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).

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.

2-Methoxy-1,4-Naphthoquinone (MNQ) Suppresses Protein Kinase C βI, δ, and ζ Expression in Raji Cells.

Protein Kinase C (PKC) is widely documented to be involved in the regulation of cancer cell growth, proliferation, survival, inflammation and apoptosis. This study evaluates the capability of 2-Methoxy-1,4- Naphthoquinone (MNQ) in regulating PMA-induced PKC expression in human Burkitt’s lymphoma cell line (Raji cells). MNQ exhibited stronger anti-tumour-promoting activity than genistein based on the inhibitory assay of Epstein-Barr virus (EBV) activation. The IC50 values attained were 2.92 and 7.40 μM, respectively. The suppressive effects of MNQ on PKC expression was determined by using the PepTag® non-radioactive detection of PKC assay. The IC50 values achieved for staurosporine and rottlerin (standard control), and MNQ were 0.01, 6.38, and 13.13 μM, respectively. These preliminary results indicate that MNQ specifically suppressed the expression of PKC βI, δ, and ζ in a concentration-dependent manner in Raji cells.

An comparative study of the selective killing action of antibacterial protein from the embryonic cells of the musca domestica on human myeloid leukemia cells K562 / 重庆医学

Objective To stimulate the embryonic cells of the musca domestica with lipopolysaccharide(LPS) for production of antibacterial protein and to extract antibacterial protein ,then research the inhibitory action of the antibacterial protein and homohar‐ringtonine on human myeloid leukemia cells K562 and normal human cells .Methods The logarithmic growth phase′s embryonic cells of the musca domestica were stimulated using no serum M3 insect medium which contained 20 mg/L LPS for sixteen hours . The antibacterial protein was extracted from supernatant fluid .The antibacterial protein was prepared in 40 ,80 ,160 ,320 and 640μg/mL five density groups ;the MTT experiments were used to test the inhibition of antibacterial protein on K562 cells and the hu‐man umbilical vein vascular endothelial cells .The K562 cells and human umbilical vein vascular endothelial cells were prepared HTT and antibacterial protein of the embryonic cells of the musca domestica groups ,the normal control group was established by cells itself .Effective killing rate of K562 cells and the human umbilical vein vascular endothelial cells were measured .Results The effective inhibition ratio of homoharringtonine and the antibacterial protein on K562 cells and human umbilical vein vascular endo‐thelial cells on three density groups were detected by flow cytometry .The MTT examination demonstrated that all density antibac‐terial peptides had inhibition activities on K562 cells ,but no inhibition activities on human umbilical vein vascular endothelial cell . The effective killing and wound ratio of the control group ,the homoharringtonine group and of the antibacterial protein group from the embryonic cells of the musca domestica on the K562 cells were(28 .16 ± 2 .14)% ,(81 .41 ± 1 .95)% and (82 .90 ± 3 .03)% ,re‐spectively ;the effective killing rate on human umbilical vein vascular endothelial cells were(41 .13 ± 2 .51)% ,(82 .20 ± 2 .57)% and (36 .68 ± 1 .86)% ,respectively .Conclusion Compared with the common chemotherapeutics medicine ,the merit of the antibacterial protein from the embryonic cells of the musca domestica is that it can kill the tumor cells effectively ,but would not damage the nor‐mal person cells .

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.

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 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.