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The quality control of testing and inspection laboratories operated in Korea, the United States, and Canada was compared. The basic framework of on-site evaluation operated by each country was similar in terms of evaluation procedure, document evaluation, issuance of verification certificate, and follow-up management. For conducting on-site evaluation and granting the certificate, the preparation materials and evaluation processes are subdivided in Korea, while the dates of granting the certificate are restricted to four times a year in the United States. After receiving accreditation as a testing/inspection laboratories for the first time in Canada, follow-up management is divided into re-evaluation, verification evaluation, and monitoring evaluation.

Aims Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. Methods and results Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN−/−) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (I CaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased I CaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced I CaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. Conclusion Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics.

With reference to the quality standard, ISO/IEC 17025, we conducted on-site assessments of and comparisons between test and inspection institutions in Korea and the UK. The diversity of evaluation methods used ‘in the field’ within the UK is greater than the range in Korea. Nevertheless, when assessing on-site processes in both countries, it is clear that many aspects of the quality assessment, including the roles of the evaluation committee members, the preparation of documents for evaluation, the opening meeting, the evaluation process in the field, and the closing meeting, occur in a similar order in the UK as in Korea. However, one important difference between the on-site evaluations in Korea and the UK was noted; particularly, in the UK, the level of excellence achieved by the evaluated institution is highlighted during the closing meeting.

As the third enzyme of the pentose phosphate pathway (PPP), abnormally elevated levels of 6-phosphogluconate dehydrogenase (6PGD) have been documented in various human cancers. We demonstrate that reduced cereblon (CRBN) protein expression is the underlying mechanism of elevated 6PGD expression in metastatic prostate cancer cells. We establish 6PGD as a new endogenous substrate for CRBN by demonstrating that it interacts directly with CRBN and is ubiquitinated by CRL4CRBN. In addition, CRBN negatively regulates prostate cancer cell progression and metastasis, as abnormally high 6PGD, in the absence of sufficient CRBN, enhances the metastatic potential of prostate cancer in vitro and in vivo. Our findings show convincingly that carbohydrate metabolism regulated by 6PGD is linked to prostate cancer metastasis via CRBN. Based on these data, we propose that the 6PGD-CRBN axis may be a suitable target for further research into new therapeutics for mitigating prostate cancer metastasis. Citation Format: Koushik Guchhait, Hyeon Seung Yoon, Seungheon Shin, Hyun-Su An, Hye Seung Nam, Francisco D. Yanqui-Rivera, Samara M. Oña, Miguel Á. Mendez, Seokjae Park, Eun-Kyoung Kim, Jong Yeon Hwang, Jee-Young Han, Doo Yong Chung, Daeho Park, Su-Geun Yang, Chul-Seung Park, Steve K. Cho. Cereblon inhibits prostate cancer progression and metastasis by negatively regulating 6PGD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB157.

Molecular glue degraders, such as lenalidomide and pomalidomide, bind to cereblon (CRBN) E3 ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure-activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone. As a result, we identified 34f (TD-522), which exhibits strong anti-proliferative effects in both KG-1 (EC

This paper deals with secondary cooling in a continuous caster. In particular, it deals with cooling inhomogeneity caused by spray arrangement and segmented rolls used for leading the strand. The cooling section is placed under the mold. Segmented rolls are supported by bearings in several places across the strand. Sprayed water can flow in the gaps between rolls where the bearing pocket is located. The main question that was experimentally studied is how this geometry with segmented rolls can influence homogeneity of cooling. Two experimental approaches developed for this study were applied, and both used full-scale geometrical configuration. The first one was a cold test where water flow and water distribution were observed using a transparent board with the studied surface structures (rollers and bearing pockets) and four spraying nozzles. The second one was a cooling test using a heated steel plate with rolls and bearing pockets. Cooling homogeneity was studied based on the temperature distribution on the rear side of the sample, which was recorded using an infrared camera. Homogeneity of cooling distribution was experimentally studied for three levels of cooling intensity that are used in typical cooling sections in plants. The hot tests showed that the bearing pockets do not provide significant cooling inhomogeneity despite the fact that a large amount of water flows through the gap between the rollers (which has been observed in cold tests).

Simple Summary To overcome the potential threat of drug resistance or limit of potency, the combination treatment of drugs is a promising strategy. Around 22% of patients with GCB-DLBCL carry EZH2 gain-of-function mutations and several PRC2 inhibitors are under clinical trials. Herein, we demonstrate that combination of GSK126 with pomalidomide synergistically inhibit tumor growth through inducing B-cell maturation and apoptosis in EZH2 gain-of-function mutant DLBCL. Our study provides the molecular basis of the combination strategy of PRC2 inhibitors and IMiDs in DLBCLs harboring EZH2 hyperactive mutation. Abstract Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates genes involved in cell lineage and differentiation through methylating lysine 27 on histone H3 (H3K27me3). Recurrent gain-of-function mutations of EZH2 have been identified in various cancer types, in particular, diffuse large B-cell lymphoma (DLBCL), through large-scale genome-wide association studies and EZH2 depletion or pharmacological inhibition has been shown to exert an antiproliferative effect on cancer cells, both in vitro and in vivo. In the current study, a combination of pomalidomide and GSK126 synergistically inhibited the growth of EZH2 gain-of-function mutant Diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, this synergistic effect appeared to be dependent on cereblon (CRBN), a cellular receptor of pomalidomide, but not degradation of IKAROS family zinc finger 1 (IKZF1) or IKAROS family zinc finger 3 (IKZF3). RNA sequencing analyses revealed that co-treatment with GSK126 and pomalidomide induced specific gene sets involved in B-cell differentiation and apoptosis. Synergistic growth inhibition and B-cell differentiation were further validated in xenograft mouse models. Our collective results provide a molecular basis for the mechanisms underlying the combined therapeutic effects of PRC2 inhibitors and pomalidomide on EZH2-mutated DLBCL.

Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells in vitro as well as in vivo. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET inhibitor, JQ1 efficiently induce BET protein degradation in the prostate cancer cell line 22Rv1. Consequently, cell proliferation is inhibited due to suppressed C-MYC transcription. These results, therefore, firmly suggest that the newly synthesized IMiD analog, TD-106, is a novel CRBN modulator that can be used for targeted protein degradation.

Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study.

Despite the excellent efficacy of chimeric antigen receptor (CAR T) cell therapy, concerns about its safety have been constantly raised. The side effects of CAR T cells result from an aberrantly upregulation of CAR T cell activity. Therefore, it is crucial to control the CAR T cell activity whenever the patient is at risk. For this purpose, the iCas9 system, which induces apoptosis in CAR T cell through caspase-9 dimerization by compound, has been invented and is currently going under clinical trial. However, the iCas9 system is irreversible, as the entire CAR T cell population is removed from the patient. Thus, CAR T cells, which are very expensive, should be reinfused to the patients after they recovered from the side-effect. Here, we propose a new CAR T cell safety strategy, which targets CAR "protein", not CAR "T cell". In this system, the CAR construct is modified to bear a bromodomain (BD). The addition of a BD in the CAR protein did not interfere with the original CAR functions, such as cytokine secretion and target cell lysis. Our data showed that the use of a proteolysis-targeting chimaera (PROTAC) compound against BD successfully degraded the BD-containing CAR protein. Moreover, the CAR expression is recovered when the PROTAC compound is removed from the cell, demonstrating that our system is reversible. In a target cell lysis assay, the PROTAC compound successfully suppressed the lytic activity of CAR T cells by degrading the CAR protein. In conclusion, we developed a new safety system in which CAR T cells can be "reversibly" controlled by a compound.

Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model.

Since 2007, Naturally Occurring Radioactive Materials (NORM) such as uranium-238 and radon-222 etc. in groundwater from the Community Water-supply Systems (CWS) in two islands have been studied in South Korea. In 71 samples from Ganghwa (G) Island, the maximum value of uranium-238 concentration is 72.21 μg/L. 3 CWSs (4.2%) exceeded the Maximum Contaminant Level (MCL) of 30 μg/L for uranium-238. The maximum value of radon-222 activity is 614 Bq/L. 28 CWSs (39.4 %) did not meet the United States Environment Protection Agency (US EPA) proposed Alternative Maximum Contaminant Level (AMCL) of 148 Bq/L for radon-222. At all CWS that did not meet the US EPA’s MCL or AMCL, some appropriate actions were taken such as water treatment, alternative well development, mixing water of different origins, and so forth. In the 52 CWSs of Jeju (J) Island, the maximum value of uranium-238 and radon-222 concentrations are 1.37 μg/L and 94.83 Bq/L, respectively. All values for uranium-238, gross alpha, and radon-222 meet MCL and proposed AMCL of US EPA drinking water standard. The two islands have different geological settings that are believed to be the causes of the big differences in the NORM levels. Geologically an old island has much higher NORM values than a young island formed in the Quaternary Period due to hydrogeological factors such as recharge and infiltration rates of precipitation. The residence times in the aquifers for water-rock (mineral) interactions are very different from each other.

We describe the simple and efficient synthesis of N-substituted isoquinolin-1-one derivatives. Initiating with the coupling of benzoic acids containing vinyl ethers with different amines, followed by rapid intramolecular cyclization under acidic conditions at room temperature, N-substituted isoquinolin-1-ones were furnished in high yields. The utility of this simple and mild cyclization method was demonstrated through the practical synthesis of natural product doryanine and its analogues.

Upon high-throughput screening of synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified an iminodipyridinopyrimidine (IDPP) scaffold. IDPP did not inhibit HCV replication, but exhibited very potent inhibitory activity on early and late steps of HCV life cycle. Applying an intensive structure-activity relationship (SAR) study, a promising IDPP Lead compound ( 12c ) with excellent potency (EC 50 = 10 nM), high safety margin (SI > 2000), and an acceptable stability in human and rat liver microsomes (t 1/2 >60 min) was identified. Overall, our results suggest that the IDPP scaffold could be used for the development of novel HCV interventions.

Proteolysis targeting chimeras (PROTACs) are an emerging strategy for promoting targeted protein degradation by inducing the proximity between targeted proteins and E3 ubiquitin ligases. Although successful degradation of numerous proteins by PROTACs has been demonstrated, the elements that determine the degradability of PROTAC-targeted proteins have not yet been explored. In this study, we developed von Hippel-Lindau-Cereblon (VHL-CRBN) heterodimerizing PROTACs that induce the degradation of CRBN, but not VHL. A quantitative proteomic analysis further revealed that VHL-CRBN heterodimerizing PROTACs induced the degradation of CRBN, but not the well-known immunomodulatory drug (IMiD) neo-substrates, IKAROS family zinc finger 1 (IKZF1) and −3 (IZKF3). Moreover, truncation of disordered regions of CRBN and the androgen receptor (AR) attenuated their PROTAC-induced degradation, and attachment of the disordered region to stable CRBN or AR facilitated PROTAC-induced degradation. Thus, these results suggest that the intrinsically disordered region of targeted proteins is essential for efficient proteolysis, providing a novel criterion for choosing degradable protein targets.

Understanding of the aquifer hydraulic properties and hydrochemical characteristics of water is crucial for management plan and study skims in the target area, and flow motions and chemical species of groundwater are regarded as precious information on the geological history of the aquifers and the suitability of various usages. Cations and anions of groundwater are used to estimate the characteristics and origin of groundwater. In this study, we try to evaluate the quality of groundwater based on the comparison of the physiochemical characteristics and distribution of cations and anions in groundwater from rural areas. Therefore we focused on the evaluation of groundwater as some specific purposes such as agricultural and industrial use, general types of groundwater, lithological origin of chemical component in groundwater. In this point of view, major objectives of this study were grouped as following three categories: 1) quality assessment of groundwater as a special usage (agricultural, industrial); 2) determination of groundwater types; 3) tracing of ion sources of groundwater. The quality of agricultural water was evaluated using SAR, sodium (%), RSC, PI, SSP, MH, PS, and Kelly’s ratio, and was classified as SAR (Excellent (100%)), Sodium ((Excellent (34%), Good (55%), Permissible (9%), Doubtful (1.6%), Unsuitable (0.4%)), RSC (Good (95.7%), Medium (3.5%), Bad (0.8%)), PI((Excellent (40.6%), Good (59%), Unsuitable (0.4%)), SSP ((Excellent (26.3%), Good (59.8%), Fair (13.1%), Poor (0.8%)), MH ((Acceptable (94.4%), Non-Acceptable (5.6%)), Kelly’s Ratio ((Permissible (93%), Non-Permissible (7%)), PS ((Excellent to Good (98%), Good to Injurious (1.2%), and Injurious to Unsatisfactory (0.2%)). Evaluation based on the Wilcox diagram was classified as “excellent to good” or “good to permissible”, and the water quality evaluated using the U.S. salinity Laboratory’s Diagram was classified as C1S1 (Excellent/Excellent) and C2S1 (Good/Excellent). And, in the applications of two factors of Langelier Saturation Index (LSI) and Corrosive ratio (CR), we could get similar results for defining the suitabilities of groundwater for the industrial purpose. And the groundwater samples were also classified groundwater using the Piper diagram and estimated the origin of ions using the Gibbs and Chadah diagram, and the classifications based on the Piper diagram showed that the types of the groundwater are type and type. And, estimation of dominance type (evaporation, rock, precipitation) based on the Gibbs diagram showed that the origin of anion and cation in groundwater are from the rock-dominance, and the estimation of origin of anions using the Chadha diagram showed that the most of the ionic species was originated from the interactions between alkaline earths and alkali metals contained in the soil. And through the source-rock deduction followed by the comparison of Gibbs and Chadah diagram, it was shown that the chemical components in the groundwater were mostly induced from the water-rock deduction and major types of groundwater samples following the Chadah diagram were categorized such as following group types: dolomite type, gypsum type, alkaline and alkaline earth type.

Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates genes involved in cell lineage and differentiation through methylating lysine 27 on histone H3 (H3K27me3). Recurrent gain-of-function mutations of EZH2 have been identified in various cancer types, in particular, diffuse large B-cell lymphoma (DLBCL), through large-scale genome-wide association studies and EZH2 depletion or pharmacological inhibition has been shown to exert an antiproliferative effect on cancer cells, both in vitro and in vivo. In the current study, a combination of pomalidomide and GSK126 synergistically inhibited the growth of EZH2 gain-of-function mutant Diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, this synergistic effect appeared to be dependent on cereblon (CRBN), a cellular receptor of pomalidomide, but not degradation of IKAROS family zinc finger 1 (IKZF1) or IKAROS family zinc finger 3 (IKZF3). RNA sequencing analyses revealed that co-treatment with GSK126 and pomalidomide induced specific gene sets involved in B-cell differentiation and apoptosis. Synergistic growth inhibition and B-cell differentiation were further validated in xenograft mouse models. Our collective results provide a molecular basis for the mechanisms underlying the combined therapeutic effects of PRC2 inhibitors and pomalidomide on EZH2-mutated DLBCL.

Mold heat transfer during the commercial high speed continuous casting up to 7 m/min was investigated in order to clarify the influence of various operating conditions such as casting speed, mold flux, mold thickness, thickness and height of mold coated layer and so on. A simple, but practical formula of heat flux has been derived in terms of those operating conditions by analyzing the heat flux data obtained in CEM® (Compact Endless Casting and Rolling Mill) caster based on simplified one dimensional heat transfer model. Especially, impact of mold parameters such as mold thickness, mold coated layer thickness and its height on the heat flux can be linearly expressed in the empirical formula derived. Heat flux ratio (HR), the ratio of the narrow face heat flux to the wide face one, is one of the important indicators to evaluate whether the solidified shell is evenly robust or not. Averaged HR in CEM® caster is around 0.87, which varies according to the caster specifications and operating conditions. It is suggested that the mold taper should be adjusted to maintain the HR as close to 0.87 as possible.

A series of pyridazin-3-one substituted with morpholino-pyrimidine derivatives was synthesized and evaluated as tyrosine kinase inhibitors against c-Met enzyme, and anti-proliferative activities of Hs746T human gastric cancer cell line. Most of compounds exhibited good biological activity, while compound 10, 12a, 14a displayed excellent c-Met enzyme inhibitory activities and Hs746T cell-based activities.

The isotope ratio mass spectrometer (IRMS) is an instrument that measures both of the elemental contents and isotope ratios of hydrogen, oxygen, carbon, nitrogen and sulfur in environmental samples at the same time. In this study, we want to try to get two main goals; first, to make up for setting the analytical conditions such as accuracy and precision, second, to apply for comparing of the carbon and nitrogen isotope ratio of sediments in the abandoned mine located in middle province of Korea. For the first goal, a recently introduced IRMS was used to analyze CRM (certified reference materials), which helped to make up the analytical conditions of carbon and nitrogen isotope ratios. So, the accuracy and precision of isotope ratios and elemental contents were also assessed simultaneously, and also the results were very satisfactory. The analytical results of carbon reference materials (EMA-P2) showed an accuracy of -2.801 × 10‰ ± 0.01‰ (2σ) and a precision of 0.009‰ in the mass range from 0.008 μg - 0.162 μg. For nitrogen reference materials (EMA-P2), an accuracy of -1.632‰ ± 0.72‰ (2σ) was obtained in the mass range from 0.082 - 0.162 mg. These values of accuracy and precision are higher than those reported by other studies. For the second goal, carbon and nitrogen isotopes in river sediment near abandoned mines were analyzed based on the established analytical conditions. The result suggested that carbon isotope ratios ranged from -22.5‰ - -7.5‰ and nitrogen isotope ratios from -1.9‰ - 7.9‰. By comparing the isotope ratios and sampling sites of sediment, we know that the nitrogen isotope values in samples of entrance area of mine are greater than those of the farm house area, which is indicating the effects of organic materials. So, we could guess that the newly accumulated organic materials were much more in the farm house area than mine entrance area. And a result of this study, the accuracy and precision tests of IRMS using certified reference materials were very satisfactory and optimum analytical conditions were established well. And also, it was found that the applications of isotopic analysis for environmental samples by using the IRMS could be very useful for the studies on tracing pollution sources.

Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, and its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through ALK wild type enzyme assay, we selected two compounds, KRCA-0080 and KRCA-0087, which have trifluoromethyl instead of chloride in R2 position. We characterized these newly synthesized compounds by in vitro and in vivo assays. Enzyme assay shows that KRCA-0080 is more potent against various ALK mutants, including L1196M, G1202R, T1151_L1152insT, and C1156Y, which are seen in crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our compounds downregulate the cellular signaling, such as Akt and Erk, by suppressing ALK activity to inhibit the proliferation of the cells harboring EML4-ALK. Interestingly, our compounds induced strong G1/S arrest in H3122 cells leading to the apoptosis, which is proved by PARP-1 cleavage. In vivo H3122 xenograft assay, we found that KRCA-0080 shows significant reduction in tumor size compared to crizotinib and KRCA-0008 by 15–20%. Conclusively, we report a potent ALK inhibitor which shows significant in vivo efficacy as well as excellent inhibitory activity against various ALK mutants.

A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure-activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC50=2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines. Here, we report the synthesis and evaluation of novel 6-aminopurine derivatives and present molecular docking models of compound 81 with CDK2 and CDK5.

We identified a novel class of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds as potent HIV-1 replication inhibitors serendipitously during the process of evaluation of triazolothienopyrimidine (TTPM) compounds. Herein, we report synthesis and biological evaluation of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds using a cell-based full replication assay to identify thienopyrimidines 6 and 30, which could be further utilized as viable lead compounds.

In this report we describe 2-iminobenzimidazole (IBI) analogs, identified during the course of a phenotypic high-throughput screening campaign, as novel hepatitis C virus (HCV) inhibitors. A series of IBI derivatives was synthesized and evaluated for their inhibitory activity against infectious HCV. Among the IBIs derivatives studied in this work, we identified promising compounds with high antiviral efficacy, high selectivity index and good microsomal stability. Noteworthy, the IBI series exhibited inhibitory activity on early and late steps of the viral cycle, but not in the HCV replicon system demonstrating a mechanism of action distinct from clinical-stage and approved anti-HCV drugs. Overall, our results suggest that IBIs are predestinated for further exploration as lead compounds for novel HCV interventions.

The synthesis of 3,3′-bis-7-indolylmethane derivatives is important for their further development as pharmaceutical compounds and other synthetic purposes. Herein, we describe the zinc- or acid-mediated cross-coupling reaction of 7-azaindoles with aldehydes, such as paraformaldehyde, alkyl aldehydes, aryl aldehydes, enal, and α-ketoaldehyde, providing the corresponding C3-linked bis-7-azaindole derivatives, which are a crucial class towards the development of novel bioactive compounds. High levels of site selectivity and functional group tolerance were observed. Synthesized 3,3′-bis-7-azaindole derivatives were evaluated against human breast adenocarcinoma cells (MCF-7) and human ovarian carcinoma cells (SKOV-3), respectively. Notably, compounds 3s and 4e displayed promising anticancer properties competitive with anticancer doxorubicin as a positive control.

We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC50=120nM for Trypanosoma b. brucei, 18nM for Trypanosoma b. rhodesiense, and 38nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC50

In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, 28, 29, 36, and 42 showed promising anti-ALK activities in enzymatic- and cell-based assays. In vivo H3122 xenograft model study showed that compound 29 effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.

We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei. Herein we disclose extensive structure–activity relationship and structure–property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC50 = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.

We identified a novel class of triazolothienopyrimidine (TTPM) compounds as potent HIV-1 replication inhibitors during a high-throughput screening campaign that evaluated more than 200,000 compounds using a cell-based full replication assay. Herein, we report the optimization of the antiviral activity in a cell-based assay system leading to the discovery of aryl-substituted TTPM derivatives (38, 44, and 45), which exhibited significant inhibition of HIV-1 replication with acceptable safety margins. These novel and potent TTPMs could serve as leads for further development.

This study was undertaken to investigate the influence of Pb contaminant dispersal from an abandoned mine. For the study, 23 samples of sediment and soil were collected around the abandoned mine located in southwest of Korea. Pb concentrations and isotope ratios of sediment samples were analyzed through ICP-OES (Optima 5300 DV, Perkin Elmer) and MC-ICP-MS (Plasma II, Nu), respectively. The sediment samples collected in the main stream from the mine entrance showed high Pb concentrations of 139 - 1079 mg/kg, while Pb concentrations of the other sites were 19 - 29 mg/kg. Pb isotope ratios of the main stream sediments were 2.4854 - 2.4883 for 208Pb/207Pb and 1.1693 - 1.1740 for 206Pb/207Pb. On the other hand, the Pb isotopic compositions of sediments collected from the other sites were clearly different from those of ore deposits. The Pb isotope ratios versus inverse concentrations plot showed high linear correlation between the main stream, the tributary stream and one of the downstream sites representing the two end member mixing system between these sites. According to the binary mixing equation, the relative contribution of Pb pollutants from the abandoned mine to the downstream area were approximately 33% - 36%.

The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound 10 shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC50 of 1.8 nM. Furthermore, pharmacokinetic profiles of 10 is apparently better than that of ceritinib. In murine xenograft studies, compound 10 turns out to be as active as ceritinib, suggesting that further optimization of 10 may lead to clinical candidates overcoming ALK mutant issues.