Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds

Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by the known multicyclic ligands, UNC669 and UNC926, which are the first reported small molecule ligands for a methyl-lysine binding domain. We hypothesized that reducing the conformational flexibility of the key amine moiety of UNC669 would result in a unique set of ligands. Twenty-five novel compounds containing a fused bi- or tricyclic amine or a spirocyclic amine were designed and synthesized. To gauge the potential of these amine-containing compounds to interact with Kme regulatory proteins, the compounds were screened against a panel of 24 protein methyltransferases. Compound 13 was discovered as a novel scaffold that interacts with SETD8 and could serve as a starting point for the future development of PKMT inhibitors

The Study of Photophysical Properties of Organic Lanthanide Hybrid Materials and Their Applications

University of Technology Sydney. Faculty of Science.Significant progress has been made in recent years to produce a new generation of dye-lanthanide hybrid materials with physicochemical properties for various applications. The lanthanide complexes, where organic ligands are engineered to chelate individual lanthanide ions, are broadly used in analytical, biological, and clinical applications. However, the visible emission suffers from low penetration depth in biological tissues, the synthesis of hetero-dinuclear complexes remains challenging because lanthanide ions are chemically similar, and there is a lack of systems for comprehensive study of ligand-lanthanide energy transfer. To this end, the primary focus of my thesis is to develop near-infrared probes, hetero-dinuclear compounds and energy transfer platforms based on lanthanide complexes for energy transfer study and sensing applications (Chapter 2, 3, & 4). In Chapter 2, I design and synthesize an ytterbium complex-based sensor for the detection of Hg²⁺ ions. In Chapter 3, I report a pair of stoichiometric terbium-europium complexes as molecular thermometers and study their energy transfer properties. In Chapter 4, I investigate the spectral structure and intensity changes of a pair of dinuclear complexes. Learning from lanthanide complexes, considerable progress has recently been made to exploit the hybrid structure of lanthanide-doped inorganic nanoparticles “coated” with organic dyes. This has resulted in hybrid materials that have many benefits, for example, large absorption cross-section, easy modification, tuneable spectral bands, long lifetimes, and large (anti)-Stokes shift. To improve the performance of upconversion process, near-infrared dyes with high quantum yields are required for efficient sensitisation of lanthanide nanoparticles, and diverse energy transfer systems are required for brighter upconversion emissions. Therefore, the parallel program of my thesis is to develop brighter dye-lanthanide nanoparticle upconversion systems, including dye-sensitised upconversion nanoparticles (Chapter 5) and ytterbium-mediated upconversion system (Chapter 6). In Chapter 5, I exploit a dye sensitised upconversion nanoparticle with highly enhanced upconversion emission by developing a NIR dye (TPEO-IR783) with a quantum yield of 22.46% which is 3 times higher than that of reported UCNP sensitiser, IR806. In Chapter 6, I develop an ytterbium nanoparticle-mediated upconversion system and the design bypasses the specific requirement of traditional sensitisers in TTA system, providing a wide range of opportunities for deep light penetration applications. Overall, this thesis has eight chapters, including the introduction of dye-lanthanide hybrid materials (Chapter 1), three lanthanide complex-based projects (Chapter 2, 3, & 4), two dye-lanthanide nanoparticle-based projects (Chapter 5 & 6), experimental details (Chapter 7) and conclusions and perspectives (Chapter 8)

Synthesis of Highly Substituted 4<i>H</i>‑Pyrido[1,2‑<i>a</i>]pyrimidines via a One-Pot Three-Component Condensation Reaction

A one-pot three-component reaction, involving condensation of 2-aminopyridines, aldehydes, and ketones/aldehydes under trifluoromethanesulfonic acid catalysis, provides rapid access to highly substituted novel 4<i>H</i>-pyrido­[1,2-<i>a</i>]­pyrimidines

Synthesis of Highly Substituted 4<i>H</i>‑Pyrido[1,2‑<i>a</i>]pyrimidines via a One-Pot Three-Component Condensation Reaction

A one-pot three-component reaction, involving condensation of 2-aminopyridines, aldehydes, and ketones/aldehydes under trifluoromethanesulfonic acid catalysis, provides rapid access to highly substituted novel 4<i>H</i>-pyrido­[1,2-<i>a</i>]­pyrimidines

Synthesis and preliminary structure-activity relationship study of 3-methylquinazolinone derivatives as EGFR inhibitors with enhanced antiproliferative activities against tumour cells

In this paper, a set of 3-methylquniazolinone derivatives were designed, synthesised, and studied the preliminary structure-activity relationship for antiproliferative activities. All target compounds performed significantly inhibitory effects against wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and tumour cells (A431, A549, MCF-7, and NCI-H1975). In particular, compound 4d 3-fluoro-N-(4-((3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)phenyl)benzamide showed higher antiproliferative activities against all tumour cells than Gefitinib (IC50 of 3.48, 2.55, 0.87 and 6.42 μM, respectively). Furthermore, compound 4d could induce apoptosis of MCF-7 cells and arrest in G2/M phase at the tested concentration. Molecular docking and ADMET studies showed that compound 4d could closely form many hydrogen bonds with EGFRwt-TK. Therefore, compound 4d is potential to develop as novel anti-cancer drug

Learning from lanthanide complexes: The development of dye-lanthanide nanoparticles and their biomedical applications

Coordination chemistry has been widely studied in lanthanide complexes, where organic ligands are used to chelate individual lanthanide ions, and the complexes are broadly used in analytical, biological, and clinical applications. Significant progress has recently been made to exploit the hybrid structure of lanthanide doped inorganic nanoparticles "coated" with organic dyes. This attributes to the fast developments of nanoscience and technology centred around well-controlled nanocrystal synthesis and engineering, with a variety of shape, size, composition and structures towards the desirable functions. There are a lot of similarities between the two forms of lanthanide materials, waiting for a systematic analysis to guide the emerging field of nanocrystal-dye hybrids. Therefore, we survey here the principles for the design of dye-lanthanide energy transfer systems and analyse the remarkable successes made in hybrid dye-lanthanide nanosystems. (C) 2020 Elsevier B.V. All rights reserved

Smart Drug-Delivery System of Upconversion Nanoparticles Coated with Mesoporous Silica for Controlled Release

Drug-delivery vehicles have garnered immense interest in recent years due to unparalleled progress made in material science and nanomedicine. However, the development of stimuli-responsive devices with controllable drug-release systems (DRSs) is still in its nascent stage. In this paper, we designed a two-way controlled drug-release system that can be promoted and prolonged, using the external stimulation of near-infrared light (NIR) and protein coating. A hierarchical nanostructure was fabricated using upconversion nanoparticles (UCNPs)—mesoporous silica as the core-shell structure with protein lysozyme coating. The mesoporous silica shell provides abundant pores for the loading of drug molecules and a specific type of photosensitive molecules. The morphology and the physical properties of the nanostructures were thoroughly characterized. The results exhibited the uniform core-shell nanostructures of ~four UCNPs encapsulated in one mesoporous silica nanoparticle. The core-shell nanoparticles were in the spherical shape with an average size of 200 nm, average surface area of 446.54 m2/g, and pore size of 4.6 nm. Using doxorubicin (DOX), a chemotherapy agent as the drug model, we demonstrated that a novel DRS with capacity of smart modulation to promote or inhibit the drug release under NIR light and protein coating, respectively. Further, we demonstrated the therapeutic effect of the designed DRSs using breast cancer cells. The reported novel controlled DRS with dual functionality could have a promising potential for chemotherapy treatment of solid cancers

Responsive Regulation of Energy Transfer in Lanthanide‐Doped Nanomaterials Dispersed in Chiral Nematic Structure

Abstract The responsive control of energy transfer (ET) plays a key role in the broad applications of lanthanide‐doped nanomaterials. Photonic crystals (PCs) are excellent materials for ET regulation. Among the numerous materials that can be used to fabricate PCs, chiral nematic liquid crystals are highly attractive due to their good photoelectric responsiveness and biocompatibility. Here, the mechanisms of ET and the photonic effect of chiral nematic structures on ET are introduced; the regulation methods of chiral nematic structures and the resulting changes in ET of lanthanide‐doped nanomaterials are highlighted; and the challenges and promising opportunities for ET in chiral nematic structures are discussed

Wafer-Scale Gold Nanomesh via Nanotransfer Printing toward a Cost-Efficient Multiplex Sensing Platform

Multiplex sensing platforms via large-scale and cost-efficient fabrication processes for detecting biological and chemical substance are essential for many applications such as intelligent diagnosis, environmental monitoring, etc. For the past decades, the performance of those sensors has been significantly improved by the rapid development of nanofabrication technologies. However, facile processes with cost-effectiveness and large-scale throughput still present challenges. Nano-transfer printing together with the imprinting process shows potential for the efficient fabrication of 100 nm structures. Herein, a wafer-scale gold nanomesh (AuNM) structure on glass substrates with 100 nm scale features via nano-imprinting and secondary transfer printing technology is reported. Furthermore, potential sensing applications are demonstrated towards biochemical substance detection by using AuNM structures as highly responsive substrates for achieving the surface enhanced Raman spectroscopy (SERS), and as working electrodes of electrochemical analysisfor the detection of metallic ions. In the SERS detection mode, different nucleotides can be detected down to 1 nm level and distinguished via theirunique fingerprint patterns. As for electrochemical analysis mode, Pb2+ ions can be detected out of other interfering components with concentration down to 30 nm. These multimodal sensing mechanisms provide complementary informationand pave the way for low-cost and high-performance sensing platforms.ISSN:2365-709XISSN:2365-709

Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy

Abstract Background Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity. Methods Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade. Results We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1. Conclusions This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically “hot” and “cold” cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy