Applications and constructions of benzazepine scaffolds in drug molecular design / 药学学报

Benzazepine is a kind of fused ring structure, which is composed of nitrogen-containing seven-membered ring and benzene ring. The introduction of benzazepine scaffolds into compounds can not only adjust the physicochemical properties, maintain or enhance the biological activities of the compounds, but also improve the pharmacokinetic properties, increase the brain permeability, and reduce the toxicity of hERG of the compounds, which is one of the privileged scaffolds for rational design and structural optimization of drug molecules. Benzazepine scaffolds can be constructed by different synthetic methods such as Dickmann condensation reaction, Mitsunobu reaction, Pictet-Spengler reaction, CMD reaction, multicomponent reactions (MCRs), metal catalysis reactions and asymmetric catalysis etc., which play an important role in enriching the structure diversity of drug molecules.

Abirritation of Discogenic Pain Model in SD Rats by Paravertebral Ozone Injection / 中山大学学报(医学科学版)

@#【Objective】To investigate the analgesic and degenerated regularity of paravertebral ozone injection in the discogenic pain model of SD rats ，and to reveal the mechanism of analgesic effect of ozone preliminarily.【Methods】 Male SD rats（n = 65）were randomly divided into control group（n = 15），model group（n = 25）and ozone group（n = 25）. The L5- 6 intervertebral discs of SD rats in model group and ozone group were punctured to establish discogenic pain models. Ozone was injected paravertebrally in ozone group rats on the 22nd day after modeling. The rats in control group were normal. A quantitative allodynia assessment technique and MRI were used to detect the 50% mechanical withdrawal threshold（50%MWT）and Pfirrmann grade of L5-6 intervertebral discs at different time intervals. The expression of tumor necrosis factor-α（TNF- α）and calcitonin gene-related peptide（CGRP）in left dorsal root ganglion and sciatic nerve were detected by western blot.【Results】The 50% MWT of both hind paws were different from each other in three groups at each time after the 22nd day after modeling（P < 0.05）. In the ozone group，the 50% MWT rose on the 22nd day after modeling（left 7.6±6.8，right 3.6±1.0，P < 0.05 vs pre-ozone injection），and reached the peak on the 24th day after modeling（left 10.6±8.2，right 7.9±6.7，P < 0.05 vs pre-ozone injection），and maintained this level until the 56th day after molding. In the ozone group，the L5-6 intervertebral disc degeneration was apparently visible compared with model group（P < 0.05）. The expression of TNF- α and CGRP in dorsal root ganglion and sciatic nerve were different from each other in three groups（model>ozone>control，P < 0.05）.【conclusions】Paravertebral ozone injection can alleviate the pain of discogenic pain model rats，but aggravates the degeneration of the lumbar disc. Paravertebral ozone injection can reduce the expression of TNF-α and CGRP in the sciatic nerve and dorsal root ganglia of discogenic pain model rats.

Effect analysis of the cesarean scar pregnancy with intervention treatment and expectant treatment / 中国实用妇科与产科杂志

OBJECTIVE: To discuss the clinical significance of cesarean scar pregnancy with expectatant treatment.METHODS: Collect 21 cases of CSP between 2012 and 2017 in the Third Affiliated Hospital of Guangzhou Medical University.Group A had 8 cases who were pregnant again after intervention treatment,and group B had 13 cases who insisted on expecting treatment.We summarized clinical indexes of both groups,such as preserving uterus,bladder rupture,admission to ICU,blood transfusion,placenta implantation,etc. in order to further study the significance of expecting treatment for CSP.RESULTS: All of group A were pregnant again after intervention treatment,of whom 1 was CSP again and hysterectomy was performed at 15 weeks due to placenta implantation,while another 7 were uterine pregnancy,of whom 3 were term birth and had no placenta implantation,and another 4 were terminated in response to the requirements of patients,of whom 1 was treated with drug abortion and 3 underwent dilatation and curettage.Uterus was preserved in the 7 women,and there was no bladder rupture,no admission to ICU,no blood transfusion,and no placenta implantation.Among the 13 cases in group B, 6 cases underwent cesarean section during third trimester,including 3 cases of premature delivery and 3 cases of delivery at 37 weeks.5 cases were pregnant to second trimester,containing 4 cases received hysterectomy and 1 case suffered subtotal hysterectomy.2 cases were pregnant to first pregnancy, including 1 case of abdominal nidus resection, 1 case of ultrasound-guided dilation and curettage;Among the13 patients, 4 cases underwent bladder rupture, 4 cases lost uterus, 5 cases were admitted to the ICU, and 10 cases required blood transfusion.Placental implantation occurred in 11 cases who were pregnant to second and third trimester.CONCLUSION: Most of CSP with expecting treatment will develop into placenta implantation inevitably in the late stage of pregnancy.The patients with CSP can be pregnant again after early intervention and have extremely low possibility of a second CSP.

Design, synthesis and bioactivity of aryl piperazine benzob1,4oxazine derivatives / 药学学报

Compounds with serotonin reuptake inhibition/5-HT(1A) dual activity were used to build 3D pharmacophore model as a training molecules by Discover Studio. Based on the model, 8 novel aryl piperazine benzo[b][1,4] oxazine derivatives were designed and synthesized, and their structures were confirmed by 1H NMR and HR-MS. Biological evaluation illustrated that compounds VI(1) and VI(7) showed potent functional activities at both 5-HT transporter and 5-HT(1A) receptor, which can be used as lead compounds to guide future research of design and synthesis of potent novel compounds.

Synthesis and analgesic activities of phenyl piperazinyl aralkyl ketone derivatives / 药学学报

To explore novel non-opioid analgesic agents, 16 compounds were synthesized and their structures were confirmed by 1H NMR and HR-MS. YX0611-1 was treated as the leading compound. The results of mice writhing model and hot plate model showed that compounds 2, 7, 8, 9, 11 and 15 had obvious analgesic activities in vivo. The test of affinity to mu, delta, kappa receptor displayed that active compounds didn't act on opioid receptor. The results of preliminary toxicity and pharmacokinetic tests showed that compound 7 had better safety and pharmacokinetic properties than that of YX0611-1, and it deserved further development.

Synthesis and antidepressant activities of aryl alkanol piperidine derivatives / 药学学报

To explore novel monoamine reuptake inhibitor with antidepressant activity, a series of substituted aryl alkanol piperidine derivatives were designed and synthesized. All of them were new compounds, and their structures were confirmed with 1H NMR and HR-MS. The results showed that compounds 4, 5 and 8 displayed strong 5-HT, NA and DA reuptake inhibiting activities in vitro. Among the tested compounds, 4, 5 and 13 exhibited potent antidepressant activities in the mice forced swimming test. Compounds 4 and 5 have potent antidepressant activities and are worth further development.

Synthesis and anti-tumor activities of N-(aminopyridine) benzamide derivaties / 药学学报

To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, on the basis of preliminary studies, sixteen N-(2-amino-4-pyridine) benzamide derivaties (class A) and sixteen N-(2-amino-3-pyridine) benzamide derivaties (class B) were designed and prepared, and their structures were confirmed by 1H NMR and HR-MS individually. The results showed that 30 target compounds except V-20 and V-21 had HDACs inhibitory activity and V -13, V -14, V -16 were equal to CI-994 at 200 micromol x L(-1) in vitro. Compounds V-30, V-31 and V-32 exhibited potent inhibitory activities on Hut78, Jurkat E6-1, A549, K562 and MDA-MB-435s.

Design, synthesis and antalgic activities of aralkyl-ketone-4-piperidol derivatives / 药学学报

A series of aralkyl-ketone-4-piperidol derivatives were synthesized and tested for their analgesic activities. All of the novel 30 compounds were prepared from 4-piperidone and alpha-halo-aralkyl-ketone through five steps, including Boc protection, nucleophilic addition in presence of CeCl3/NaI catalyst, deprotection, condensation and salification. Their structures were confirmed by 1H NMR and HRMS. Preliminary in vivo pharmacological trials showed that most of the synthesized compounds revealed analgesic effects. Among the tested compounds, 8, 13 and 22 exhibited potent analgesic activities in both mice writhing and mice hot plate model. The three compounds have low affinity for mu, delta, kappa receptors, which is a chance to find a better precursor of non-opioid analgesic for further optimization.

Synthesis and anti-tumor activities of N-substituted benzamide derivatives / 药学学报

To explore novel histone deacetylase (HDACs) inhibitors with anti-tumor activity, MS-275, a HDACs inhibitor, was prepared and used as a lead compound to design new N-substituted benzamide derivatives. MS-275 and eleven target compounds were obtained, and their structures were confirmed by 1H NMR and HR-MS individually. The results showed that the activity of compound 9d was equal to MS-275 in HDACs inhibition tests in vitro and worthy of further investigation. Compound 5c, 5d and 9c displayed obvious dose-effect relationship, which possessed moderate HDACs inhibitory activities. Ten compounds except 9e had selective inhibitory activities on Hut78.

Design and synthesis of nitrogen-containing benzoheterocyclic derivatives and their antipsychotic activities / 药学学报

A series of nitrogen-containing benzoheterocyclic derivatives were synthesized and tested for their antipsychotic activities. Their structures were confirmed by 1H NMR and HR-MS. Preliminary in vitro pharmacological trials showed that most of the target compounds have high affinity with D2 and 5-HT(2A) receptors. Among the tested compounds, 20 exhibited the highest affinity and D2 partial agonist activity. In vivo studies showed 20 has potent antipsychotic activities on apomorphine mice model, which is a chance to find a better precursor of D2 partial agonist for further optimization.

Synthesis and central none-opioid analgesic activity of SIPI5047 / 药学学报

Compound SIPI5047 was synthesize by using piperazine as starting material in five reaction steps, and its central none-opioid analgesic activity was studied. Its analgesic activity, pharmacological mechanism, action type and drug dependence were well studied in vivo and in vitro. The results show that SIPI5047 has potent analgesic activities in vivo, which is quite similar to morphine and also much more powerful than paracetamol. SIPI5047 has no efficacy to reduce fever or inflammation, but has an obvious action on central nervous system. SIPI5057 has no apparent affinity with the mu-receptor and it is an antagonist that acts on the polyamine site of the NMDA receptor. SIPI5057 appears no drug dependence. SIPI5047 is a novel central none-opioid analgesic agent and more worthy of further research as a new drug candidate.

Design and synthesis of aralkyl-ketone piperazine derivatives and their antalgic activities / 药学学报

To synthesize aralkyl-ketone piperazine derivatives as analgesic agents, the N atom of the one side of piperazine ring is protected by formyl group firstly, then the unprotected N atom is alkylated to prepare aralkyl-ketone piperazine derivatives. Their analgesic biological activities were well studied by mice writhing model, rat hot plate model and rat tail flick model. Sixty four compounds were synthesized and pharmacological tests in vivo revealed these compounds have potent analgesic activities, especially compound I12, I14, I14 I21 and I37. These four compounds are more worthy for further research.