Modulation of active center distance of hybrid perovskite for boosting photocatalytic reduction of carbon dioxide to ethylene.

Solar-driven photocatalytic CO2 reduction is an energy-efficient and sustainable strategy to mitigate CO2 levels in the atmosphere. However, efficient and selective conversion of CO2 into multi-carbon products, like C2H4, remains a great challenge due to slow multi-electron-proton transfer and sluggish C-C coupling. Herein, a two-dimensional thin-layered hybrid perovskite is fabricated through filling of oxygen into iodine vacancy in pristine DMASnI3 (DMA = dimethylammonium). The rational-designed DMASnI3(O) induces shrinkage of active sites distance and facilitates dimerization of C-C coupling of intermediates. Upon simulated solar irradiation, the DMASnI3(O) photocatalyst achieves a high selectivity of 74.5%, corresponding to an impressive electron selectivity of 94.6%, for CO2 to C2H4 conversion and an effective C2H4 yield of 11.2 µmol g-1 h-1. In addition, the DMASnI3(O) inherits excellent water stability and implements long-term photocatalytic CO2 reduction to C2H4 in a water medium. This work establishes a unique paradigm to convert CO2 to C2+ hydrocarbons in a perovskite-based photocatalytic system.

Transmission characteristics of vortex frozen waves in different obstacle channels.

The obstacle in a channel is a typical scenario for free-space optical (FSO) communications, however, it will destroy the information in channels, especially for the orbital angular momentum (OAM) multiplexing systems and cause performance degradation. Motivated by the feature of predefining intensity profile, here we propose to use frozen wave (FW) carrying OAM for the FSO communications to mitigate the influence of obstacles on the beam propagation. The key idea is to design the longitudinal intensity profile of FW to distribute the beam energy of the location where the obstacle exists over a large region and focus again on the central region after the obstacle for propagation. By analyzing the cases under different sizes, positions, and shapes of the obstacles with on-axis and off-axis scenarios, it has been demonstrated that the detection probability of OAM mode carried by FW can be improved by 0.35 and 0.15 in short-distance and long-distance transmission scenarios, respectively, when compared to that carried by Bessel-Gaussian beam. It demonstrates the FWs have great potential in the OAM-based FSO communications, especially for the obstacle channels.

A cross-scale study on the relationship between urban expansion and ecosystem services in China.

Clarifying the relationship between urban expansion and ecosystem services (ESs) is critical for sustainable management of land resources and ecosystems. However, little is known about the relationship between the two at the cross-scale (particularly at the national-provincial scale). Therefore, we conducted a systematic assessment of the spatiotemporal dynamics and the relationship between urban expansion and ESs including food production (FP), soil conservation (SC), carbon sequestration (CS), and water yield (WY) in China from 1992 to 2020 on the national-provincial scale. The results show that China's urban expansion took up a large amount of cropland, accounting for 79.35% of the newly-added built-up land. Shandong had the largest expansion scale and the highest speed, Shanghai had the most pronounced expansion intensity, and more than 50% of the provinces were dominated by outlying expansion pattern. In terms of total change, the three ESs of FP, SC, and WY increased by 286.5 × 106 t, 1893.61 × 106 t, and 8337.20 × 106 mm, respectively, and CS decreased by 683.90 × 106 Mg C. However, in the urban expansion area, FP and CS net decreased by 1757.6 × 104 t and 19,640.19 × 104 Mg C, respectively, while SC and WY net increased by 347.52 × 104 t and 20,264.11 × 104 mm, respectively. Shandong contributed the most to changes in ESs in urban expansion areas. Urban expansion was significantly negatively correlated with FP and CS with the correlation coefficients > -0.8; it was significantly positively correlated with SC and WY, with coefficients of 0.714 and 0.413, respectively, and urban expansion had a lagged effect on ESs. The impact of urban expansion on ESs had a spatial spillover effect and showed prominent spatial clustering in Anhui, Henan, and Shandong. Based on these results, we proposed urban planning countermeasures grounded in the perspective of ES improvement, which would provide policy references for the sustainable management of the ecological environment and land resources.

Targeting Trim69 alleviates high fat diet (HFD)-induced hippocampal injury in mice by inhibiting apoptosis and inflammation through ASK1 inactivation.

The prevalence of obesity is growing, and high fat diet (HFD)-induced obesity can alter the brain and cognition. However, the link between HFD, hippocampal function, and inflammation is still not fully understood. Tripartite motif (TRIM) family has been implicated in various cellular processes, such as apoptosis, neurogenesis, and innate immune responses. Trim69, a member of TRIM family, was investigated in the present study to determine its role in HFD-induced hippocampal damage. Here, we first found that hippocampal Trim69 expression was markedly down-regulated in wild-type (WT) mice challenged with HFD. Trim69 knockout (KO) mice exhibited an exaggerated version of the metabolic disorder after HFD challenge, as evidenced by their increased body weight and elevated insulin resistance. HFD-induced hippocampal injury was further aggravated by Trim69 deletion, as confirmed by the reduced survival of neurons and increased level of apoptotic cell death. In addition, the inflammatory response triggered by HFD was more pronounced in the hippocampi of Trim69-KO mice after blockage of the activation of the nuclear factor kappa B (NF-κB) signaling pathway. Phosphorylation of mitogen-activated protein kinase (MAPK) kinase 4 (MKK4), MKK7, and c-Jun N-terminal kinase (JNK) in the hippocampi of HFD-challenged mice was intensified by the loss of Trim69. Hippocampal-apoptosis-signal-regulating kinase 1 (ASK1) phosphorylation was also found to be up-regulated by HFD, especially in mice with Trim69 deletion. Of note, we found that Trim69 directly interacted with and deubiquitinated ASK1 in microglial cells. Microglial cell-specific suppression of Trim69 exacerbated inflammation and apoptosis in response to lipopolysaccharide (LPS). Trim69 over-expression markedly alleviated LPS-induced inflammatory response and apoptotic cell death in microglial cells. Together, these results indicated that Trim69 might be a functionally essential inhibitor of ASK1 activation during the pathogenesis of hippocampal inflammation and apoptosis, and it could serve as a novel molecular target for obesity-associated brain damage.

Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay.

DOT1L (the disruptor of telomeric silencing 1-like), through its methyltransferase activity of H3K79, plays essential roles in transcriptional regulation, cell cycle regulation, and DNA damage response. In addition, DOT1L is believed to be involved in the development of MLL-rearranged leukemia driven by the MLL (mixed-lineage leukemia) fusion proteins, which thus to be a crucial target for leukemia therapy. Hence, discovering of novel DOT1L inhibitors has been in a great demand. In this study, we initiated the discovering process from setting up the AlphaLISA based High Throughput Screening (HTS) assay of DOT1L. Combining with radioactive inhibition assay and Surface Plasmon Resonance (SPR) binding assay, we identified compound 3 and its active analogues as novel DOT1L inhibitors with IC50 values range from 7 µM to 20 µM in vitro. Together with the analysis of structure activity relationships (SAR) and binding modes of these compounds, we provided clues to assist in the future development of more potent DOT1L inhibitors. Moreover, compounds 3 and 9 effectively inhibited the proliferation of MLL-rearranged leukemia cells MV4-11, which could induce cell cycle arrest and apoptosis. In conclusion, we developed a HTS platform based on AlphaLISA method for screening and discovery of DOT1L novel inhibitor, through which we discovered compound 3 and its analogues as potent DOT1L inhibitors with promising MLL-rearranged leukemia therapeutic application.

Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors.

A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC50 values of 1.06 ±â€¯0.35 µM, 5.72 ±â€¯1.56 µM and 3.55 ±â€¯1.28 µM, respectively. Such inhibitors expressed significant binding interactions with DOT1L by surface plasmon resonance (SPR)-based binding assay. The results of molecular docking experiments suggested that they could occupy the SAM binding pocket of DOT1L. Compounds 8h and 9e exhibited better inhibitory activities but poor selectivities against the both MLL-rearranged MV4-11 cells and the non MLL-rearranged Kasumi-1 cells than those of 3a and 3e, which suggested that the introduction of the amino side chain would be beneficial for their anti leukemia cells proliferation activities, possibly due to the improvement of the fat solubility. Additionally, the direct cellular inhibition activities were found that compound 9e could effectively down-regulate both the level of H3k79 methylation and MLL-rearranged leukemia gene expression of Hoxa9 and Meis1 in MV4-11 in the qRT-PCR and western blot studies. These observations suggested DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds, which made their poor selectivities against leukemia cells proliferation.

Discovery of novel DNA methyltransferase 3A inhibitors via structure-based virtual screening and biological assays.

DNA methyltransferases are involved in diverse biological processes and abnormal methylation patterns play essential roles in cancer initiation and progression. DNA methyltransferase 3A (DNMT3A) acting as a de novo DNA methyltransferase, has gained widespread attention especially in haematological diseases. To date, large numbers of DNMTs inhibitors have been discovered, however, the small molecular inhibitors targeting DNMT3A are still in its infancy. In this study, structure-based virtual screening in combination with biological assays was performed to discovery potent novel DNMT3A inhibitors. Compound 40 and 40_3 displayed comparable in vitro inhibitory activity against DNMT3A with IC50 values of 46.5µM and 41µM, respectively. Further binding mode analysis suggested these molecules inhibit DNMT3A activity through binding the S-adenosyl-l-methionine (SAM) pocket. Overall, 40 and 40_3 may serve as novel scaffolds for further optimization and small molecular probes for investigating DNMT3A function.

Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays.

Histone methyltransferases are involved in many important biological processes, and abnormalities in these enzymes are associated with tumorigenesis and progression. Disruptor of telomeric silencing 1-like (DOT1L), a key hub in histone lysine methyltransferases, has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias and validated to be a potential therapeutic target. In this study, we identified a novel DOT1L inhibitor, DC_L115 (CAS no. 1163729-79-0), by combining structure-based virtual screening with biochemical analyses. This potent inhibitor DC_L115 shows high inhibitory activity toward DOT1L (IC50 = 1.5 µM). Through a process of surface plasmon resonance-based binding assays, DC_L115 was founded to bind to DOT1L with a binding affinity of 0.6 µM in vitro. Moreover, this compound selectively inhibits MLL-rearranged cell proliferation with an IC50 value of 37.1 µM. We further predicted the binding modes of DC_L115 through molecular docking analysis and found that the inhibitor competitively occupies the binding site of S-adenosylmethionine. Overall, this study demonstrates the development of potent DOT1L inhibitors with novel scaffolds.

Relationship between perceived organisational support, self-efficacy, proactive personality and career self-management among nurses: a moderated mediation analysis.

OBJECTIVES: Career self-management is believed to be a critical behaviour in the new career era. However, the underlying mechanisms that stimulate nurses' career self-management are unclear. The aim of this study was to examine the mediating effect of self-efficacy and the moderating effect of proactive personality on the relationship between perceived organisational support and career self-management among nurses. DESIGN: This was a cross-sectional survey. SETTING AND PARTICIPANTS: A total of 1866 nurses from 15 hospitals across 15 cities in China were recruited for this study. PRIMARY AND SECONDARY OUTCOME MEASURES: The Perceived Organizational Support Scale, General Self-efficacy Scale, Proactive Personality Scale and Individual Career Management Questionnaire were used. Data were analysed using moderated mediation regressions with Hayes' PROCESS macro in SPSS version 26.0. RESULTS: General self-efficacy mediated the relationship between perceived organisational support and career self-management. Proactive personality moderated the direct (B=0.043, p<0.001, 95% CI 0.026 to 0.060) and indirect relationship (B=0.098, p<0.001, 95% CI 0.074 to 0.123) between perceived organisational support and career self-management. Further, the positive effects of perceived organisational support on general self-efficacy and career self-management were stronger for nurses with a high level of proactive personality. The model explained 47.2% of the variance in career self-management. CONCLUSION: The findings highlight the crucial benefits of self-efficacy and important conditional effects of perceived organisational support on nurses' career self-management.

Hydrogen-substituted graphdiyne encapsulated cuprous oxide photocathode for efficient and stable photoelectrochemical water reduction.

Photoelectrochemical (PEC) water splitting is an appealing approach for "green" hydrogen generation. The natural p-type semiconductor of Cu2O is one of the most promising photocathode candidates for direct hydrogen generation. However, the Cu2O-based photocathodes still suffer severe self-photo-corrosion and fast surface electron-hole recombination issues. Herein, we propose a facile in-situ encapsulation strategy to protect Cu2O with hydrogen-substituted graphdiyne (HsGDY) and promote water reduction performance. The HsGDY encapsulated Cu2O nanowires (HsGDY@Cu2O NWs) photocathode demonstrates a high photocurrent density of -12.88 mA cm-2 at 0 V versus the reversible hydrogen electrode under 1 sun illumination, approaching to the theoretical value of Cu2O. The HsGDY@Cu2O NWs photocathode as well as presents excellent stability and contributes an impressive hydrogen generation rate of 218.2 ± 11.3 µmol h-1cm-2, which value has been further magnified to 861.1 ± 24.8 µmol h-1cm-2 under illumination of concentrated solar light. The in-situ encapsulation strategy opens an avenue for rational design photocathodes for efficient and stable PEC water reduction.

Peritoneal carcinomatosis with intraperitoneal immunotherapy: current treatment options and perspectives.

INTRODUCTION: Peritoneal carcinomatosis (PC) is an advanced malignancy that is not sensitive to systemic conventional chemotherapy. Treatment options for PC are usually palliative rather than curative. Cytoreductive surgery and hyperthermic intraperitoneal (IP) chemotherapy are associated with limited efficacy in patients with PC. However, the peritoneum can produce effective immunity by inducing T-lymphocyte recruitment and proliferation, and the unique immune environment of the peritoneum provides the rationale for IP immunotherapy in PC. AREAS COVERED: The authors retrieved relevant documents of IP immunotherapy for PC from PubMed and Medline. This review elaborates on the knowledge of the peritoneal immune microenvironment and IP immunotherapy for PC covering immune stimulators, radioimmunotherapy, catumaxomab, cancer vaccines, chimeric antigen receptor (CAR)-T cells, and immune checkpoint inhibitors. EXPERT OPINION: The prognosis of PC is poor. However, the peritoneal cavity is a unique immune compartment with abundant immune cells which can produce effective immunity. IP immunotherapy may be a promising strategy in patients with PC.

Case report: Long-term partial response of apatinib plus paclitaxel as second-line therapy in a patient with metastatic gastric cancer.

Gastric cancer is the second most prevalent cancer and the second leading cause of cancer-related death in China. The prognosis of metastatic gastric cancer is poor with a median overall survival of 8-10 months. Apatinib, an oral small-molecule, selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, is approved as third-line or subsequent therapy for gastric cancer in China. Several recent small-scale studies and case reports showed that it may be great help in improvement of prognosis as second-line treatment in patients with advanced or metastatic gastric cancer. Here, we present a case of advanced gastric adenocarcinoma with multiple hepatic metastases who was treated with apatinib plus paclitaxel as second-line therapy, realized a long progression-free survival of 37 months. Until 29 January 2022, the disease remains an efficacy of partial response. We believe that the good outcome of this case is not an accident, because of the typically hyper-vascular of his liver metastases, the treatment toxicities of hypertension and proteinuria, all may be potential predictive biomarkers for anti-angiogenic treatments.

Efficacy and safety of raltitrexed plus S-1 versus regorafenib in patients with refractory metastatic colorectal cancer: a real-world propensity score matching study.

Background: Raltitrexed plus S-1 (RS) and regorafenib both showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. This study aims to compare the effectiveness and safety of two different regimens in patients with refractory mCRC. Methods: This retrospective cohort study included mCRC patients who were treated with RS or regorafenib from February 2017 to June 2021. A propensity score matching (PSM) analysis was conducted to balance the baseline characteristics of all patients. Progression-free survival (PFS), overall survival (OS), tumor response, and safety of two regimens were evaluated. Results: A total of 187 patients were included in our study, with 107 patients in the RS group and 80 patients in the regorafenib group. After PSM, 78 pairs were recognized. Patients treated with RS had a semblable PFS compared to those treated with regorafenib before PSM (4.8 months vs 5.5 months, p = 0.400) and after PSM (4.7 months vs 5.4 months, p = 0.430). Patients in the RS group were associated with a longer OS than those in the regorafenib group (13.4 months vs 10.1 months, p = 0.010). A similar trend of OS was also obtained in the matched cohort (13.3 months vs 10.0 months, p = 0.024). Both objective response rate (12.8% vs 5.1%, p = 0.093) and disease control rate (53.8% vs 46.2%, p = 0.337) in the RS cohort were higher than those in the regorafenib group, without significant differences. Adverse events (AEs) of each group were well tolerated. Conclusion: Patients treated with RS demonstrated a longer OS than those treated with regorafenib and had manageable AEs, which could be recognized as a primary choice for refractory mCRC. Plain Language Summary: Efficacy and Safety of Raltitrexed plus S-1 Versus Regorafenib in Patients with Refractory Metastatic Colorectal Cancer: A Real-world Propensity Score Matching StudyBoth raltitrexed plus S-1 (RS) and regorafenib showed considerable efficacy for metastatic colorectal cancer (mCRC) patients. No study has compared the two regimens yet. Therefore, we compare the efficacy and safety between RS and regorafenib to provide an optimal treatment option. We retrospectively included patients with mCRC who failed at least two standard treatments. All enrolled patients received RS or regorafenib treatments. We conducted a propensity score matching to eliminate differences in the enrolled patients. After the analysis, we found no significant differences in progression-free survival in patients between the two groups. However, patients treated with RS had a longer OS than those treated with regorafenib, whether before matching (13.4 months vs 10.1 months, p = 0.010) or after matching (13.3 months vs 10.0 months, p = 0.024). In addition, the adverse effects caused by cancer-related therapy were tolerable for the patient. Certainly, this is a non-randomized retrospective study with a small sample size, so we conducted a propensity score matching to minimize potential bias. Importantly, this is the first research comparing the two treatments, and we believe that the results of this article could present a primary choice for clinical doctors dealing with patients with standard treatments that failed mCRC.

The neuroprotective effects of cyclin-dependent kinase-5 inhibition in mice with Niemann-Pick disease type C.

In order to investigate the neuroprotective effects of cyclin-dependent kinase-5 (cdk-5) inhibition in mice with Niemann-Pick disease type C (NPC) (npc(-/-)), recombinant adeno-associated virus (rAAV) carrying the small interfering RNA (siRNA) specific for cdk-5 gene was injected into 3-day-old npc(-/-) mice intracerebroventricularly. The rAAV-GFP-injected age-matched npc(-/-) mice and non-surgery age-matched npc(-/-) mice were employed as controls (n=6-10/group). From the 4th to 8th week after the treatment, mice were weighed, and evaluated for limb motor activity by using the coat hanger test once a week. Eight-week-old npc(-/-) mice were sacrificed by decapitation, and brains were quickly dissected and halved sagittally. Immunohistochemistry, Western blotting, and HE staining were used to evaluate the neuropathology in npc(-/-) mice. The results showed that rAAV-cdk-5-siRNA-GFP significantly reduced the number of axonal spheroids, delayed the death of Purkinje neurons, ameliorated motor defects in npc(-/-) mice, and significantly attenuated the hyperphosphorylation of tau proteins. These data suggested that inhibition of cdk-5 activity has neuroprotective effect on neurons in NPC mice.

Biochemical Studies and Molecular Dynamic Simulations Reveal the Molecular Basis of Conformational Changes in DNA Methyltransferase-1.

DNA methyltransferase-1 (DNMT1) plays a crucial role in the maintenance of genomic methylation patterns. The crystal structure of DNMT1 was determined in two different states in which the helix that follows the catalytic loop was either kinked (designated helix-kinked) or well folded (designated helix-straight state). Here, we show that the proper structural transition between these two states is required for DNMT1 activity. The mutations of N1248A and R1279D, which did not affect interactions between DNMT1 and substrates or cofactors, allosterically reduced enzymatic activities in vitro by decreasing kcat/ Km for AdoMet. The crystallographic data combined with molecular dynamic (MD) simulations indicated that the N1248A and R1279D mutants bias the catalytic helix to either the kinked or straight conformation. In addition, genetic complementation assays for the two mutants suggested that disturbing the conformational transition reduced DNMT1 activity in cells, which could act additively with existing DNMT inhibitors to decrease DNA methylation. Collectively, our studies provide molecular insights into conformational changes of the catalytic helix, which is essential for DNMT1 catalytic activity, and thus aid in better understanding the relationship between DNMT1 dynamic switching and enzymatic activity.

Discovery of Novel Disruptor of Silencing Telomeric 1-Like (DOT1L) Inhibitors using a Target-Specific Scoring Function for the (S)-Adenosyl-l-methionine (SAM)-Dependent Methyltransferase Family.

The disruptor of telomeric silencing 1-like (DOT1L) protein is a histone H3K79 methyltransferase that plays a key role in transcriptional elongation and cell cycle regulation and is required for the development and maintenance of MLL-rearranged mixed lineage leukemia. Much effort has been dedicated toward discovering novel scaffold DOT1L inhibitors using different strategies. Here, we report the development and application of a target-specific scoring function, the SAM score, for (S)-adenosyl-l-methionine (SAM)-dependent methyltransferases, for the discovery of novel DOT1L inhibitors. On the basis of the SAM score, we successfully identified a novel class of DOT1L inhibitors with a scaffold of [1,2,4]-triazolo-[3,4-b][1,3,4]-thiadiazole, in which compound 6 exhibits an IC50 value of 8.3 µM with selectivity versus other tested SAM-dependent methyltransferases. In cellular studies, 6 selectively targets DOT1L, blocks the proliferation of mixed lineage leukemia cell lines, and causes cell cycle arrest and apoptosis. Moreover, we analyzed the putative binding modes of 6 and its analogues obtained by molecular docking, which may assist with the future development of DOT1L inhibitors with improved potency and selectivity profiles.

Discovery and Optimization of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Pharmacophore- and Docking-Based Virtual Screening.

Histone methyltransferases are involved in various biological functions, and these methylation regulating enzymes' abnormal expression or activity has been noted in several human cancers. Within this context, SET domain-containing (lysine methyltransferase) 7 (SET7, also called KMT7, SETD7, SET9) is of increasing significance due to its diverse roles in biological functions and diseases, such as diabetes, cancers, alopecia areata, atherosclerotic vascular disease, HIV, and HCV. In this study, DC-S100, which was discovered by pharmacophore- and docking-based virtual screening, was identified as the hit compound of SET7 inhibitor. Structure-activity relationship (SAR) analysis was performed on analogs of DC-S100 and according to the putative binding mode of DC-S100, structure modifications were made to improve its activity. Of note, compounds DC-S238 and DC-S239, with IC50 values of 4.88 and 4.59 µM, respectively, displayed selectivity for DNMT1, DOT1L, EZH2, NSD1, SETD8, and G9a. Taken together, DC-S238 and DC-S239 can serve as leads for further investigation as SET7 inhibitors and the chemical toolkits for functional biology studies of SET7.

Identifying novel selective non-nucleoside DNA methyltransferase 1 inhibitors through docking-based virtual screening.

The DNA methyltransferases (DNMTs) found in mammals include DNMT1, DNMT3A, and DNMT3B and are attractive targets in cancer chemotherapy. DNMT1 was the first among the DNMTs to be characterized, and it is responsible for maintaining DNA methylation patterns. A number of DNMT inhibitors have been reported, but most of them are nucleoside analogs that can lead to toxic side effects and lack specificity. By combining docking-based virtual screening with biochemical analyses, we identified a novel compound, DC_05. DC_05 is a non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity toward other AdoMet-dependent protein methyltransferases. Through a process of similarity-based analog searching, compounds DC_501 and DC_517 were found to be more potent than DC_05. These three potent compounds significantly inhibited cancer cell proliferation. The structure-activity relationship (SAR) and binding modes of these inhibitors were also analyzed to assist in the future development of more potent and more specific DNMT1 inhibitors.