Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring.

Gestational diabetes mellitus (GDM) is a pregnancy-related complication characterized by abnormal glucose metabolism in pregnant women and has an important impact on fetal development. As a bridge between the mother and the fetus, the placenta has nutrient transport functions, endocrine functions, etc., and can regulate placental nutrient transport and fetal growth and development according to maternal metabolic status. Only by means of placental transmission can changes in maternal hyperglycemia affect the fetus. There are many reports on the placental pathophysiological changes associated with GDM, the impacts of GDM on the growth and development of offspring, and the prevalence of GDM in offspring after birth. Placental epigenetic changes in GDM are involved in the programming of fetal development and are involved in the pathogenesis of later chronic diseases. This paper summarizes the effects of changes in placental nutrient transport function and hormone secretion levels due to maternal hyperglycemia and hyperinsulinemia on the development of offspring as well as the participation of changes in placental epigenetic modifications due to maternal hyperglycemia in intrauterine fetal programming to promote a comprehensive understanding of the impacts of placental epigenetic modifications on the development of offspring from patients with GDM.

Discovery of novel pyrrolo[2,3-d]pyrimidines as potent menin-mixed lineage leukemia interaction inhibitors.

To interfere the Menin-MLL interaction using small molecular inhibitors has been shown as new treatment of several special hematological malignancies. Herein, a series of Menin-MLL interaction inhibitors with pyrrolo[2,3-d]pyrimidine scaffold were designed, synthesized and evaluated. Among them, compound A6 exhibited potent binding affinity with an IC50 value of 0.38 µM, and strong anti-proliferative activity against MV4-11 cells with an IC50 value of 1.07 µM. Further study showed A6 reduced the transcriptional levels of HOXA9 and MEIS1 genes. Moreover, A6 induced cellular apoptosis, arrested the cell cycle in G0/G1 phase, and reversed the differentiation arrest in a concentration-dependent manner. This study suggested compound A6 was as a novel potent Menin-MLL interaction inhibitor, and it proved that introduction of 4-amino pyrrolo[2,3-d]pyrimidine to occupy the P10 hydrophobic pocket was new idea for design of novel Menin-MLL interaction inhibitors.

Anticancer effect of covalent purine-containing EGFR TKI, ZZC4 and its mechanism of action through network pharmacology.

AIMS: Epidermal growth factor receptor (EGFR) has been documented in many malignancies as participating in the progression of cancer cells. Here, we present a novel EGFR tyrosine kinase inhibitor, ZZC4, and examine its effect on cancer cell proliferation, migration, and tumor-bearing xenograft models. MAIN METHODS: The antiproliferative effect of ZZC4 was assessed in vitro by MTT assay, colony formation, and wound healing assay and in vivo with tumor-bearing xenograft nude mice. Further, Western blotting analysis and computational network pharmacology were used to explore and understand the mechanism of ZZC4. KEY FINDINGS: The results showed that ZZC4 potently inhibited the proliferation of lung, breast, and melanoma cells, and was more sensitive to lung cancer cells HCC827, H1975, and breast cancer cell T47D. In vitro findings were corroborated in vivo as results showed the suppressive effect of ZZC4 on HCC827 and H1975 tumor growth. Western blotting analysis confirmed that ZZC4 is an effective inhibitor of the EGFR pathways as it down-regulated p-EGFR, p-Akt, and p-MAPK. Computational molecular docking confirmed the strong binding affinity between ZZC4 and EGFR. Moreover, network pharmacology suggested that ZZC4 might play a suppressive role in the progression of malignancies with EGFR/PI-3K/Akt axis dysregulation or in cancer-related drug resistance. SIGNIFICANCE: Our study showed that ZZC4 is an anticancer drug candidate.

Modification of osimertinib to discover new potent EGFRC797S-TK inhibitors.

The EGFRC797S mutation is a dominant mechanism of acquired resistance after the treatment of non-small cell lung cancer (NSCLC) with osimertinib in clinic. To date, there is no inhibitor approved to overcome the resistance caused by osimertinib. In this study, a series of compounds with phenylamino-pyrimidine scaffold deriving from osimertinib were designed, synthesized and evaluated as fourth-generation EGFRC797S-TK inhibitors. Consequently, compound Os30 exhibited potent inhibitory activities against both EGFRDel19/T790M/C797S TK and EGFRL858R/T790M/C797S TK with IC50 values of 18 nM and 113 nM, respectively. Moreover, Os30 can powerfully inhibit the proliferation of KC-0116 (BaF3-EGFRDel19/T790M/C797S) and KC-0122 (BaF3-EGFRL858R/T790M/C797S) cells. In addition, Os30 can suppress EGFR phosphorylation in a concentration-dependent manner in KC-0116 cells, arrest KC-0116 cells at G1 phase and induce the apoptosis of KC-0116 cells. More importantly, Os30 showed potent antitumor efficacy in the KC-0116 cells xenograft nude mice tumor model with the tumor growth inhibitory rate of 77.6% at a dosage of 40 mg/kg. These findings demonstrate that modification of osimertinib can discover new potent EGFRC797S-TK inhibitors, and compound Os30 is a potent fourth-generation EGFR inhibitor to treat NSCLC with EGFmRC797S mutation.

Design, synthesis and bioactivity evaluation of selenium-containing PI3Kδ inhibitors.

PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC50 value of 0.16 µM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.

Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors.

The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 µM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

Design, synthesis and biological evaluation of novel selective PI3Kδ inhibitors containing pyridopyrimidine scaffold.

Aim: In our study compounds with pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. Methods: The biological activity of compounds was evaluated by ADP-Glo Luminescence assay, MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide] assay, western blotting and flow cytometry, respectively. Results: Compounds A1, A5 and A7 containing pyrido[3,2-d]pyrimidine inhibited phosphoinositide 3-kinase-δ (PI3Kδ) at subnanomolar levels and had good δ-isoform selectivity. A1, A5 and A7 showed significant inhibitory effects against SU-DHL-6 cells and effectively inhibited Akt phosphorylation in a good concentration-dependent manner. A7 induced apoptosis and caused cell cycle arrest in SU-DHL-6 cells. Docking studies showed that A1, A5 and A7 bound tightly to PI3Kδ through key hydrogen bonding interactions. Conclusion: This study suggests that employing pyrido[3,2-d]pyrimidine can facilitate the design of novel potent and selective PI3Kδ inhibitors.

Design, synthesis and evaluation of new pyrimidine derivatives as EGFRC797S tyrosine kinase inhibitors.

The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFRC797S mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFRC797S-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFRdel19/T790M/C797S) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFRdel19/T790M/C797S. Based on these results, A5 turned out to be effective reversible EGFRC797S-TKIs which can be further developed.

Discovery of potent and selective PI3Kδ inhibitors bearing amino acid fragments.

The selective inhibition of PI3Kδ is a potential therapeutic strategy for the treatment of hematologic malignancies. Herein, we report a series of compounds bearing amino acid fragments as potent and selective PI3Kδ inhibitors. Among them, compound A10 exhibited sub-nanomolar PI3Kδ potency. In cellular assays, A10 achieved strong antiproliferation against SU-DHL-6 cells, and caused cell cycle arrest, and induced apoptosis in SU-DHL-6 cells. The docking study showed that A10 tightly bound to PI3Kδ protein with a planar-shaped conformation. Collectively, compound A10 represented a promising potent and selective PI3Kδ inhibitor bearing amino acid fragement albeit with moderate selectivity over PI3Kγ but superior selectivity against PI3Kα and ß. This study suggested that using the amino acid fragments instead of the pyrrolidine ring is new strategy for design of potent PI3Kδ inhibitors.

Dynamic Evolving Exothermicity Steers Ultrafast Formation of a Correlated Triplet Pair State.

Singlet fission (SF) presents an attractive solution to overcome the Shockley-Queisser limit of single-junction solar cells. The conversion from an initial singlet state to final triplet is mediated by the correlated triplet pair state 1(T1T1). Despite significant advancement on 1(T1T1) properties and its role in SF, a comprehensive understanding of the energetic landscape during SF is still unclear. Here, we study an unconventional SF system with excited-state aromaticity, i.e., cyano-substituted dipyrrolonaphtheridinedione derivative (DPND-CN), using time-resolved spectroscopy as a function of the temperature. We demonstrate that the population transfer from S1 to 1(T1T1) is driven by a time-dependent exothermicity resulting from the coherent coupling between electronic and spin degrees of freedom. This is followed by thermal-activated dissociation of 1(T1T1) to yield free triplets. Our results provide some new insight into the SF mechanism, which may guide the development of new efficient and stable SF materials for practical applications.

Progress of small molecules for targeted protein degradation: PROTACs and other technologies.

Recent years have witnessed the rapid development of targeted protein degradation (TPD), especially proteolysis targeting chimeras. These degraders have manifested many advantages over small molecule inhibitors. To date, a huge number of degraders have been excavated against over 70 disease-related targets. In particular, degraders against estrogen receptor and androgen receptor have crowded into phase II clinical trial. TPD technologies largely expand the scope of druggable targets, and provide powerful tools for addressing intractable problems that can not be tackled by traditional small molecule inhibitors. In this review, we mainly focus on the structures and biological activities of small molecule degraders as well as the elucidation of mechanisms of emerging TPD technologies. We also propose the challenges that exist in the TPD field at present.

Triple-Helical Self-Assembly of Atomically Precise Nanoclusters.

The construction of helical nanosized superstructures has long been a challenging pursuit, and little has been achieved in terms of atomic-level manipulation. Herein, intercluster hierarchical triple-helical structures were presented from all-thiol-stabilized Au6Cu6(4-MeOBT)12 nanoclusters by investigating their structures from both molecular and supramolecular aspects. Based on the atomically precise structure, the mechanism of intercluster assembly was elucidated, and the results indicated an intracluster rotation-induced self-assembly process. Specifically, the presence of abundant intermolecular interactions, including π-π stacking, C-H···O hydrogen bonding, and C-H···π interactions, was found to be beneficial for the organization of the triple-helical superstructure of metal clusters. Moreover, DFT calculations and UV-vis, Raman, and transient absorption measurements were performed to observe the different electronic structures between the nanocluster monomers and helical aggregates. Overall, this work presents an exciting example of the hierarchical triple-helical assembly of atomically precise nanoclusters, which allows an in-depth understanding of complex helical structures/behaviors at the atomic level.

Design, synthesis, and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors.

MicroRNA-21 (miRNA-21) is highly expressed in various tumors. Small-molecule inhibition of miRNA-21 is considered to be an attractive novel cancer therapeutic strategy. In this study, fluoroquinolone derivatives A1-A43 were synthesized and used as miRNA-21 inhibitors. Compound A36 showed the most potent inhibitory activity and specificity for miRNA-21 in a dual-luciferase reporter assay in HeLa cells. Compound A36 significantly reduced the expression of mature miRNA-21 and increased the protein expression of miRNA-21 target genes, including programmed cell death protein 4 (PDCD4) and phosphatase and tensin homology deleted on chromosome ten (PTEN), at 10 µM in HeLa cells. The Cell Counting Kit-8 assay (CCK-8) was used to evaluate the antiproliferative activity of A36; the results showed that the IC50 value range of A36 against six tumor cell lines was between 1.76 and 13.0 µM. Meanwhile, A36 did not display cytotoxicity in BEAS-2B cells (lung epithelial cells from a healthy human donor). Furthermore, A36 significantly induced apoptosis, arrested cells at the G0/G1 phase, and inhibited cell-colony formation in HeLa cells. In addition, mRNA deep sequencing showed that treatment with A36 could generate 171 dysregulated mRNAs in HeLa cells, while the expression of miRNA-21 target gene dual-specificity phosphatase 5 (DUSP5) was significantly upregulated at both the mRNA and protein levels. Collectively, these findings demonstrated that A36 is a novel miRNA-21 inhibitor.

Discovery of Novel, Potent, and Selective Small-Molecule Menin-Mixed Lineage Leukemia Interaction Inhibitors through Attempting Introduction of Hydrophilic Groups.

Introduction of the N,N-dimethylaminoethoxy group to pyrido[3,2-d]pyrimidine led to the discovery of menin-mixed lineage leukemia (MLL) interaction inhibitor C20. C20 showed strong binding affinity to menin protein and achieved sub-micromolar potency in cell growth inhibition. C20 had good selectivity for the inhibition of the interaction between menin and MLL in the kinase profile evaluation. Pharmacokinetic studies demonstrated that C20 possessed good stability and low clearance rate in liver microsomes and acceptable bioavailability in rats. Subsequent oral administration of C20 showed potent antitumor activity in the MV4;11 subcutaneous xenograft models of MLL-rearranged leukemia. The docking study showed that C20 bound highly with menin, and the N,N-dimethylaminoethoxy group occupied the F9 pocket of menin. This study proved that introducing a hydrophilic group into the F9 pocket of menin would be a new strategy for the design of menin-MLL interaction inhibitors with potent binding affinity and improved physical properties.

Allyl phenyl selenides as H2O2 acceptors to develop ROS-responsive theranostic prodrugs.

Reactive oxygen species (ROS)-responsive prodrugs have received significant attention due to their capacity to target tumors to relieve the side effects caused by chemotherapy. Herein, a series of novel H2O2-activated theranostic prodrugs (CPTSe1-CPTSe7) were developed containing allyl phenyl selenide moieties as H2O2 acceptors. Compared with conventional boronate ester-based prodrug CPT-B, CPTSe1 was more stable in human plasma and showed a more complete release of camptothecin (CPT) in H2O2 inducing experiment. The selectively activated fluorescence signals of CPTSe1 in tumor cells make it useful for real-time monitoring of CPT release and H2O2 detection. Furthermore, excellent selectivity of CPTSe1 was achieved for tumor cells over normal cells. Our results provide a new platform for the development of H2O2-responsive theranostic prodrugs.

Flavanthrene derivatives as photostable and efficient singlet exciton fission materials.

Singlet exciton fission (SF) is believed to have the potential to break the Shockley-Queisser limit for third-generation solar cell devices, so it has attracted great attention. Conventional linear acene based SF materials generally suffer from low triplet energy and poor photostability. We report herein two flavanthrene derivatives, EH-Fla and TIPS-Fla, as new photostable singlet exciton fission materials. These N-doped two-dimensional angular fused acenes have three sets of aromatic Clar sextets, making them significantly more stable than linear acenes with only one sextet. Time-resolved spectroscopy characterization reveals that the SF process occurs in the polycrystalline films of EH-Fla and TIPS-Fla, with maximal triplet yields of 32% and 159%, respectively. The SF processes of these two molecules are mediated by excimer states. In EH-Fla, the low-lying excimer prevents the SF process from occurring effectively, resulting in a low triplet yield. In contrast, the excimer state in TIPS-Fla is mixed with strong CT coupling, which prompts efficient SF and results in a high triplet yield. Our results show that flavanthrene is a promising SF chromophore for photoenergy conversion applications, while a fine-tune of the intermolecular interaction is crucial for achieving high SF efficiency.

Metal-free photo-induced sulfidation of aryl iodide and other chalcogenation.

A photo-induced C-S radical cross-coupling of aryl iodides and disulfides under transition-metal and external photosensitizer free conditions for the synthesis of aryl sulfides at room temperature has been presented, which features mild reaction conditions, broad substrate scope, high efficiency, and good functional group compatibility. The developed methodology could be readily applied to forge C-S bond in the field of pharmaceutical and material science.

Novel compound ZCJ14, a gefitinib analog, exhibited prominent anti-cancer effect among several cancer cell lines.

AIM: ZCJ14, a gefitinib analog, exhibited prominent anti-cancer effect both in vitro and in vivo. The present study aims to investigate the inhibitory effects of ZCJ14 on human cancer cells, and explored its possible mechanism of action. MAIN METHODS: The inhibitory effect of ZCJ14 on human-derived tumor cells in vitro was mainly measured by MTT and colony formation assays. The nude mouse xenograft models were established to figure out the inhibitory effect of ZCJ14 on solid tumors in vivo. Western blotting assays were used to detect the phosphorylation level of EGFR down-streaming proteins and the proteomic technique was used to study the proteome alterations of cancer cells triggered by ZCJ14. KEY FINDINGS: ZCJ14 inhibited the proliferation of A549 (lung cancer), HCT116 (colorectal cancer) and MCF-7 (breast cancer) cells in vitro with 48 h IC50 values of 0.83, 0.85 and 0.92 µM, respectively. It suppressed the growth of A549, NCI-H1975, NCI-H1299 and MCF-7, HCT116 tumors in mouse xenograft models, and had almost no toxicity. At the same dose, the inhibitory effect of ZCJ14 on solid tumors was better than the corresponding positive drugs. ZCJ14 does not exert anti-tumor effects through inhibition of EGFR pathway, but by enhancing steroid biosynthesis and inhibiting ubiquitin-mediated proteolysis. SIGNIFICANCE: Based on the excellent anti-tumor effect of ZCJ14 on human tumor cell lines, it can be used as an effective anti-tumor drug candidate. In addition, the results of proteomic study in this paper can provide clues for further study of the anti-tumor mechanism of ZCJ14.

Overcoming C797S mutation: The challenges and prospects of the fourth-generation EGFR-TKIs.

The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have accomplished impressive clinical achievements in the treatment of non-small-cell lung cancer (NSCLC). Nonetheless, the acquired drug resistance largely limits their clinical use. The tertiary C797S mutation in the kinase domain of EGFR is one of the major mechanisms responsible for the drug resistance. Therefore, much attention has been focused on the development of the fourth-generation EGFR-TKIs to target triple mutant epidermal growth factor receptor (EGFR) with C797S mutation. In this review, we outline the panorama of the fourth-generation EGFR-TKIs reported up to now with the attention paid on the design strategy, binding mode and antitumor activity of these EGFR-TKIs. We also discuss the challenges and prospects of the fourth-generation EGFR-TKIs.

Identification of benzamides derivatives of norfloxacin as promising microRNA-21 inhibitors via repressing its transcription.

MicroRNA-21 is a carcinogenic microRNA, whose overexpression arises in a variety of tumor tissues. Hence, microRNA-21 a prospective target for cancer treatment, and regulation of microRNA-21 by small molecule inhibitors is deemed as a promising approach for tumor therapy. In this work, to discover potent microRNA-21 inhibitor, series of 4-(N-norfloxacin-acyl)aminobenzamides were designed and synthesized, and their inhibitory effects were appraised by utilizing dual luciferase reporter assays. The results indicated that compound A7 was the most efficient microRNA-21 small molecule inhibitor. What's more, A7 suppressed the migration of Hela cells and the colony formation of Hela and HCT-116 cells as well as promoted apoptosis of Hela cells. In the mechanism study, results of RT-qPCR certified that A7 could reduce the level of mature microRNA-21 via disrupting its expression at the transcriptional level of its primary form "pri-miR-21", which was distinct from most previous inhibitors directly binding with pre-miR-21. Noticeably, Western blotting and RT-qPCR uncovered A7 could upregulate the expression PTEN, EGR1 and SLIT2, which are the downstream functional targets of microRNA-21. These findings demonstrated that A7 was a promising microRNA-21 small molecule inhibitor and 4-(N-norfloxacin-acyl) aminobenzamide can serve as a new scaffold for discovery of potent microRNA-21 inhibitor.