS</b>It can be concluded that the ethyl acetate extract of stem bark of M. zapota L. possesses significant antitumour activity.</p>

In vitro anti-leishmanial and anti-tumour activities of a pentacyclic triterpenoid compound isolated from the fruits of Dregea volubilis Benth Asclepiadaceae

Purpose: Dregea volubilis Benth, commonly known as Jukti in Bengal, is used in the treatment of boils and abscesses from ancient times. The purpose of this study is to elucidate the active compounds and as well as their anti-leishmanial and anti-tumour activities. Methods: Dried and crushed fruits of Dregea volubilis were extracted by petroleum ether (40 - 60°C); the best solvent system had first been verified by analytical Thin Layer Chromatography (TLC). The extract was subjected to TLC and column chromatography (CC) to isolate the pure compounds. Spectra data were obtained by Infra Red pectroscopy, Mass Spectroscopy and Nuclear Magnetic Resonance - Proton Magnetic Resonance (PMR), Carbon Magnetic Resonance (CMR) and Distortionless Enhancement by Polarization Transfer (DEPT) - for structure elucidation of the isolated compound(s). One of the compounds isolated was screened for anti-leishmanial activity against promastigotes of Leishmania donovani and anti-tumour activity on K562 leukemic cell line. Results: A pentacyclic triterpenoid compound was isolated and designated as taraxerone, and then characterized as d-friedoolean-14-en, 3 one together with ß-sitosterol and a long chain lipid fraction.. This compound showed in vitro anti-leishmanial activity against promastigotes of Leishmania donovani(strain AG 83) and anti-tumour activity on K562 leukemic cell line. Conclusion: A pentacyclic triterpenoid compound designated as taraxerone and characterized as Dfriedoolean-14-en, 3 one together was successfully isolated. The structure was determined on the basis of spectral analysis (IR, MASS, NMR (PMR, CMR and DEPT) and the compound demonstrated in vitro anti-leishmanial and anti-tumour activities

Old Enzyme with New Interest:Review of Newly Understood NEP Functions and Its Potential Renglators / 中国生物化学与分子生物学报

Neprilysin(NEP)is a type Ⅱ integral membrane glycoprotein of the M13 zinc metalloprotease family．As a neuropeptide degrading enzyme,NEP has been discovered to possess an increasing amount of organ-specific functions from central nervous system to peripheral tissues since it was fimfly identified in 1974．For example,NEP has been shown to have an anti-tumour effect by inhibition of cell migration and proliferation while induction of an programmed cell death dependent of both its enzymatic activity and direct protein-protein interactions with key molecules involved in signal transduction pathways:NEP Was also implicated to have neuropmtective effect by preventing the accumulation of the neurotoxic amyloid β-peptide (Aβ)in brain．Through investigating the progression of various human diseases,impaired NEP expression and activity were found to occur frequently．Based on these findings,modulation of NEP levels in pathological cells is considered to be therapeutically applicable as a strategy to recover normal cell functions and thereafter relieve symptoms of diseases．Great research effort is being contributed to the study of regulatory mechanisms involved in expression and activity of this enzyme,and a number of encouraging results have already been achieved．Besides androgens,well-recognised regulators of NEP transcription in prostate,the female hormone oestrogen,aqueous extract of willow herb,components of green tea and neuropeptides bombesin,somatostatin as well as the intracellular domain of amyloid precursor protein were all shown to have a stimulatory effect on NEP expression and／or its activity．

Research of drug screening model based on recombinant hPPAR?-LBD as a target protein for lipid metabolism / 重庆医科大学学报

Objective:To establish a method of antitumor drug screening model based on recombinant hPPAR?-LBD as a target protein for lipid metabolism. Methods:pReceiver-B01-PPAR?- LBD expression plasmid was constructed and transferred into Escherichia coli BL2(1DE3)competent cells. Growth conditionswere optimized to induce soluble expression of hPPAR?-LBD recombinant protein. Purification was carried out by Nickel affinity chromatography. Ligand binding activity of the recombinant protein was determined by novel size exclusion chromatography and high performance liquid chromatography(SEC-HPLC)method with rosiglitazone as reference ligand and GW9662 as antagonist. Results:Under optimal conditions (16℃,0.6 mmol/L IPTG and induction time 20 h),the soluble recombinant protein was expressed successfully. After one-step purification with Nickel affinity chromatography,41 mg of recombinant protein with more than 95% purity could be obtained from per liter Luria-Bertani(LB)medium. The Kd and percentage ofspecific bindingofrosiglitazone and tetrazanbigen tohPPAR?-LBDare 625 nmol/L,65% and 1 000 nmol/L,60%,respectively.Conclusion:In this study,a fast,stable and simple method could be used successfully to screen antitumor drug.

Research progress of thalidomide in combination therapy for the treatment of tumor / 中国临床药理学与治疗学

Following the reports of its teratogenicity,thalidomide was banned from the market in the 1960s.Later,researches discovered the teratogenicity was caused by inhibiting angiogenesis,and at that time the antiangiogenesis effect was considered an important factor in anti-tumour.Since then,many other anti-tumour mechanisms of thalidomide had been revealed and thalidomide was considered a kind of potential antitumor drug and was researched widely.This article focuses on the anti-tumour mechanisms of thalidomide and its use in combination therapy for the treatment of solid tumor.

A new 85 kDa, breast tumour associated antigen — A potential diagnostic and prognostic agent.

In an attempt to develop measures for early diagnosis and prognosis of the disease and to explore association of murine mammary tumour virus (MuMTV) or related virus in breast cancer, we purified a breast tumour associated antigen (BTAA) from the breast tumour tissues of untreated female cancer patients. The BTAA purified by DEAE discontinuous column chromatography followed by SE-HPLC was an 85 kDa glycoprotein. A high level of circulating antibodies against this antigen was observed, using ELISA, in all the untreated female breast cancer patients. The BTAA was not immunologically related to MuMTV antigens but strongly resembled an 83 kDa glycoprotein tumour associated antigen, purified from MuMTV induced mouse mammary tumour. In patients after surgical removal of the breast tumour, the circulating antibodies to the BTAA decreased gradually, but reappeared in the patients with secondary metastasis. In healthy age matched women or in female patients with carcinoma of tissues other than breast, no significant titre of the BTAA antibodies was observed.

STUDIES ON THE PHARMACOLOGICAL ACTIVITIES OF HAI CI BAO ORAL LIQUID / 中国海洋药物

This study investigated the pharmacological activities of Hai Ci Bao oral liquid (HCB) refined from the extracts of Stichopus variegatus Semper. The results showed that HCB can prolong significantly the life of Drosophila melanogaster , increase the SOD activity of erythrocytes in mice,possesse the anti-stress action of anti - fatigue and tolerance to high temperature etc,enhance animal growth and increase immunological organ weight,and have definite inhibiting effect on animal transplanting tumour.

THE ANTITUMOUR AND IMMUNOMODULATING EFFECT OF EXOPOLYSACCHARIDES PRODUCED BY LACTOBACILLUS DELBRUECCKII SSP.BULGARICUS / 营养学报

Objective To study the antitumour, immunomodulating and enterobacteria regulating effects of exopolysaccharides (EPS). Method The suppressive rate of growth of sarcoma 180, the index of immunity, and the intestinal microflora were determined. Results (1) EPS inhibited the growth of sarcoma 180 by oral for BALB/c mice significantly. The suppressive rate at the dose of 120mg/kg bw?d was 42.7%. (2) At the dose of 120mg/kg bw?d the index of thymus and IL-2 in serum increased significantly. There was increasing trend in respect of TNF-? and killing activation of NK cell. (3) The amounts of Lactobacillus in groups treated with EPS increased significantly, and the amounts of Enterobacteriacea and Enterococcus droped significantly. Conclusion EPS had the antitumour effect in vivo, and could modulate the immune function, improve the microbial balance in the intestinal tract of tumour bearing mice to some extent. So the antitumour mechanism was probably correlated with the immunomodulating effect.