To discover novel fluoroquinolone lead compounds as possible anti-infective or/and antitumor chemotherapies, combination principle of pharmacophore-based drug design, a series of novel tricyclic fluoroquinolone title compounds, [1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives ( 5a-5p), were designed and synthesized with a fused [1,2,4]-triazine ring unit. Their structures were characterized by spectral data and elemental analysis and the in vitro antibacterial and anti-cell proliferation activities were also evaluated. The results showed that the titled compounds exhibited more significant inhibitory activities against drug-resistant bacteria (Methicillin-resistant Staphylococcus aureus and multi drug-resistant Escherichia coli strains) and three tested cancer cell lines (human hepatoma SMMC-7721, murine leukemia L1210 and human murine leukemia HL60 cells). Interestingly, SAR showed that compounds with electron-donating groups attached to benzene ring had stronger antibacterial activity than antitumor activity, but electron-withdrawing compounds displayed more potential antitumor activity than antibacterial activity, especially antitumor activity of nitro compounds was comparable to comparison doxorubicin. Thus, novel triazine-fused tricyclic fluoroquinolones as potent anti-infective or/and antitumor lead compounds are valuable to pay attention and for further development.
Animals ; Anti-Bacterial Agents ; chemical synthesis ; chemistry ; Antineoplastic Agents ; chemical synthesis ; chemistry ; Carboxylic Acids ; Carcinoma, Hepatocellular ; Cell Line ; Cell Proliferation ; Drug Design ; Escherichia coli ; drug effects ; Fluoroquinolones ; chemical synthesis ; chemistry ; HL-60 Cells ; Humans ; Leukemia L1210 ; Liver Neoplasms ; Methicillin-Resistant Staphylococcus aureus ; drug effects ; Mice ; Naphthyridines ; Triazines

Objective To evaluate combination of cholcdochoscopy or duodenoscopy with therapeutic laparoscopy (LCDCS) in treatment of detail choledochus stones. Methods Laparoscopic cholecystectomy was firstly performed and followed by choledochoscopy or duodenoscopy. Procedures of therapeutic choledochoscopy were as follows: choledochoscopic exploration via cystic duct remnant, choledochotomy, electrohydralic lithothipsy, drainage of bile duct with ureteral catheter via cystic duct remnant, T-tube drainage, or the suture of duct incision. Procedures of therapeutic duodenoscopy were as follows: access to the common bile duct and duodenum through ureteric catheter and zebra guidewire via cholecystic duct remnant, duodenoscopy via oral cavity into the duodenum papilla, papillotomy with needle-knife or arch-like electro-knife along the ureteric catheter or zebra guidewire, and stone clearance in the common bile duct with the reticulation and balloon of duodenescopy. Results Combination therapy were given to 191 cholelithiasis patients with detail choledochus stones. Combined choledochoscopy were performed in 117 patients. Stones were completely removed and average operation time was 114 min. Bile leakage occurred in 7 cases, but was cured with drainage. Postoperative imaging showed 2 cases of bile duct stenosis at primary closure of duct incision. Combined duodenescopic procedures were performed in 74 patients. Papillotomy and stone clearance were successfully performed in 68 patients, 5 others of whom underwent successful papillotomy only, and another underwent other operations. Average operation time was 97 min. Post-operation mild acut pancreatitis developed in 6 patients. No perforation of intestine or bile duct, bleeding, severe pancreatitis, or death was observed in each group. Conclusion LCDCS was safe and effective with appropriate indications.

Objective To explore the operative methods and indications of duodenoscopic papillotomy during the course of operation(IEPT)for cholelithiasis.Methods Cholecystectomy was firstly conducted under the condition of laparoscopy or open laparotomy.For the gross choledochus,the common bile duct was cut open to clear the stones.The ureteric catheter and zebra guidewire were inserted into the common bile duct and duodenum.Then they were inserted via duodenoscopy into thepapillum of duodenum.The papillary stenosis was removed with electro-knife by pin-head-like and arch-like to track along the ureteric catheter and zebra guidewire.For the tiny choledochus,the ureterie catheter and zebra guidewire were inserted via the cholecystic duct remnant into the common bile duct and duodenum.Then they were inserted via duodenoscopy to perform papillotomy to clear the stones of the common bile duct with the reticulation and the balloon of duodenoscopy.Results Forthe gross choledochus,IEPT in laparoscopy was successful in 45 cases and the other 2 received other operation.IEPT in open laparotomy was successful in 5 cases.For the tiny choledochus,IEPT in laparoscopy was successful in 73 cases and the other 1 underwent other operation.IEPT in open laparotomy was successfulin 2 cases.Conclusion If patients are suitable,IEPT is safe and effective in the hands of skilled endoscopiests for laparoscopy and open laparotomy.

AIM: To compare the safety and effectiveness of pars plane filtering(PPF)and trabeculectomy(TRA)on neovascular glaucoma(NVG).

METHODS: This retrospective comparison was done in 12 patients(one eye with NVG in each)who were treated with PPF surgery and 15 patients who were treated during the same period with TRA, one eye was treated in each patient. Intraocular pressure(IOP), complete surgical success rate, peripheral anterior chamber depth(PACD), postoperative anterior chamber morphology, visual acuity and complications were observed and compared between the two groups.

RESULTS: The IOP was significantly reduced at each time point after the surgery 1, 3d, 1wk, 1, 3mo after operation(P<0.05), and there was no significant between-group difference at any time point(P >0.05). The rate of complete success observed 3mo after operation was superior in PPF group(92% vs 53%, P<0.05). PACD was found to be deeper at 1wk after the operation in PPF group as compared with the values before the operation and was deeper than that in TRA group(P<0.05); while this comparison in TRA group showed no significant change(P>0.05). After the operation, the anterior chamber angle was open and the anterior chamber was deepened in PPF group. No significant changes in visual acuity before and after the operation within each group and between groups were observed 3mo after the surgery(P>0.05). The incidence of postoperative hemorrhage in anterior chamber was lower in PPF group(8% vs 47%, P<0.05).

CONCLUSION: Both PPF and TRA surgery can successfully control IOP of NVG. However, PPF surgery appeared to be superior as having a higher complete success rate. In addition, PPF surgery makes the anterior chamber deeper and wider, and result in fewer severe postoperative complications.

Neovascular eye disease, which is characterized by pathological neovascular formation, is a major disease threatening visual health. In recent years, neovascular eye disease has become a serious public health problem and attracted widespread attention, with the incidence increasing year by year. Pathological neovascularization is formed under the mutual inclusion and interaction of a variety of cellular components and pathological factors. It is often difficult to achieve ideal therapeutic effect if we intervene only one of the factors. Therefore, it is in an urgent need to conduct a more in-depth study in the pathological process of neovascularization and explore new factors that regulate neovascularization in order to find more effective treatments of neovascular eye diseases. In recent years, pericyte has been proved to play important roles in the occurrence and development of various neovascular eye diseases and interventions for pericytes will affect the pathological process of these diseases. This article will review the specific roles of pericytes in some common neovascular eye diseases and the factors regulating pericytes in these diseases, which would provide new ideas in the treatment of neovascular eye diseases.

To explore the effect of bone marrow camouflaged with methoxy polyethylene glycol (mPEG) on allogeneic bone marrow transplantation, 60 BALB/c(H-2d) mice were randomly divided into 3 groups after irradiation by 8.0 Gy of (60)Co gamma ray. A group was given RPMI 1640 0.5 ml in tail vein. B group was infused with the bone marrow cells (1 x 10(7)) mixed with the spleen cells (1 x 10(7)) of donor 615(H-2k) mice. C group was transplanted with same dose cells, which were camouflaged with mPEG before infusion. Severity GVHD was determined by total manifestation of mice, survival rate, survival time and histo-pathological microscopy, and engraftment of allogeneic bone marrow was evaluated by chromosome examination. The results showed that 75% mice in B group had severe adverse manifestations, such as hunched posture, diarrhea and loss of hair. Occurrence of the same adverse manifestations in C group was 35% and significantly lower than that in B group (P Animals ; Bone Marrow Transplantation ; adverse effects ; methods ; Female ; Graft vs Host Disease ; etiology ; mortality ; prevention & control ; Leukocyte Count ; Male ; Mice ; Mice, Inbred BALB C ; Polyethylene Glycols ; therapeutic use ; Random Allocation ; Survival Analysis ; Survival Rate ; Transplantation, Homologous ; Whole-Body Irradiation

OBJECTIVETo study if methoxy polyethylene glycol modification (mPEG) affects grafts versus leukemia (GVL) when donor bone marrow mononuclear cells are camouflaged with mPEG in murine bone marrow transplantation (BMT).

METHODSSixty (BALB/c(H-2d) x 615(H-2k))F(1) mice were divided into four groups randomly. Mice in group A were only irradiated with 8.0 Gy (60)Cogamma, and mice in the other groups were inoculated intraperitoneally with 1 x 10(6) L615 cells 3 days before irradiation with the same dose (60)Cogamma. BALB/c(H-2d) mice were sacrificed and bone marrow cells and spleen cells were collected. The bone marrow cells (1 x 10(7)) were mixed with the spleen cells (1 x 10(7)), which were camouflaged or not camouflaged with mPEG, were transplanted into irradiated leukemia mice in C and D groups. GVL effects were assessed by L615 cells proportion in peripheral blood, histopathological changes and survival time.

RESULTSSevere GVHD was observed in group C (without mPEG modification), and the mice rapidly died, the mean survival time was 6.9 days. The mice in irradiated group (group B) with leukemia cell died of leukemia. The average survival time of group D (with mPEG modification) was 24.2 days, which was longer than that of the other groups (P < 0.05), and the survival rate of group D (27%) was significantly higher than that of the others (P < 0.05), 11 mice (11/15) died of leukemia and the others were still alive.

CONCLUSIONThe camouflage with mPEG modification is capable of preserving GVL effect and preventing GVHD in mice BMT.

Animals ; Bone Marrow Transplantation ; Female ; Graft vs Host Disease ; prevention & control ; Graft vs Leukemia Effect ; Male ; Mice ; Mice, Inbred BALB C ; Polyethylene Glycols ; pharmacology

OBJECTIVENeuroblastoma is the most common malignant solid tumor in children under 4 years. Amplification of MYCN oncogene is associated with advanced-stage disease, rapid tumor progression, resistance to treatment, and poor outcome. Matirne has the anti-tumor activity. This study was designed to investigate the effects of matrine on LA-N-5 cell line proliferation and MYCN gene mRNA expression.

METHODSNeuroblastoma LA-N-5 cells were treated by 0.25, 0.50, 0.75 or 1.00 mg/mL matrine. MTT was used to measure the levels of the proliferation of LA-N-5 cells cultured with different concentrations of matrine. MYCN gene mRNA expression in LA-N-5 cells was measured using real time RT-PCR with SYBR GREEN I fluorescence.

RESULTSThe proliferation of LA-N-5 cells was obviously inhibited by matrine in a dose- and time- dependent manner. Matrine of 1.00 mg/mL treatment for 72 hrs produced a best effect, with an inhibitory rate of LA-N-5 cell proliferation of 36.3% and an inhibitory rate of MYCN gene mRNA expression of 44.6%.

CONCLUSIONSMatrine may inhibit the growth of neuroblastoma cells and down-regulate MYCN mRNA expression. It may be promising as a new drug for treatment of neuroblastoma.

Alkaloids ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; N-Myc Proto-Oncogene Protein ; Neuroblastoma ; drug therapy ; metabolism ; pathology ; Nuclear Proteins ; genetics ; Oncogene Proteins ; genetics ; Quinolizines ; pharmacology ; RNA, Messenger ; analysis

To discover novel antitumor rhodanine unsaturated ketones, a series of fluoroquinolone (rhodanine α, β-unsaturated ketone) amine derivatives (5a-5r) were designed and synthesized with fluoroquinolone amide scaffold as a carrier. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS. The in vitro anti-proliferative activity against Hep-3B, Capan-1 and HL60 cells was evaluated by MTT assay. The results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. The SAR revealed that some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing carboxyl or sulfonamide substituent were comparable to or better than comparison doxorubicin against Capan-1 cells. As such, it suggests that fluoroquinolone (rhodanine α, β-unsaturated ketone) amines are promising leads for the development of novel antitumor fluoroquinolones or rhodanine analogues.
Amides ; chemical synthesis ; pharmacology ; Antineoplastic Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Fluoroquinolones ; chemical synthesis ; pharmacology ; HL-60 Cells ; Humans ; Ketones ; chemical synthesis ; pharmacology ; Rhodanine ; chemical synthesis ; pharmacology

To discover novel antitumor fluoroquinolone lead compounds from a rational modification for antibacterial fluoroquinolones, a fused heterocyclic ketone corresponding to thiazolo[2,3- b][1,2,4]triazolone used as a bioisosteric replacement of the C-3 carboxylic acid group of ciprofloxacin 1, and further modification by a Claisen condensation reaction with substituted benzaldehydes formed novel fluoroquinolone C-3 fuse heterocyclic α, β-unsaturated ketones as the title compounds (6a-6r), separately. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS, and the in vitro anti-proliferative activity against human hepatoma Hep-3B cells, pancreatic Capan-1 cells and leukemia HL60 cells was evaluated by a MTT assay. The preliminary results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. In particular, compounds carrying an electron-withdrawing carboxyl (6k, 6m) or sulfonamide substituent (6q, 6r) attached to benzene ring were comparable to or better than constractive drug doxorubicin against Capan-1 cells. As such, it suggests that it is favorable for a fused heterocyclic α, β-unsaturated ketone scaffold instead of the C-3 carboxylic acid group to improve the antitumor activity of fluoroquinolones.
Anti-Bacterial Agents ; Antineoplastic Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Ciprofloxacin ; analogs & derivatives ; Fluoroquinolones ; chemical synthesis ; pharmacology ; HL-60 Cells ; Humans ; Ketones ; pharmacology ; Structure-Activity Relationship