Synthesis and Anticancer Evaluation of Sulfur Containing 9-anilinoacridines.

BACKGROUND: DNA topoisomerases are a class of enzymes that play a critical role in fundamental biological processes of replication, transcription, recombination, repair and chromatin remodeling. Amsacrine (m-AMSA), the best-known compound of 9-anilinoacridines series, was one of the first DNA-intercalating agents to be considered a Topoisomerase II inhibitor. OBJECTIVES: A series of sulfur-containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer activity. METHODS: Cell viability was assessed by the MTT assay. The topoisomerase II inhibitory assay was performed using the Human topoisomerase II Assay kit, and flow cytometry was used to evaluate the effects on the cell cycle of K562 cells. Molecular docking was performed using the Schrödinger Maestro program. RESULTS: Compound 36 was found to be the most cytotoxic of the sulfide series against SW620, K562, and MCF-7. The limited SAR suggested the importance of the methansulfonamidoacetamide side chain functionality, the lipophilicity, and the relative metabolic stability of 36 in contributing to the cytotoxicity. Topoisomerase II α inhibitory activity appeared to be involved in the cytotoxicity of 36 through the inhibition of decatenation of kinetoplast DNA (kDNA) in a concentration- dependent manner. Cell cycle analysis further showed Topo II inhibition through the accumulation of K562 cells in the G2/M phase of the cell cycle. The docking of 36 into the Topo II α-DNA complex suggested that it may be an allosteric inhibitor of Topo II α. CONCLUSION: Compound 36 exhibits anticancer activity by inhibiting topoisomerase II, and it could further be evaluated in in vivo models.

A Review of the Admission System for Mental Disorders in South Korea.

This study presents a comprehensive overview of the characteristics of mental health problems and admission system in South Korea. We compared the mental health-related indicators data from South Korea to data from other Organization for Economic Cooperation and Development (OECD) countries. South Korea was identified as the country with the highest suicide rate, the longest length of stay in hospitals for mental disorders, and the highest number of psychiatric care beds. These results can be explained by considering the admission system for mental disorders. We reviewed the admission system and the Mental Health Promotion and Welfare Act, providing direction for improving the system.

Anti-Inflammatory and Antioxidant Properties of Peptides Released from ß-Lactoglobulin by High Hydrostatic Pressure-Assisted Enzymatic Hydrolysis.

BACKGROUND: ß-lactoglobulin hydrolysates (BLGH) have shown antioxidant, antihypertensive, antimicrobial, and opioid activity. In the current study, an innovative combination of high hydrostatic pressure and enzymatic hydrolysis (HHP-EH) was used to increase the yield of short bioactive peptides, and evaluate the anti-inflammatory and antioxidant properties of the BLGH produced by the HHP-EH process. METHOD: BLG was enzymatically hydrolyzed by different proteases at an enzyme-to-substrate ratio of 1:100 under HHP (100 MPa) and compared with hydrolysates obtained under atmospheric pressure (AP-EH at 0.1 MPa). The degree of hydrolysis (DH), molecular weight distribution, and the antioxidant and anti-inflammatory properties of hydrolysates in chemical and cellular models were evaluated. RESULTS: BLGH obtained under HHP-EH showed higher DH than the hydrolysates obtained under AP-EH. Free radical scavenging and the reducing capacity were also significantly stronger in HHP-BLGH compared to AP-BLGH. The BLGH produced by alcalase (Alc) (BLG-Alc) showed significantly higher antioxidant properties among the six enzymes examined in this study. The anti-inflammatory properties of BLG-HHP-Alc were observed in lipopolysaccharide-stimulated macrophage cells by a lower level of nitric oxide production and the suppression of the synthesis of pro-inflammatory cytokines. Peptide sequencing revealed that 38% of the amino acids in BLG-HHP-Alc are hydrophobic and aromatic residues, which contribute to its anti-inflammatory properties. CONCLUSIONS: Enzymatic hydrolysis of BLG under HHP produces a higher yield of short bioactive peptides with potential antioxidant and anti-inflammatory effects.

Lower-pole intracapsular tonsillectomy in obstructive sleep apnea patients.

CONCLUSION: Lower-pole intracapsular tonsillectomy (LPIT) is a valuable surgical technique capable of decreasing post-operative bleeding in obstructive sleep apnea (OSA) patients. OBJECTIVE: This study performed LPIT to simultaneously reduce post-operative bleeding of lower pole and prevent recurrent tonsillitis of upper pole and compared its effects to extracapsular tonsillectomy (ET). METHODS: ET was performed in the extracapsular plane, with complete monopolar dissection. In LPIT, the upper pole of palatine tonsil was removed by electrocautery with the extracapsular plane, followed by removal of the lower-pole by plasma ablation with the intracapsular plane. Post-operative bleeding incidence, bleeding site, and degree of pain were compared between the two groups. RESULTS: Three hundred and forty-seven patients diagnosed of OSA with polysomnography were enrolled. ET was performed in 152 patients and LPIT in 195 patients. There were no significant differences in post-operative pain between the two groups. The LPIT group showed significantly lower total bleeding incidence than the ET group (4.1% vs 9.2%; p = .05). In particular, lower-pole bleeding incidence was lower in the LPIT group than the ET group (1.0% vs 5.3%; p = .02).

[Medroxyprogesterone Acetate as Part of Palliative Care for Terminal-Stage Breast Cancer Patients--A Report of Two Cases].

Various effective strategies have recently been described in the treatment of breast cancer, including endocrine therapy, chemotherapy, and molecular-targeted therapy, providing long-term survival benefits even after cancer recurrence. However, terminal-stage patients experience side effects and worse quality of life (QOL), in addition to deterioration of their general condition caused by the progression of the disease itself. When providing the best supportive care, use of anti-cancer drugs is not taboo and can represent a good option as long as physical, social, psychological, and spiritual supports are provided to both the patients and their families. Medroxyprogesterone acetate (MPA) is an endocrine therapeutic drug. In Japan, MPA is used only as a late-line endocrine therapy for breast cancer recurrence because many other endocrine therapy drugs are much more effective and MPA increases the risk of thrombosis and obesity. Here, we report 2 patients with breast cancer who reached terminal stage more than 10 years after the first diagnosis. MPA was administered as the final-line treatment. During that time, their appetite and QOL improved and the patients became more active than when they had been undergoing aggressive anticancer treatment. Both patients spent quality time with their families until their death. MPA may be a good option as part of palliative care of breast cancer patients in terminal stage.

CK0403, a 9­aminoacridine, is a potent anti­cancer agent in human breast cancer cells.

3­({4­[4­(Acridin­9­ylamino)phenylthio]phenyl}(3­hydroxypropyl)amino)propan­1­ol (CK0403) is a sulfur­containing 9­anilinoacridine analogue of amsacrine and was found to be more potent than its analogue 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2­hydroxyethyl)amino)ethan­1­ol (CK0402) and amsacrine in the inhibition of the topoisomerase II­catalyzed decatenation reaction. A previous study by our group reported that CK0402 was effective against numerous breast cancer cell lines, and the combination of CK0402 with herceptin enhanced its activity in HER2(+) SKBR­3 cells. In order to identify novel chemotherapeutic agents with enhanced potency, the present study explored the potential of CK0403 in the treatment of breast cancer. First, the growth inhibitory activity of CK0403 in the breast cancer cell lines MCF­7, MDA­MB­231, BT474 and SKBR­3, as well as in the non­cancerous MCF­10A cell line, was examined using a sulforhodamine B assay. The results showed that CK0403 exerted more potent growth inhibitory activity than CK0402 in all of the breast cancer cell lines except MCF­7. SKBR­3 and MDA­MB­231 were the most sensitive cell lines tested, and the combination of CK0403 with herceptin in HER2(+) SKBR­3 cells enhanced the growth inhibitory activity of CK0403. Analysis of cell cycle alterations induced by CK0403 in SKBR­3 cells revealed that, similarly to CK0402, CK0403 induced G2/M­phase arrest with a decreased S- and G0/G1-phase ratio. In addition, it was shown that CK0403 induced apoptosis more effectively than CK0402 in SKBR­3 cells. Further analysis of autophagy protein 5 (Atg5) indicated that CK0403 induced more cleaved Atg5 than CK0402 and other chemotherapeutic agents tested. Of note, although still relatively potent, CK0403 exhibited reduced growth inhibitory activity under hypoxic conditions, which can induce autophagy. Collectively, the present results supported that CK0403 is highly potent and more effective than CK0402 against estrogen receptor-negative and HER2­overexpressing breast cancer cell lines, suggesting its future application for chemotherapy in breast cancer.

A colorimetric probe to determine Pb(2+) using functionalized silver nanoparticles.

A simple and sensitive colorimetric method for the determination of Pb(2+) ions in aqueous samples was developed using 1-(2-mercaptoethyl)-1,3,5-triazinane-2,4,6-trione (MTT) functionalized silver nanoparticles (MTT-AgNPs). The Pb(2+) ion acted as the metal center of the coordination complex, which formed N-Pb(2+)-O coordination bonds with the MTT-AgNPs, shortening the interparticle distance, and inducing aggregation of the MTT-AgNPs. This aggregation resulted in a dramatic color change from yellow to dark blue. Using this methodology, the concentration of Pb(2+) ions in environmental samples could be quantitatively detected with the naked eye or by using UV-vis spectrometry. Also, we found that the selectivity and sensitivity of detection were noticeably improved in the pH range of 7-8, at which a more obvious color change was observed. The absorption ratios (A625/A395) of the modified AgNP solution exhibited a linear correlation with Pb(2+) ion concentrations within the linear range of 0.1-0.6 µg mL(-1), and the limits of detection in tap and pond water were 0.02 and 0.06 µg mL(-1), respectively. This cost-effective sensing system allows for the rapid and facile determination of Pb(2+) ions in aqueous samples.

Occupational Exposure to Diesel Particulate Matter in Municipal Household Waste Workers.

OBJECTIVE: The purposes of this study were to determine the following: 1) the exposure levels of municipal household waste (MHW) workers to diesel particulate matter (DPM) using elemental carbon (EC), organic carbon (OC), total carbon (TC), black carbon (BC), and fine particulate matter (PM 2.5) as indicators; 2) the correlations among the indicators; 3) the optimal indicator for DPM; and 4) factors that influence personal exposure to DPM. METHODS: A total of 72 workers in five MHW collection companies were assessed over a period of 7 days from June to September 2014. Respirable EC/OC samples were quantified using the thermal optical transmittance method. BC and PM 2.5 were measured using real-time monitors, an aethalometer and a laser photometer. All results were statistically analyzed for occupational and environmental variables to identify the exposure determinants of DPM. RESULTS: The geometric mean of EC, OC, TC, BC and PM 2.5 concentrations were 4.8, 39.6, 44.8, 9.1 and 62.0 µg/m3, respectively. EC concentrations were significantly correlated with the concentrations of OC, TC and BC, but not with those of PM 2.5. The exposures of the MHW collectors to EC, OC, and TC were higher than those of the drivers (p<0.05). Workers of trucks meeting Euro 3 emission standard had higher exposures to EC, OC, TC and PM 2.5 than those working on Euro 4 trucks (p<0.05). Multiple regression analysis revealed that the job task, European engine emission standard, and average driving speed were the most influential factors in determining worker exposure. CONCLUSIONS: We assessed MHW workers' exposure to DPM using parallel sampling of five possible indicators. Of these five indicators, EC was shown to be the most useful indicator of DPM exposure for MHW workers, and the job task, European emission standard, and average driving speed were the main determinants of EC exposure.

Synthesis and evaluation of sulfonylethyl-containing phosphotriesters of 3'-azido-3'-deoxythymidine as anticancer prodrugs.

A series of bis(sulfonylethyl) and mono(sulfonylethyl) phenyl phosphotriesters of zidovudine (3'-azido-3'-deoxythymidine, AZT) were synthesized as potential anticancer prodrugs that liberate AZT monophosphate via nonenzymatic ß-elimination mechanism. Stability studies demonstrated that all the synthesized prodrugs spontaneously liberate AZT monophosphate with half-lives in the range of 0.07-278.8h under model physiological conditions in 0.1M phosphate buffer at pH 7.4 and 37 °C. Analogous to aldophosphamide, the elimination rates were accelerated in the presence of reconstituted human plasma under the same conditions. Among the compounds, 3, 4, 8, and 10 were comparable or superior to AZT against five established human cancerous cell lines in vitro. Moreover, the selected compounds were equally sensitive to both the wild-type osteosarcoma 143 B and the thymidine kinase-deficient 143 B/TK(-) cell lines. The findings are consistent with that these compounds deliver AZT monophosphate intracellularly.

Allergic diseases in children with otitis media with effusion.

OBJECTIVES: Recent studies have shown that allergic diseases may be associated with the pathogenesis of recurrent otitis media with effusion (OME). We aimed to assess the relationship between OME and allergic diseases and other types of disease in children with OME. We also evaluated the between group differences in the characteristics of middle ear effusion. MATERIALS AND METHODS: We evaluated 370 patients diagnosed with OME between January 2007 and December 2012 and, as a control group, 100 children with no medical history of OME but who had undergone blood tests and MAST-CLA (multiple allergosorbent test - chemiluminescent assay) were selected. RESULT: Among the allergic diseases, the incidence of allergic rhinitis alone was significantly higher in children with OME (33.8%) than without OME (16.0%) (p<0.05). The rate of adenoid, but not tonsil, hypertrophy was significantly greater in patients with than without OME also (p<0.05). When we evaluated the characteristics of middle ear effusion (MEE) in patients with OME, we found that 186 had serous, 129 had mucous and 55 had purulent MEE. Of these patients, 75 (40.3%), 36 (27.9%) and 14 (25.5%), respectively, had allergic rhinitis and the rates of allergic rhinitis and asthma were significantly higher in the serous group than in the mucous group (p<0.05). CONCLUSION: Allergic rhinitis was significantly more frequent among pediatric patients with than without OME, although the rates of other allergic diseases did not differ in these two groups. The likelihoods of allergic rhinitis and asthma were higher in patients with serous than with mucous MEE.

Clinical analysis of auricular benign masses.

BACKGROUND AND OBJECTIVES: Auricular masses are growths on the outer ear that have not been well characterized clinically. We assessed the clinical nature and treatment of auricular benign masses in patients at our institution. SUBJECTS AND METHODS: We retrospectively identified 63 patients with auricular benign masses who underwent excision and biopsy from May 1970 to April 2011. We determined the site, cause, size, pathology and postoperative results of these auricular masses. RESULTS: Auricular benign masses occurred most commonly on the lobule (44.4%), followed by the tragus (20.6%), crus of helix (11.1%), triangular fossa (6.3%), crus of antihelix-antitragus (3.1%) and scapha (1.5%). Pathologically, the most common type of auricular mass was epidermal cysts (25.3%), followed by hypertrophic scar (12.6%), fibrous tissue-accessory ear (9.5%), chronic inflammation-nevus (7.9%), keloid (6.3%), hemangioma (4.7%), and skin tag-seborrheic keratosis (3.1%). CONCLUSIONS: The most common site of auricular benign masses is the lobule and most common pathology is an epidermal cyst.

Changes in taste function related to obesity and chronic otitis media with effusion.

OBJECTIVE: To evaluate changes in taste threshold in patients with chronic otitis media with effusion (COME) and their relationship with body mass index. A relationship has been suggested between pediatric obesity and COME, and we hypothesized that changes in taste function may occur in children with COME and that such changes may be associated with changes in body weight. DESIGN: A prospective, nonrandomized, case-control study. SETTING: A university tertiary care center. SUBJECTS: The experimental group comprised 42 children with COME who underwent tympanostomy tube insertion, and the control group, 42 children without otitis media with effusion. Patients were enrolled between September 2007 and August 2009. MAIN OUTCOME MEASURE: Taste threshold was measured by electrogustometry, and 4 standard taste solutions (sucrose, sodium chloride, citric acid, and quinine hydrochloride) were used in chemical taste tests. RESULTS: Body mass index was significantly higher in the COME than in the control group (P = .02). Electrogustometry showed that the anterior part of the tongue had a significantly higher taste threshold in the COME than in the control group (anterior right, P = .03; anterior left, P = .04), and chemical taste test results showed that sweet and salty tastes were significantly lower in the COME group (sweet, P = .02; salty, P = .04). CONCLUSION: These results showed that COME can cause changes in taste and that these changes may be related to pediatric obesity.

Airborne bacteria concentrations and related factors at university laboratories, hospital diagnostic laboratories and a biowaste site.

AIMS: To evaluate concentrations of airborne bacteria in university laboratories, hospital diagnostic laboratories, and a biowaste site in Seoul, Korea. To measure total airborne bacteria (TAB), the authors assessed sampling site, type of ventilation system, weather and detection of Gram-negative bacteria (GNB), indoors and outdoors. METHOD: An Andersen one-stage sampler (Quick Take 30; SKC Inc) was used to sample air at a flow rate of 28.3 l/min for 5 min on nutrient medium in Petri dishes located on the impactor. A total of 236 samples (TAB, 109 indoor and nine outdoor; GNB, 109 indoor and nine outdoor) were collected three times in each spot from the 11 facilities to compare airborne bacteria concentrations. RESULTS: TAB concentrations ranged from undetectable to 3451 CFU/m³ (mean 384 CFU/m³), and GNB concentrations from undetectable to 394 CFU/m³ (mean 17 CFU/m³). TAB concentrations were high in window-ventilated facilities and facilities in which GNB were detected; concentrations were also high when it was rainy (all p values <0.05). TAB concentrations correlated significantly with GNB (r=0.548, p<0.01), number of bacteria species (r=0.351, p<0.01) and temperature (r=0.297, p<0.01). The presence of heating, ventilating, and air conditioning (HVAC), the number of TAB species and the detection of GNB affect TAB concentrations in laboratories. CONCLUSIONS: It is recommended that special attention be given to regular control of indoor environments to improve the air quality of university and hospital laboratories.

Review on Potential Risk Factors in Wafer Fabrication Process of Semiconductor Industry / 대한산업의학회지

OBJECTIVES: To associate work in the semiconductor industry, including silicon wafer fabrication, with cancer risks or mortality and other adverse health effects, the operation of wafer fabrication should initially be understood. A detailed study on the fabrication operation allows retrospective exposure to be assessed and wafer fabrication workers to be classified into similar exposure groups. Therefore, the objective of this study was to comprehensively review silicon wafer fabrication operations and related hazardous materials and agents. METHODS: The literatures related to semiconductor industry processes were reviewed from an occupational health viewpoint based on wafer manufacturing, wafer fabrication and packaging. The focus was especially related to the hazardous materials used in wafer fabrication industries. RESULTS: During the fabrication of silicon wafers, many toxic chemicals, a strong electric field and hazardous equipment are used. The process allows the integration of a three-dimensional array of electric circuits onto a silicon wafer substrate. Wafers are sliced from single crystal silicon and subject to a series of steps during the fabrication process, which alternatively adds and then selectively removes materials in layers from the surface of the wafer to create different parts of the completed integrated circuit. There are four major steps in this process; patterning, junction formation, thin film and metallization. CONCLUSIONS: In order to associate exposure to the hazard agents generated during wafer fabrication operations with adverse health effects the details of the operation should be completely studied, which will be helpful in both exposure assessments and epidemiological studies.

Potentiation of the growth inhibition activity of 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) by Herceptin in SKBR-3 human breast cancer cells.

The 9-aminoacridine derivative, 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl) amino)ethan-1-ol (CK0402) was selected as a potential anticancer agent among a series of sulfur-containing 9-aminoacridine analogues. CK0402 is a topoisomerase II inhibitor and has been shown to exert impressive anticancer activities in both in vitro and in vivo assays. In the present study, we tested the effects of CK0402 in a panel of established human breast cancer cells with varying ER and HER2/neu status. The ER(-) and HER2-overexpressing SKBR-3 cells were the most sensitive cells tested in growth inhibition to CK0402 treatment, and the growth inhibition was in a time-and concentration-dependent manner. In addition, CK0402 also induced stronger G(2)/M arrest, apoptosis and autophagy in SKBR-3 cells than in ER(+) and HER2(-) MCF-7 cells. To the best of our knowledge, CK0402 is the first 9-aminoacridine analogue to induce autophagy. These findings suggest that CK0402 may be effective against the more aggressive and malignant ER(-) and HER2-overexpressing breast cancer. Towards this end, we further demonstrated that the combination of CK0402 and Herceptin exhibited synergistic/additive cytotoxic effects in SKBR-3 cells using the median-effect/combination-index isobologram methodology (CI value). Our results indicate that the combination of CK0402 and Herceptin may be a potential therapeutic option against the more aggressive ER(-) and HER2-overexpressing breast cancer.

Caspase-dependent cell death mediates potent cytotoxicity of sulfide derivatives of 9-anilinoacridine.

9-anilinoacridine contains a tricyclic and planar aromatic structure that enables DNA intercalation and inhibition of topoisomerase II. Two recently developed sulfide derivatives of 9-anilinoacridines, 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) and 3-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(3-hydroxypropyl)amino)propan-1-ol (CK0403), displayed potent cytotoxic activity in multiple cancer cell lines. In-vitro enzymatic assay demonstrated that CK0402 and CK0403 directly inhibit decatenation reaction of topoisomerase IIalpha. Cells exposed to CK0403 showed DNA fragmentation, and activation of caspase-3 and caspase-2, indicating that it triggers caspase-dependent apoptosis. This was further supported by the fact that cytotoxicity of these drugs is attenuated by pharmacological inhibition of caspases with z-VAD-FMK. Studies with wild-type and p53 primary mouse embryonic fibroblasts demonstrated that p53 does not play a significant role in cell death process initiated by this kind of drug. In addition, pharmacological inhibition of poly(ADP-ribose) polymerase-1activity moderately enhanced cytotoxic activity of sulfide 9-anilinoacridine, suggesting that poly(ADP-ribose) polymerase-1 may have a protective function against 9-anilinoacridine-induced cell death process.

Characteristics of PM10, PM2.5, CO2 and CO monitored in interiors and platforms of subway train in Seoul, Korea.

This study was performed to investigate the concentration of PM(10) and PM(2.5) inside trains and platforms on subway lines 1, 2, 4 and 5 in Seoul, KOREA. PM(10), PM(2.5), carbon dioxide (CO(2)) and carbon monoxide (CO) were monitored using real-time monitoring instruments in the afternoons (between 13:00 and 16:00). The concentrations of PM(10) and PM(2.5) inside trains were significantly higher than those measured on platforms and in ambient air reported by the Korea Ministry of Environment (Korea MOE). This study found that PM(10) levels inside subway lines 1, 2 and 4 exceeded the Korea indoor air quality (Korea IAQ) standard of 150 microg/m(3). The average percentage that exceeded the PM(10) standard was 83.3% on line 1, 37.9% on line 2 and 63.1% on line 4, respectively. PM(2.5) concentration ranged from 77.7 microg/m(3) to 158.2 microg/m(3), which were found to be much higher than the ambient air PM(2.5) standard promulgated by United States Environmental Protection Agency (US-EPA) (24 h arithmetic mean: 65 microg/m(3)). The reason for interior PM(10) and PM(2.5) being higher than those on platforms is due to subway trains in Korea not having mechanical ventilation systems to supply fresh air inside the train. This assumption was supported by the CO(2) concentration results monitored in tube of subway that ranged from 1153 ppm to 3377 ppm. The percentage of PM(2.5) in PM(10) was 86.2% on platforms, 81.7% inside trains, 80.2% underground and 90.2% at ground track. These results indicated that fine particles (PM(2.5)) accounted for most of PM(10) and polluted subway air. GLM statistical analysis indicated that two factors related to monitoring locations (underground and ground or inside trains and on platforms) significantly influence PM(10) (p<0.001, R(2)=0.230) and PM(2.5) concentrations (p<0.001, R(2)=0.172). Correlation analysis indicated that PM(10), PM(2.5), CO(2) and CO were significantly correlated at p<0.01 although correlation coefficients were different. The highest coefficient was 0.884 for the relationship between PM(10) and PM(2.5).

Sulfonyl-containing nucleoside phosphotriesters and phosphoramidates as novel anticancer prodrugs of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP).

A series of sulfonyl-containing 5-fluoro-2'-deoxyuridine (FdU) phosphotriester and phosphoramidate analogues were designed and synthesized as anticancer prodrugs of FdUMP. Stability studies have demonstrated that these compounds underwent pH dependent beta-elimination to liberate the corresponding nucleotide species with half-lives in the range of 0.33-12.23 h under model physiological conditions in 0.1 M phosphate buffer at pH 7.4 and 37 degrees C. Acceleration of the elimination was observed in the presence of human plasma. Compounds with an FdUMP moiety (4-9) were considerably more potent than those without (1-3) as well as 5-fluorouracil (5-FU) against Chinese hamster lung fibroblasts (V-79 cells) in vitro. Addition of thymidine (10 microM) reversed the growth inhibition activities of only 5-FU and the compounds with an FdUMP moiety, but had no effect on those without. These results are consistent with thymidylate synthase as the target of the prodrugs.

Synthesis and antitumor activity of sulfur-containing 9-anilinoacridines.

A series of sulfur-containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer potential. Among the compounds, both diol-containing compounds, 2a and 3, were the most cytotoxic of the sulfide series against V-79 cells in vitro (IC(90) = 2.1 microM and 1.9 microM, respectively). Among the non-alkyl-substituted compounds (7-9), compounds with electron-donating substitution para to the sulfide (7 and 9) were more cytotoxic than the electron-withdrawing nitro-substituted compound 8. The limited SAR suggested the importance of hydroxyl functionality along with its location for the cytotoxicity in the series. A preliminary anticancer screening against P388 leukemia showed that 2a is highly active in vivo as well. Topoisomerase II inhibitory activity appeared to be involved in the cytotoxicity of compound 2a. Sulfoxide compound 2b, which is 6-7-fold less cytotoxic than its sulfide 2a, appears to be a potential bioreductive anticancer prodrug on the basis of its bioreductive metabolism findings.

Sulfonyl-containing aldophosphamide analogues as novel anticancer prodrugs targeted against cyclophosphamide-resistant tumor cell lines.

A series of sulfonyl-group containing analogues of aldophosphamide (Aldo) were synthesized as potential anticancer prodrugs that liberate the cytotoxic phosphoramide mustards (PM, IPM, and tetrakis-PM) via beta-elimination, a nonenzymatic activation mechanism. Kinetic studies demonstrated that all these compounds spontaneously liberate phosphoramide mustards with half-lives in the range of 0.08-15.2 h under model physiological conditions in 0.08 M phosphate buffer at pH 7.4 and 37 degrees C. Analogous to Aldo, the rates of beta-elimination in all compounds was enhanced in reconstituted human plasma under same conditions. The compounds were more potent than the corresponding phosphoramide mustards against V-79 Chinese hamster lung fibroblasts in vitro (IC(50) = 1.8-69.1 microM). Several compounds showed excellent in vivo antitumor activity in CD2F1 mice against both P388/0 (Wild) and P388/CPA (CP-resistant) tumor cell lines.