A drug is composed of fragments with their functional and structural characteristics. Functional fragments contain structural elements known as pharmacophores which generate the bioactivity of the drugs, while structural fragments assemble the functional fragments into a specific skeleton also crucial for the activity. Although drug molecules possess structural diversity and complexity, the fragments usually have some similarity. They normally have simple texture, low molecular weight and log P. The aim of fragment-based drug discovery is to classify and screen the collections of fragments and subsequently expand, link, or merge them to obtain new chemical entities. This theory refines the traditional structure-based and the high throughput screen-based drug discovery strategy, and facilitates the reduction of molecular size and the improvement of drug-like properties, which will certainly increase the probability of developing new drugs. In this article, we reviewed the concept, methodology of fragment-based drug discovery and detailed a number of examples to illustrate the optimization strategies of this discovery method.

Aim: The tandem Claisen rearrangement/Diels-Alder reaction in ionic liquid was carried out to find better changes for the conversion. Methods: The synthesis started with replaced benzoic acid via acylation, cycli-zation, demethylation, allylation and then tandem Claisen rearrangement/Diels-Alder reaction in trational solvent and ionic liquid separately. Results: BmimBF_4 raised the yield of the target compound and shortened the reaction time compared with the traditional solvent Conclusion: BmimBF_4 can promote the tandem Claisen rearrange-ment/Diels-Alder reaction.

A series of 5-amino-2-( benzylthio ) thiazole-4-carboxamide derivatives were designed and synthesized to discover novel compounds with anti-tumor activity. Compounds DDO-5401-DDO-5416 were synthesized using 2-amino-2-cyanoacetamide as the start material. The structures of the synthesized compounds were confirmed by IR, 1 H NMR and ESI-MS. The in vitro anti-tumor activities of the synthesized compounds were determined by MTT assay in HCT116 , HepG2 , A549 , MDA-MB-231 and MCF-7 cell lines. Target compounds showed good anti-tumor activity especially in A549 cell line. SAR study showed that electron donating groups were more favorable than electron absorption ones. Compound DDO-5413 exhibited noteworthy activity in MDA-MB-231 and MCF-7 cell lines with IC50 value lower than the positive reference dasatinib. It suggested that DDO-5413 might be the candidate for further investigation.

Objective: The survival of colorectal cancer in Qidong City, Jiangsu Province from 1972 to 2016 was analyzed to provide a basis for the evaluation of prognosis and the formulation of prevention and control measures. Methods: Colorectal cancer data were obtained from the Qidong Cancer Registration and Reporting System, and the follow-up was up to December 31, 2021. The observed survival rate (OSR) and relative survival rate (RSR) were calculated by SURV 3.01 software, and the trend test was performed by Hakulinen's likelihood ratio test. The Joinpoint regression model was used to calculate the average annual percentage change (AAPC) of survival, and the ARIMA model was used to predict the trend of colorectal cancer survival. Results: There were 8 637 new cases of colorectal cancer in Qidong from 1972 to 2016. Dividing 1972-2016 into 9 periods at 5-year intervals, the 5-year OSR from 1972-1976 to 2012-2016 increased from 21.86% to 48.86%, and the 5-year RSR increased from 26.45% to 59.91%. The increasing trend of RSR was statistically significant (χ(2)=587.47, P<0.001). From 1972 to 2016, the survival rates of colorectal cancer in different sexes in Qidong were similar, and the 5-year RSR was 44.63% for men and 44.07% for women. Since the 1990s, the 5-year OSR and RSR for men have been lower than those for women. From 1972 to 2016, the 5-year RSR of colorectal cancer in Qidong was significantly improved in the 65-74 and ≥75-year-old groups, but the survival rate of the ≥75-year-old group was still the lowest (36.78%), followed by the 35-44-year-old group ( 43.04%). The time trend showed that the overall AAPC of colorectal cancer 5-year RSR in Qidong from 1972 to 2016 was 2.50% (t=16.45, P<0.001). The upward trend of different sexes was consistent, and the increase was greater in women (AAPC for males=2.18%, AAPC for females=2.54%, both P<0.05). The 5-year RSR of colorectal cancer in each age group showed an upward trend, and the AAPCs of the 35-44, 45-54, 55-64, 65-74, and ≥75-year-old groups were 1.54%, 1.83%, 2.00%, 3.51% and 4.35%, respectively (all P<0.05). The prediction results of colorectal cancer survival rate showed that the 5-year RSR of colorectal cancer in Qidong will increase to 71.62% by 2026. Conclusions: The overall survival rate of colorectal cancer patients in Qidong has been greatly improved, but there is still room for improvement. We should continue to pay attention to the early diagnosis and early treatment of colorectal cancer.
Male ; Humans ; Female ; Aged ; Adult ; Survival Rate ; Prognosis ; Software ; Likelihood Functions ; Colorectal Neoplasms ; China/epidemiology* ; Incidence

Objective: To describe the epidemic characteristics of stomach cancer mortality in Qidong between 1972 and 2016. Methods: The cancer registry data of stomach cancer death and population during 1972-2016 in Qidong was collected. The mortality of crude rate (CR), China age-standardized rate (CASR), world age-standardized rate (WASR), 35-64 years truncated rate, 0-74 years cumulative rate, cumulative risk, percentage change (PC), annual percent change (APC) were calculated. Results: During 1972-2016, a total of 15 863 (male: 10 114, female: 5 749) deaths occurred attributed to stomach cancer, accounting for 16.04% of all cancers, with CR of 31.37/100 000 (CASR: 12.97/100 000, WASR: 21.39/100 000). The truncated rate of 35-64, cumulative rate of 0-74, and cumulative risk were 28.86/100 000, 2.54%, and 2.51%, respectively. For male, the CR, CASR, WASR were 40.53/100 000, 17.98/100 000, 30.13/100 000, respectively, and for female, the CR, CASR, WASR were 22.45/100 000, 8.52/100 000, 13.92/100 000, respectively. Age-specific mortality analysis showed that the mortality of each age group under 25-year-old group was less than 1/100 000. The CR increased with age. The 50-year-old group reached and exceeded the average mortality of the population, and more than 80-year-old group reached the peak of death. During 1972-2016 in Qidong, The PCs in CR, CASR, and WASR of stomach cancer were 55.43%, -52.02%, -43.60%. The APC were 0.54%, -2.30%, -2.08%, respectively. Period mortality analysis showed that except for the 75-year-old group, the mortality of stomach cancer decreased significantly. Conclusions: The crude mortality of stomach cancer increases slightly in Qidong, while the CASR and WASR decrease significantly. However, stomach cancer is still one of the malignant tumors that most affect health and seriously threat lives.
Adult ; Aged ; Aged, 80 and over ; China/epidemiology* ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Registries ; Stomach Neoplasms/epidemiology*

Objective: To analyze the survival of esophageal cancer cases in Qidong, Jiangsu Province from 1972 to 2016, and provide a basis for the prognosis evaluation and prevention of esophageal cancer patients. Methods: The data of esophageal cancer were obtained from the Qidong Cancer Registration and Reporting System, and the follow-up date ended December 31, 2021. Observed survival rate (OSR) and relative survival rate (RSR) were calculated by SURV 3.01 software, and Hakulinen's likelihood ratio test was used for statistical difference comparison. Joinpoint regression model was used to conduct the average annual percentage change (AAPC) in esophageal cancer survival rate, and the ARIMA model was used to predict the trend of esophageal cancer survival rate. Results: During 1972 to 2016, there were 5 112 new cases of esophageal cancer in Qidong. The OSR of esophageal cancer at 1, 5 and 10 years were 24.43%, 6.93% and 4.43%, and the RSR at 1, 5 and 10 years were 25.88%, 9.35% and 8.34%, respectively. Dividing 1972-2016 into 9 periods, compared with 1972-1976, the 5-year RSR from 2012-2016 increased from 4.47% to 17.85%, and the RSR trend of the 9 periods was statistically significant (χ(2)=263.43, P<0.001). The survival rate of female with esophageal cancer was slightly higher than that of male, however, there was no significant difference in RSR between male and female (χ(2)=9.40, P=0.401). The 5-OSR and 5-RSR for male were 6.73% and 9.11%, and for female were 7.37% and 9.87%, respectively. The 5-RSR for the age groups of 45-54, 55-64, 65-74, and over 75 years old were 11.99%, 11.21%, 8.17% and 7.08%, respectively. There was a statistically significant difference in RSR among different age groups (χ(2)=98.19, P<0.001). The time trend results showed that the overall AAPC of the 5-RSR of esophageal cancer in Qidong from 1972 to 2016 was 3.89% (t=11.98, P<0.001). The 5-RSR uptrend was consistent among different genders, and the uptrend was greater in female (AAPC=4.25% for male, and AAPC=5.72% for female, P<0.05). Furthermore, the 5-RSR of esophageal cancer in all age groups showed an upward trend, and the upward trend was statistically significant in the 55-64-year-old group (AAPC=4.23%, P<0.05) and the 65-74-year-old group (AAPC=6.82%, P<0.05), there was no statistical significance in the 45-54-year-old group (AAPC=2.17%, P>0.05) and more than 75 years old group (AAPC=1.82%, P>0.05). Survival rate prediction of esophageal cancer showed that by 2026, 5-RSR will increase to 24.79%. Conclusions: During 1972 to 2016, the overall survival rate of esophageal cancer in the whole population of Qidong has improved to a certain extent, but there is still a large room for improvement. More emphasis should be continued to strengthen on the early diagnosis and early treatment of esophageal cancer.
Humans ; Female ; Male ; Aged ; Middle Aged ; Survival Rate ; Esophageal Neoplasms ; Prognosis ; Rural Population ; Software

BACKGROUND: It is manifested in epidemiology and clinical observation that lipoprotein (a) is a new risk factor of cerebrovascular disease and is closely related to cerebral ischemic stroke.OBJECTIVE: To discuss the relationship between levels of high serum lipoprotein (a) and stroke.DESIGN: Case controlled analysis.SETTING: Neurological Institute of Xiangya Hospital of Central South University.METHODS: Totally 294 patients with stroke were selected from Neurological Department of Xiangya Hospital of Central So, uth University between September 1999 and March 2002. Of them, 159 cases were regarded as cerebral infarction group and other 135 cases as acute hypertensive cerebral hemorrhage group. In cerebral infarction group, 109 patients had atherosclerotic cerebral infarction and 50 patients had lacunar cerebral infarction, and 94patients with contimuous health examination were regarded as health examination group. Serum lipoprotein (a) in each group was assayed with "sandwich enzyme-linked immuno-sorbent assay". According to whether the value of lipid was normal or not, patients with atherosclerotic cerebral infarction and acute hypertensive cerebral hemorrhage were divided into two groups. Comparisons between the two groups were assayed with single sample t test, and multiple liner regression was used to assay whether sex, hypertension and value of lipid were related to the level of serum lipoprotein (a).MAIN OUTCOME MEASURES: ① Comparisons of serum lipoprotein (a)among atherosclerotic cerebral infarction group, lacunar cerebral infarction group, acute hypertensive cerebral hemorrhage group and health examination group. ② Correlated analysis between serum lipoprotein (a) and lipid.RESULTS: Among 294 patients, 94 cases in control group entered the final analysis. ① Comparisons of serum lipoprotein (a) among atherosclerotic cerebral infarction group, lacunar cerebral infarction group, acute hypertensive cerebral hemorrhage group and health examination group: Levels of serum lipoprotein (a) in atherosclerotic cerebral infarction group and cerebral hemorrhage group were higher than those in health control group (P ＜ 0.05), and concentration of lipoprotein (a) in atheroosclerotic cerebral infarction group was increased as compared with that in acute hypertensive cerebral hemorrhage group (P ＜ 0.05). Also, level of lipoprotein (a) in lacunar cerebral infarction group was a little higher than that in control group,but the difference was not significant (P ＞ 0.05). ② Correlated analysis between serum lipoprotein (a) and lipid: Levels of lipoprotein (a) in both normal lipid group and abnormal lipid group were assayed with single sample t test, and the results showed that levels in the two groups were similar (P ＞ 0.05). Multiple liner regression was used to assay whether sex,hypertension and value of lipid were related to level of serum lipoprotein (a).CONCLUSION: Levels of lipoprotein (a) may be an independent risk factor for cerebral hemorrhage and atherosclerotic cerebral infarction.

BACKGROUND: Alginic sodium diester (ASD) possesses neuroprotective function because of its selective calcium antagonist effects.OBJECTIVE: To compare the influences of ASD on intraneuronal Ca2+content and nerve cell apoptosis before and after reperfusion in focal cerebral ischemic rats.DESIGN: Randomized controlled observation.SETTING: Neurological Department of Xiangya Hospital Affiliated to South China University; Laser Orthopedic Surgery of the First Hospital Affiliated to Southern China University.MATERIALS: This experiment was carried out between November 2003and April 2004 at the Neurological Department of Xiangya Hospital Affiliated to South China University. A total of 65 male SD rats were recruited and randomized into 6 groups; 17 got lost during the experiment, and the other 48 rats completed the experiment with 8 rats in each group.METHODS: In sham operation group, an incision was made on rats' cervical skin and sutured. Right cerebral middle artery was occluded in rats of ischemic group, ASD 5 mg/kg preischemic group, ASD 5 mg/kg postischemic group, ASD 10 mg/kg preischemic group, and ASD 10 mg/kg postischemic group. After that, rats in all but ischemic group were subjected to intraperitoneal injection of various dosage of ASD or excipient 30minutes before reperfusion and 5 hours after reperfusion. FCM was used to determine intraneuronal Ca2+ content and rate of nerve cell apoptosis;meanwhile, neurological dysfunction was scored.MAIN OUTCOME MEASURES: [1] Influence of ASD on the score for neurological dysfunction, intraneuronal Ca2+ fluorescence intensity, and neuronal apoptosis in rats with right cerebral middle artery ischemia. [2]Correlation of behavioral obstacle score with intraneuronal Ca2+ fluorescence intensity and neuronal apoptosis in rats with right cerebral middle artery ischemia.RESULTS: Totally 65 rats were enrolled in this study, 17 of which got lost and the other 48 rats entered the result analysis. [1] Influence of ASD on the score for neurological dysfunction, intraneuronal Ca2+ fluorescence intensity, and neuronal apoptosis in rats with right cerebral middle artery ischemia: The score was obviously reduced in ASD 5 mg/kg preischemic group, ASD 5 mg/kg postischemic group, ASD 10 mg/kg preischemic group and ASD 10 mg/kg postischemic group as compared with ischemic group (1.80±0.21, 2.20±0.23, 1.20±0.11, 2.00±0.22, 3.40±0.65); moreover,functional improvement was more obvious due to pre-reperfusional administration than post-reperfusional administration. Intraneuronal Ca2+ concentration was reduced after ASD administration at different degrees and lower than that of ischemic group. Decrement of intraneuronal Ca2+ concentration was found most obvious due to 10 mg/kg ASD administration 30 minutes before reperfusion, approximately reduced by 70%; moreover, neuronal apoptosis rate on the ischemic side was obviously suppressed by ASD administration, displaying time-dependent manner, with apoptotic suppression effect more obvious in pre-reperfusional group than in post-reperfusional group (5.68%, 10.03%; 4.00%, 9.91%). [2] Correlation of behavioral obstacle score of right cerebral middle artery ischemic rats with intraneuronal Ca2+ fluorescence intensity and membrane associated protein/propidium iodide apoptosis: Obvious positive correlation was found between behavioral obstacle score and intraneuronal Ca2+ fluorescence intensity and detection rate of membrane associated protein/propidium iodide apoptosis (r=0.51,0.62, P ＜ 0.05); intraneuronal Ca2+ fluorescence intensity was also positively correlated with the detection rate of membrane associated protein/propidium iodide apoptosis (r=0.84, P ＜ 0.05).CONCLUSION: [1] ASD can exert anti-apoptosis effect by suppressing the increment of intraneuronal Ca2+ concentration, thus having neuroprotective function and ultimately improving neurological dysfunction. [2] Its effect displays time-dependent manner, and neurological functional improvement is more obvious by pre-reperfusional administration than by post-operational administration.

Latest researches have indicated that wogonin, a naturally occurring flavonoid, could sensitize tumor cells to apoptosis, selectively induce apoptosis in the malignant tumor cells, inhibit tumor angiogenesis, reverse drug resistance as well as promote tumor cell death synergistically with other anti-cancer agents. This paper sum-marizes the involving mechanisms of wogonin's anti-tumor effects.

Inhibitors of kinesin spindle protein (KSP) are a promising class of anticancer agents that cause mitotic arrest and induce apoptosis of tumor cells. A series of novel tetrahydro-beta-carboline derivatives were synthesized as kinesin spindle protein inhibitor and evaluated as potential antitumor agents. All compounds showed promising KSP inhibitiory activity. Compounds 8 and 9 exhibited better antitumor activity (Lung/A549, Stomach/AGS) than CK0106023 with GI50/IC50 values (1.07/1.62 and 1.46/3.27 micromol x L(-1), 1.09/>10 and 1.22/6.33 micromol x L(-1), respectively).