Design, synthesis, and antitumor activity of desmosdumotin C analogues.

Desmosdumotin C (Des C), a natural product isolated from the roots of Desmos dumosus, has shown good antitumor activity. A three dimensional quantitative structure-activity relationship (QSAR) study using the comparative molecular field analysis (CoMFA) method was performed on 32 Des C analogues. Based on the QSAR, 18 new Des C analogues were designed and synthesized. An efficient three-step synthetic strategy toward Des C and its analogues was developed from commercial available 2, 4, 6-trihydroxyacetophenone. All synthesized compounds were evaluated against a panel of human cancer cell lines and showed ED50 values ranging from 1.1 to 25.1 µΜ.

Recent Pricing Negotiations on Innovative Medicines Pilot in China: Experiences, Implications, and Suggestions.

The China National Formulary (CNF) for reimbursable drug use, also known as the National Reimbursement Drug List (NRDL), was formally established in 2000, revised in 2004 and 2009, and covers 52% of China's population under the government urban health insurance programs. A third major and long-awaited update to the formulary was completed in February 2017 based on intensive reviews by a group of experts in medicine, pharmacology, health economics, and health policy. Shortly after this major update, a pilot project at the central government level was implemented for negotiations mainly on innovative but expensive medicines that were still outside the National Formulary. The pilot, conducted between March and July 2017, eventually reached an overall agreement rate of 81.8% regarding approved indications and drug prices between China's government and the pharmaceutical companies. This pilot showcased numerous leading edge features including a working definition of innovative medicines and opportunities to submit dossiers on drug clinical and economic information. This pilot covered 44 medications for negotiations in a breakthrough attempt to increase the appropriate access to innovative but expensive medicines. The implications to the future of the CNF go beyond the drugs included in the pilot. This paper describes the background of the CNF and the negotiation pilot. In addition, authors of this paper make six recommendations critical to CNF future developments, including enhancing criteria and process for evaluations, standardizing the dossier format, specifying data requirements, refining pricing calculation, and cultivating evaluation professional development.

Willingness to pay per quality-adjusted life year: is one threshold enough for decision-making?: results from a study in patients with chronic prostatitis.

OBJECTIVE: To estimate the willingness to pay (WTP) per quality-adjusted life year (QALY) ratio with the stated preference data and compare the results obtained between chronic prostatitis (CP) patients and general population (GP). METHODS: WTP per QALY was calculated with the subjects' own health-related utility and the WTP value. Two widely used preference-based health-related quality of life instruments, EuroQol (EQ-5D) and Short Form 6D (SF-6D), were used to elicit utility for participants' own health. The monthly WTP values for moving from participants' current health to a perfect health were elicited using closed-ended iterative bidding contingent valuation method. RESULTS: A total of 268 CP patients and 364 participants from GP completed the questionnaire. We obtained 4 WTP/QALY ratios ranging from $4700 to $7400, which is close to the lower bound of local gross domestic product per capita, a threshold proposed by World Health Organization. Nevertheless, these values were lower than other proposed thresholds and published empirical researches on diseases with mortality risk. Furthermore, the WTP/QALY ratios from the GP were significantly lower than those from the CP patients, and different determinants were associated with the within group variation identified by multiple linear regression. CONCLUSIONS: Preference elicitation methods are acceptable and feasible in the socio-cultural context of an Asian environment and the calculation of WTP/QALY ratio produced meaningful answers. The necessity of considering the QALY type or disease-specific QALY in estimating WTP/QALY ratio was highlighted and 1 to 3 times of gross domestic product/capita recommended by World Health Organization could potentially serve as a benchmark for threshold in this Asian context.

Health-related quality of life in Chinese patients with chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVE: To examine the health-related quality of life (HRQoL) and factors associated with HRQoL in Chinese patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using two generic preference-based HRQoL instruments, EQ-5D (plus EQ-VAS) and SF-6D, with the results compared with general population. METHOD: CP/CPPS patients were recruited from two tertiary referral hospitals, and the general populations were randomly approached. After informed consent, subjects were interviewed using EQ-5D, EQ-VAS and SF-6D, and their socio-demographic and medical information was solicited. RESULTS: Compared to the general population (n = 364), CP/CPPS patients (n = 268) reported significantly worse HRQoL with median score of the EQ-5D utility index (0.73 vs. 0.85), SF-6D utility index (0.76 vs. 0.81), and EQ-VAS (70.0 vs. 85.0). Multiple linear regression analyses showed pain symptom had the strongest predictive power for HRQoL, compared to symptom duration and urinary symptom. Socio-demographic factors and comorbidities did not significantly contribute to poorer HRQoL. CONCLUSION: CP/CPPS patients experienced deteriorated HRQoL with lower health-related utility scores compared to general population, and pain severity was the main physical symptom predicting decreased health-related utility. Further studies are needed to provide the reference utility index for the comparison and better characterizing the influence of geographic and cultural factors on variation of health-related utility of CP/CPPS patients.

Validation and comparison of EuroQol and short form 6D in chronic prostatitis patients.

OBJECTIVE: Generic, preference-based health-related quality of life (HRQoL) instruments is increasingly used in health-care decision-making process. However, to our knowledge, no such HRQoL instrument has been validated or used in chronic prostatitis. We therefore aimed to assess and compare the psychometric properties of EuroQol (EQ-5D) and Short Form 6D (SF-6D) among chronic prostatitis patients in China. METHODS: Consenting patients were interviewed using EQ-5D and SF-6D. Convergent and discriminative construct validities were examined with five and two a priori hypotheses, respectively. Sensitivity was compared using receiver operating characteristic (ROC) curves and relative efficiency (RE) statistics. Agreement between instruments was assessed with intra-class correlation coefficients and Bland-Altman plot, while factors affecting utility difference were explored with multiple liner regression models. RESULTS: In 268 subjects, mean (SD) EQ-5D and SF-6D utility scores were comparable at 0.73 (0.15) and 0.75 (0.10), respectively. Five of the seven hypotheses for construct validity were fulfilled in both instruments. The areas under ROC of them all exceeded 0.5 (P < 0.001). SF-6D had 9.7-19.9% higher efficiency than EQ-5D at detecting the difference in chronic prostatitis symptom severity. Despite no significant difference in utility scores between two instruments, lack of agreement was observed with low intraclass correlation coefficient (0.218-0.630) and Bland-Altman plot analysis. Chronic prostatitis symptom severity significantly (P < 0.05) influenced differences in utility scores between EQ-5D and SF-6D. CONCLUSIONS: Both EQ-5D and SF-6D are demonstrated to be valid and sensitive HRQoL measures in Chinese chronic prostatitis patients, with SF-6D showing better HRQoL dimension coverage, greater sensitivity, lower ceiling effect, and more rational distribution. Further research is needed to determine longitudinal response and reliability.

[Study for drug-resistance of epithelial ovarian cancer by serum protein profiling].

OBJECTIVE: To develop the rationales for ovarian cancer-specific protein profiles in serum and to analyze the protein profiles of multidrug resistance P-glucoprotein (MDR1) and multidrug resistance-associated protein (MRP) positive and negative expression sets for a rapid and sensitive serum protein pattern. METHOD: Serum protein profiles from 36 epithelial ovarian cancer cases were compared with 30 healthy controls using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (DELDI-TOF-MS). Blinded test was conducted subsequently for identification of the protein pattern. Expression of MDR and MRP were detected in set of training cases by immunohistochemistry. The spectra were analyzed statistically between positive and negative groups. RESULTS: Twenty-nine peaks were significantly different between ovarian cancer and healthy controls (P < 0.01, 15 peaks up-regulated and 14 down-regulated). A set of three peaks, at 5 486, 6 463 and 8 575 m/z respectively, were selected from 29 sense peaks as an ovarian cancer biomarker. The sensitivity was 100% and specificity 93.33%. Identification by blinded validation indicated a positive predictive value of 90%. MDR1 expression in ovarian cancer was 69.4 %. Twenty peaks were significantly different between positive and negative sets (P < 0.01). MRP expression in ovarian cancer was 63.8%. But one peak was detected (P < 0.01). CONCLUSION: It was an ideal pattern for employing the SELDI mass spectrum approach to diagnose ovarian cancer and select the multidrug resistance cases. Serum biomarkers for detecting drug resistance in ovarian cancer can be established on the basis of MDR1 immunohistochemistry.

Anti-nociceptive activity of aqueous fraction from the MeOH extracts of Paederia scandens in mice.

AIM OF THE STUDY: We examined the effects of the aqueous fraction (AF) on nociception models mice induced by the chemical and the thermal stimuli so as to elucidate the analgesic activity and provide scientific basis for the clinical use of Paederia scandens. MATERIALS AND METHODS: The AF of MeOH extract from P. scandens was evaluated on anti-nociceptive activity in mice using chemical and thermal models of nociception. RESULTS: Given orally, the aqueous fraction at doses of 200, 400 and 800 mg/kg produced significant inhibitions on chemical nociception induced by intraperitoneal acetic acid and subplantar formalin injections and on thermal nociception in the tail-flick test and in the hot plate test. More significant inhibition of nociception was observed at dose of 800 mg/kg of this fraction. In the pentobarbital sodium -induced sleeping time test and the open-field test, the aqueous fraction neither significantly enhanced the pentobarbital sodium -induced sleeping time nor impaired the motor performance, indicating that the observed anti-nociception was unlikely due to sedation or motor abnormality. CONCLUSIONS: These results suggested that the aqueous fraction produced anti-nociception possibly related to the iridoid glycosides and polysaccharides in this fraction.

[Progress in study of flavonoids from Annonaceae and biological activities of these compounds].

More than 50 new flavonoids derived from Annonaceae are reported in the last two decades. Many genuses in Annonaceae contain flavonoids having structural novelty and broad pharmacological activities. Due to the pharmacological interest of some of these compounds, chemical investigations on this topic have grown considerably in the decades. Here the biological activities of some of these flavonoids are also briefly discussed.

Stellettins L and M, cytotoxic isomalabaricane-type triterpenes, and sterols from the marine sponge Stelletta tenuis.

Two new isomalabaricane-type triterpenes, stellettins L (1) and M (2), and three new sterols (3-5) were isolated from the marine sponge Stelletta tenuis collected in the South China Sea. Chemical structures were established from spectroscopic data and comparison with known compounds. In addition, spectroscopic data reported for the known sterol 24-methylene-27-methylcholest-5-en-3beta-ol-7-one (6) were revised. Compounds 1 and 2 exhibited significant cytotoxic activity against stomach cancer (AGS) in vitro.

Antitumor agents 259. Design, syntheses, and structure-activity relationship study of desmosdumotin C analogs.

Desmosdumotin C (1) and its analogs previously showed potent, selective in vitro anticancer activity. To explore structure-activity relationships of 1 and further increase potency and selectivity, 15 novel analogs (7-15 and 21-26) were synthesized and evaluated for cytotoxity against several human tumor cell lines, as well as inhibition of human endothelial (HUVEC) replication. 4-Bromo-3',3',5'-tripropyl analog 26 showed significant cytotoxity against A549, A431, 1A9, and HCT-8 with ED50 values of 1.0, 1.2, 0.9, and 1.3 mug/mL, respectively. Compound 26 also strongly inhibited the growth of matched tumor cells, KB-VIN and its parent cell KB. Furthermore, analogs 13 and 21 were over 5-fold more potent against KB-VIN than KB. Bromination of ring-B and tripropyl functionalization of ring-A enhanced activity, while alkylation of ring-B promoted KB-VIN/KB selectivity. 2-Furyl analog 16 showed selective activity against HUVEC, suggesting that it may have potential as a new prototype for angiogenesis inhibition.

Total synthesis and bioactivity of unique flavone desmosdumotin B and its analogs.

The first total synthesis of a unique flavone natural product, desmosdumotin B (1), was accomplished. Furthermore, three novel flavonoids, 6-8, and a novel chalcone, 9, were synthesized. The new compounds were evaluated as in vitro inhibitors of human cancer cell growth. The synthetic 1 showed significant cytotoxic activity against a multi-drug resistant cell line (KB-VIN) with an ED50 value of 2.0 microg/mL compared to >40 microg/mL against the parental KB cell line. Flavone 7 displayed selective activity against 1A9 ovarian carcinoma with an ED50 value of 0.7 microg/mL. Selected 1-analogs and synthetic intermediates were also screened for antitumor-promoting effects as inhibitors of EBV-EA activation. Among them, trihydroxyacetophenone derivatives 11 and 14 showed good activity.

Antitumor agents 243. Syntheses and cytotoxicity of desmosdumotin C derivatives.

New analogs of desmosdumotin C (1), in which other aromatic rings replaced the terminal phenyl group and the A-ring was modified, were synthesized. Compounds 2-9, 13, and 16 were evaluated in vitro against human tumor cell replication. The 4-bromophenyl analog (2) showed potent cytotoxic activity in four different tumor cell lines.

Anti-AIDS agents. Part 57: Actein, an anti-HIV principle from the rhizome of Cimicifuga racemosa (black cohosh), and the anti-HIV activity of related saponins.

Actein (1), a tetracyclic triterpenoid from the rhizome of Cimicifuga racemosa (black cohosh), and 82 related triterpenoid and steroidal saponins isolated from higher plants were evaluated for anti-HIV activity as a continuing study to discover potential anti-AIDS agents from natural products. Actein showed potent activity and another twelve saponins showed moderate activity. The active compounds included two steroidal, seven tetracyclic triterpenoid, and four pentacyclic triterpenoid compounds.

Intercedensides A-C, three new cytotoxic triterpene glycosides from the sea cucumber Mensamaria intercedens Lampert.

Three new triterpene glycosides, intercedensides A (1), B (2), and C (3), were isolated from the sea cucumber Mensamria intercedens Lampert, which is found in the South China Sea, and their structures have been elucidated by spectroscopic analysis (NMR and ESIMS) and chemical transformations. Intercedensides A (1) and C (3) have a conjugated double bond (22E,24-diene) in the side chain of the aglycon. Intercedenside B (2) has two beta-D-xylose and two sulfate groups in the carbohydrate chain. All three glycosides showed significant cytotoxicity against 10 human tumor cell lines with ED(50) in the range 0.6-4.0 microg/mL. Intercedenside A (1) exhibited significant in vivo antineoplastic activity against mouse Lewis lung cancer and mouse S180 sarcoma. On the basis of these initially promising results, intercedensides A-C merit further study as potential anticancer agents.

Antitumor agents. Part 218: Cappamensin A, a new In vitro anticancer principle, from Capparis sikkimensis.

A new inhibitor of in vitro tumor cell replication, cappamensin A (1) (2H-1,4-benzoxazin-3(4H)-one, 6-methoxy-2-methyl-4-carbaldehyde), was isolated from the roots of Capparis sikkimensis subsp. formosana using bioactivity-guided fractionation. The structure of 1 was established by spectroscopic methods, including 2D NMR analyses. Compound 1 displayed significant in vitro anticancer activity against ovarian (1A9), lung (A549), ileocecal (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine resistant (KB-VIN) human tumor cell lines with ED(50) values

Anti-AIDS agents 54. A potent anti-HIV chalcone and flavonoids from genus Desmos.

Sixteen flavonoids and their derivatives isolated from Desmos spp. were evaluated for inhibition of HIV replication in H9 lymphocyte cells. 2-Methoxy-3-methyl-4,6-dihydroxy-5-(3'-hydroxy)cinnamoylbenzaldehyde (12) and lawinal (6) demonstrated potent anti-HIV activity with EC(50) values of 0.022 and 2.30 microg/mL and therapeutic indexes of 489 and 45.2, respectively. Compound 12 appears to be an excellent lead for further anti-HIV drug development.

Anti-AIDS agents 49. Synthesis, anti-HIV, and anti-fusion activities of IC9564 analogues based on betulinic acid.

The betulinic acid derivative IC9564 inhibits human immunodeficiency virus (HIV)-1 entry. Among a series of IC9564 derivatives, 5 and 20 were the most promising compounds against HIV infection with EC(50) values of 0.33 and 0.46 microM, respectively. Both compounds inhibited syncytium formation with EC(50) values of 0.40 and 0.33 microM, respectively. The comparable EC(50) values in the two assays suggested that these compounds are fusion inhibitors. The structure-activity relationship data also indicated that a double bond in IC9564 can be eliminated and the statine moiety can be replaced with L-leucine while retaining anti-HIV activity.

[Studies on the chemical constituents from marine brown alga Ishige okamurai (3)].

OBJECTIVE: To study the chemical constituents of Ishige okamurai. METHOD: Compounds were isolated by Pyricularia oryzae bioassay-guided fractionation method in combination with extraction and partitionation as well as multi-chromatography. Their structures were determined by spectral analysis and chemical evidence. RESULT: Seven compounds were obtained and identified as (2S)-1-O-palmitoyl-2-O-(11Z-octadecenoyl)-3-O-beta-D-galacto-pyranosyl glycerol (I), (2S)-1-O-palmitoyl-2-O-myristoyl-3-O-(6-sulfo-alpha-D- quinovopyranosyl) glycerol (II), (2S)-1-O-palmitoyl-2-O-palmitoyl-3-O-(6'-sulfo-alpha-D- quinovopyranosyl) glycerol (III) and (2S)-1-O-palmitoyl-2-O-(11Z-octadecenoyl)-3-O-(6'-sulfo-alpha-D- quinovopyranosyl) glycerol (IV), stearic acid (V), methyl myristate(VI) and palmitic acid (VII). CONCLUSION: Compounds I-VI were isolated from the alga for the first time while I, II and IV are new natural products. I-IV showed activity causing morphological abnormality of P. oryzae mycelia.