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1.
Eur J Med Chem ; 271: 116406, 2024 May 05.
Article En | MEDLINE | ID: mdl-38688064

NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds.


Antineoplastic Agents , Drug Design , G-Quadruplexes , GTP Phosphohydrolases , Membrane Proteins , G-Quadruplexes/drug effects , Humans , Animals , GTP Phosphohydrolases/metabolism , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/metabolism , Membrane Proteins/genetics , Structure-Activity Relationship , Molecular Structure , Melanoma/drug therapy , Melanoma/pathology , Dose-Response Relationship, Drug , Cell Proliferation/drug effects , Indoles/pharmacology , Indoles/chemistry , Indoles/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , RNA/metabolism , RNA/chemistry , Protein Biosynthesis/drug effects , Alkaloids , Quinolines
2.
J Med Chem ; 66(7): 5171-5184, 2023 04 13.
Article En | MEDLINE | ID: mdl-36961300

Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS-mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti-NRAS-mutant melanoma agent and represent a new NRAS-mutant melanoma therapy option.


Melanoma , Skin Neoplasms , Humans , Animals , Mice , Phosphatidylinositol 3-Kinases/metabolism , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Cell Line, Tumor , Melanoma/drug therapy , Melanoma/genetics , Melanoma/metabolism , Mutation , Membrane Proteins/genetics , Membrane Proteins/metabolism
3.
Org Lett ; 25(7): 1099-1103, 2023 Feb 24.
Article En | MEDLINE | ID: mdl-36790117

α-Boryl ketones are traditionally challenging targets in organic synthesis. Reported herein is a mild and metal-free synthesis of α-boryl ketones via the hydration or oxidation of N-methyliminodiacetyl boronate (B(MIDA))-decorated alkynes. A new hydration system comprised of AcCl and H2O in HFIP allows the hydration of arylethynyl B(MIDA)s at room temperature with decent functional group tolerance. An oxidative carbon deletion process of propargylic B(MIDA)s is also developed for the synthesis of aliphatic α-boryl ketones. An intriguing ß-boron effect was observed to account for the unique site- and chemoselectivities. The application of the products in the synthesis of borylated heterocycles was demonstrated.

4.
J Med Chem ; 65(18): 12346-12366, 2022 09 22.
Article En | MEDLINE | ID: mdl-36053318

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.


Antineoplastic Agents , Triple Negative Breast Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Cell Line, Tumor , Cell Proliferation , DNA/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylases/metabolism , Humans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Xenograft Model Antitumor Assays , Zinc/pharmacology
5.
J Med Chem ; 65(19): 12675-12700, 2022 10 13.
Article En | MEDLINE | ID: mdl-36121464

c-MYC is a key driver of tumorigenesis. Repressing the transcription of c-MYC by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed c-MYC G4 ligand 1. Among these compounds, 19a coupled with a d-glucose 1,2-orthoester displayed better c-MYC G4 binding, stabilization, and protein binding disruption abilities than 1. Our further evaluation indicated that 19a blocked c-MYC transcription by targeting the promoter G4, leading to c-MYC-dependent cancer cell death in triple-negative breast cancer cell MDA-MB-231. Also, 19a significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by c-MYC downregulation. Notably, the safety of 19a was dramatically improved compared to 1. Our findings indicated that 19a could become a promising anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.


Antineoplastic Agents , G-Quadruplexes , 14-alpha Demethylase Inhibitors , Animals , Antineoplastic Agents/chemistry , Carbohydrates , Glucose , Humans , Imidazoles , Ligands , Mice , Proto-Oncogene Proteins c-myc/metabolism , Sugars , Sweetening Agents
6.
Molecules ; 27(10)2022 May 16.
Article En | MEDLINE | ID: mdl-35630659

The study on the mechanism and kinetics of mRNA degradation provides a new vision for chemical intervention on protein expression. The AU enrichment element (ARE) in mRNA 3'-UTR can be recognized and bound by the ARE binding protein (AU-rich Element factor (AUF1) to recruit RNase for degradation. In the present study, we proposed a novel strategy for expression regulation that interferes with the AUF1-RNA binding. A small-molecule compound, JNJ-7706621, was found to bind AUF1 protein and inhibit mRNA degradation by screening the commercial compound library. We discovered that JNJ-7706621 could inhibit the expression of AUF1 targeted gene IL8, an essential pro-inflammatory factor, by interfering with the mRNA homeostatic state. These studies provide innovative drug design strategies to regulate mRNA homeostasis.


Heterogeneous-Nuclear Ribonucleoprotein D , 3' Untranslated Regions , Heterogeneous Nuclear Ribonucleoprotein D0 , Heterogeneous-Nuclear Ribonucleoprotein D/genetics , Heterogeneous-Nuclear Ribonucleoprotein D/metabolism , RNA Stability , RNA, Messenger/genetics , RNA, Messenger/metabolism
7.
Eur J Med Chem ; 232: 114200, 2022 Mar 15.
Article En | MEDLINE | ID: mdl-35219149

Since more than 85% of lung cancer cases are non-small cell lung cancer (NSCLC), finding novel agents with anti-tumor activities is meaningful for NSCLC patients. Mitochondria is essential for cellular energy metabolism in cancer, and regulating mitochondrial bioenergetics is emerging as a practical approach for cancer treatment and prevention. The carbazole scaffold is an active structure showing anti-cancer biological activity, and the structural diversity has been expanded through the improvement and optimization of synthesizing methods. To find novel carbazole derivatives with great anti-tumor potential and explore structures variety, we designed and synthesized a series of 9-(pyrimidin-2-yl)-9H-carbazole derivatives based on the previously reported Cp∗Rh(III)/H+ tandem catalytic system. With thoroughly bioactivity exploration, we found benzo[d] [1,3]dioxol-5-yl(9-(pyrimidin-2-yl)-9H-carbazol-1-yl)methanone (compound 5n) showed notable activity in disrupting the mitochondrial homeostasis, induced cell cycle arrest and apoptosis in human adenocarcinoma cells, and finally showed anti-tumor activity in an NSCLC-xenograft mice model.


Adenocarcinoma of Lung , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Carbazoles/chemistry , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Homeostasis , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Mice , Mitochondria/metabolism
8.
Nucleic Acids Res ; 50(4): 1829-1848, 2022 02 28.
Article En | MEDLINE | ID: mdl-35166828

DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand-G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.


Antineoplastic Agents/chemistry , Breast Neoplasms , G-Quadruplexes , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Drug Design , Female , Genes, myc , Humans , Ligands , MCF-7 Cells , Mice , Promoter Regions, Genetic , Telomere
9.
J Med Chem ; 63(17): 9752-9772, 2020 09 10.
Article En | MEDLINE | ID: mdl-32697083

DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure-activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.


DNA Damage , Drug Design , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Quinazolinones/chemical synthesis , Quinazolinones/pharmacology , RecQ Helicases/antagonists & inhibitors , Telomere/genetics , Apoptosis/drug effects , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Drug Synergism , HCT116 Cells , Humans , Models, Molecular , Protein Conformation , Quinazolinones/chemistry , RecQ Helicases/chemistry , Structure-Activity Relationship
10.
Eur J Med Chem ; 192: 112172, 2020 Apr 15.
Article En | MEDLINE | ID: mdl-32163815

Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novel ß-indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound 23 (named as IQZ23) was selected for further studies. IQZ23 exerted a high efficacy in decreasing the triglyceride level (EC50 = 0.033 µM) in 3T3-L1 adipocytes. Mechanistic studies revealed the lipid-lowering activity of IQZ23 was dependent on the AMPK pathway by modulating ATP synthase activity. This activation was accompanied by mitochondrial biogenesis and oxidation capacity increased, and insulin sensitivity enhanced in pertinent cell models by various interventions. Correspondingly, IQZ23 (20 mg/kg, i.p.) treatment significantly reversed high fat and cholesterol diet (HFC)- induced body weight increases and accompanying clinical symptoms of obesity in mice but without indicative toxicity. These results indicate that IQZ23 could be a useful candidate for the treatment of obesity and related metabolic disorders.


Anti-Obesity Agents/pharmacology , Drug Discovery , Metabolic Diseases/drug therapy , Obesity/drug therapy , 3T3-L1 Cells , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/chemistry , Cell Differentiation/drug effects , Cells, Cultured , Cholesterol , Diet, High-Fat , Dose-Response Relationship, Drug , Male , Metabolic Diseases/chemically induced , Metabolic Diseases/metabolism , Mice , Mice, Inbred C57BL , Molecular Structure , Obesity/chemically induced , Obesity/metabolism , Structure-Activity Relationship
11.
Methods ; 167: 124-133, 2019 09 01.
Article En | MEDLINE | ID: mdl-31185274

Protein synthesis is critical to cell survival and translation regulation is essential to post-transcriptional gene expression regulation. Disorders of this process, particularly through RNA-binding proteins, is associated with the development and progression of a number of diseases, including cancers. However, the molecular mechanisms underlying the initiation of protein synthesis are intricate, making it difficult to find a drug that interferes with this process. Chemical probes are useful in elucidating the structures of RNA-protein complex and molecular mechanism of biological events. Moreover, some of these chemical probes show certain therapeutic benefits and can be further developed as leading compounds. Here, we will briefly review the general process and mechanism of protein synthesis, and emphasis on chemical probes in examples of probing the RNA structural changes and RNA-protein interactions. Moreover, the therapeutic potential of these probes is also discussed to give a comprehensive understanding.


Molecular Biology/methods , Protein Biosynthesis/drug effects , RNA/isolation & purification , Small Molecule Libraries/chemistry , Gene Expression Regulation/drug effects , Humans , Nucleic Acid Conformation/drug effects , Protein Biosynthesis/genetics , RNA/chemistry , RNA/drug effects , RNA-Binding Proteins/drug effects , RNA-Binding Proteins/genetics , Small Molecule Libraries/pharmacology
12.
Expert Opin Ther Pat ; 29(5): 353-367, 2019 05.
Article En | MEDLINE | ID: mdl-31068032

INTRODUCTION: The important role of MYC in tumorigenesis makes it particularly important to design MYC modulators. Over the past decade, researchers have raised a number of strategies for designing MYC modulators, some of which are already in clinical trials. This paper aims to review the patents of MYC modulators. AREAS COVERED: The important biological relevance of c-MYC and the regulation pathways related to c-MYC are briefly introduced. Base on that, the MYC modulators reported in published patents and references primarily for cancer treatment are outlined, highlighting the structures and biological activities. EXPERT OPINION: There has been a growing awareness of finding and designing MYC modulators as novel anticancer drugs over recent years. Patents involving the discovery, synthesis, and application of MYC modulators are particularly important for further development in this field. Although finding direct MYC inhibitors or binders is challenging, MYC cannot be simply defined as an undruggable target. There is still substantial evidence proving the concept that MYC modulators can benefit to the treatment of both human hematological malignancies and solid tumors. More efforts should be taken to improve the activity and specificity of MYC modulators.


Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Animals , Drug Design , Drug Development/methods , Humans , Molecular Targeted Therapy , Neoplasms/pathology , Patents as Topic , Proto-Oncogene Proteins c-myc/metabolism
13.
J Med Chem ; 62(6): 3147-3162, 2019 03 28.
Article En | MEDLINE | ID: mdl-30827110

Homologous recombination repair (HRR), a crucial approach in DNA damage repair, is an attractive target in cancer therapy and drug design. The Bloom syndrome protein (BLM) is a 3'-5' DNA helicase that performs an important role in HRR regulation. However, limited studies about BLM inhibitors and their biological effects have been reported. Here, we identified a class of isaindigotone derivatives as novel BLM inhibitors by synthesis, screening, and evaluating. Among them, compound 29 was found as an effective BLM inhibitor with a high binding affinity and good inhibitory effect on BLM. Cellular evaluation indicated that 29 effectively disrupted the recruitment of BLM at DNA double-strand break sites, promoted an accumulation of RAD51, and regulated the HRR process. Meanwhile, 29 significantly induced DNA damage responses, as well as apoptosis and proliferation arrest in cancer cells. Our finding provides a potential anticancer strategy based on interfering with BLM via small molecules.


Alkaloids/pharmacology , DNA/metabolism , Drug Discovery , Enzyme Inhibitors/pharmacology , Quinazolines/pharmacology , RecQ Helicases/antagonists & inhibitors , Recombinational DNA Repair , Alkaloids/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , DNA Breaks, Double-Stranded/drug effects , Enzyme Inhibitors/chemistry , HCT116 Cells , Humans , Quinazolines/chemistry , Rad51 Recombinase/metabolism , RecQ Helicases/metabolism
14.
Molecules ; 24(3)2019 Jan 22.
Article En | MEDLINE | ID: mdl-30678288

G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.


Drug Development , G-Quadruplexes , Ligands , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Humans , Models, Molecular , Nucleic Acids/chemistry , Nucleic Acids/metabolism , Protein Binding , Structure-Activity Relationship
15.
J Med Chem ; 61(15): 6629-6646, 2018 Aug 09.
Article En | MEDLINE | ID: mdl-29799749

The human proto-oncogene neuroblastoma RAS ( NRAS) contains a guanine-rich sequence in the 5'-untranslated regions (5'-UTR) of the mRNA that could form an RNA G-quadruplex structure. This structure acts as a repressor for NRAS translation and could be a potential target for anticancer drugs. Our previous studies found an effective scaffold, the quindoline scaffold, for binding and stabilizing the DNA G-quadruplex structures. Here, on the basis of the previous studies and reported RNA-specific probes, a series of novel p-(methylthio)styryl substituted quindoline (MSQ) derivatives were designed, synthesized, and evaluated as NRAS RNA G-quadruplex ligands. Panels of experiments turned out that the introduction of p-(methylthio)styryl side chain could enhance the specific binding to the NRAS RNA G-quadruplex. One of the hits, 4a-10, showed strong stabilizing activity on the G-quadruplex and subsequently repressed NRAS's translation and inhibited tumor cells proliferation. Our finding provided a novel strategy to discover novel NRAS repressors by specifically binding to the RNA G-quadruplex in the 5'-UTR of mRNA.


Alkaloids/chemical synthesis , Alkaloids/pharmacology , Drug Design , G-Quadruplexes/drug effects , GTP Phosphohydrolases/genetics , Indoles/chemical synthesis , Indoles/pharmacology , Membrane Proteins/genetics , Quinolines/chemical synthesis , Quinolines/pharmacology , RNA/chemistry , Styrene/chemistry , Alkaloids/chemistry , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Chemistry Techniques, Synthetic , Humans , Indoles/chemistry , Proto-Oncogene Mas , Quinolines/chemistry
16.
J Med Chem ; 61(8): 3436-3453, 2018 04 26.
Article En | MEDLINE | ID: mdl-29618208

Telomeric G-quadruplex targeting and telomere maintenance interference are emerging as attractive strategies for anticancer therapies. Here, a novel molecular scaffold is explored for telomeric G-quadruplex targeting. A series of novel schizocommunin derivatives was designed and synthesized as potential telomeric G-quadruplex ligands. The interaction of telomeric G-quadruplex DNA with the derivatives was explored by biophysical assay. The cytotoxicity of the derivatives toward cancer cell lines was evaluated by the methyl thiazolyl tetrazolium (MTT) assay. Among the derivatives, compound 16 showed great stabilization ability toward telomeric G-quadruplex DNA and good cytotoxicity toward cancer cell lines. Further cellular experiments indicated that 16 could induce the formation of telomeric G-quadruplex in cells, triggering a DNA damage response at the telomere and causing telomere dysfunction. These effects ultimately provoked p53-mediated cell cycle arrest and apoptosis, and suppressed tumor growth in a mouse xenograft model. Our work provides a novel scaffold for the development of telomeric G-quadruplex ligands.


Antineoplastic Agents/pharmacology , DNA Damage , DNA/genetics , Indoles/pharmacology , Telomere/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Discovery , Female , G-Quadruplexes , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Indoles/chemical synthesis , Indoles/therapeutic use , Ligands , Mice, Inbred BALB C , Telomerase/antagonists & inhibitors , Telomere/genetics , Telomere Shortening , Telomere-Binding Proteins/metabolism , Uterine Cervical Neoplasms/drug therapy , Xenograft Model Antitumor Assays
17.
J Med Chem ; 61(6): 2447-2459, 2018 03 22.
Article En | MEDLINE | ID: mdl-29474069

Downregulating transcription of the oncogene c-MYC is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the c-MYC promoter can suppress c-MYC transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the c-MYC G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called IZCZ-3 was found to preferentially bind and stabilize the c-MYC G-quadruplex. Further intracellular studies indicated that IZCZ-3 provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking c-MYC transcription through specific targeting of the promoter G-quadruplex structure. Notably, IZCZ-3 effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent.


Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , G-Quadruplexes , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Proto-Oncogene Proteins c-myc/biosynthesis , Animals , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Carcinoma, Squamous Cell/drug therapy , Cell Cycle Checkpoints/drug effects , Cell Division/drug effects , Cell Line, Tumor , Drug Discovery , Drug Screening Assays, Antitumor , Female , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Ligands , Mice , Mice, Inbred BALB C , Models, Molecular , Promoter Regions, Genetic/drug effects , Proto-Oncogene Proteins c-myc/genetics , Tumor Stem Cell Assay , Uterine Cervical Neoplasms/drug therapy , Xenograft Model Antitumor Assays
18.
Chem Commun (Camb) ; 54(16): 2036-2039, 2018 Feb 20.
Article En | MEDLINE | ID: mdl-29411851
19.
Angew Chem Int Ed Engl ; 57(17): 4702-4706, 2018 04 16.
Article En | MEDLINE | ID: mdl-29453903

Because of the absence of methods for tracking RNA G-quadruplex dynamics, especially the folding and unfolding of this attractive structure in live cells, understanding of the biological roles of RNA G-quadruplexes is so far limited. Herein, we report a new red-emitting fluorescent probe, QUMA-1, for the selective, continuous, and real-time visualization of RNA G-quadruplexes in live cells. The applications of QUMA-1 in several previously intractable applications, including live-cell imaging of the dynamic folding, unfolding, and movement of RNA G-quadruplexes and the visualization of the unwinding of RNA G-quadruplexes by RNA helicase have been demonstrated. Notably, our real-time results revealed the complexity of the dynamics of RNA G-quadruplexes in live cells. We anticipate that the further application of QUMA-1 in combination with appropriate biological and imaging methods to explore the dynamics of RNA G-quadruplexes will uncover more information about the biological roles of RNA G-quadruplexes.


G-Quadruplexes , RNA Folding , RNA/analysis , RNA/chemistry , Cell Survival , Fluorescent Dyes/chemistry , HeLa Cells , Humans , Optical Imaging
20.
Biochim Biophys Acta Proteins Proteom ; 1865(11 Pt A): 1372-1382, 2017 Nov.
Article En | MEDLINE | ID: mdl-28870734

Telomeric repeat factor 2 (known as TRF2 or TERF2) is a key component of telomere protection protein complex named as Shelterin. TRF2 helps the folding of telomere to form T-loop structure and the suppression of ATM-dependent DNA damage response activation. TRF2 has been recognized as a potentially new therapeutic target for cancer treatment. In our routine screening of small molecule libraries, we found that Curcusone C had significant effect in disrupting the binding between TRF2 and telomeric DNA, with potent antitumor activity against cancer cells. Our result showed that Curcusone C could bind with TRF2 without binding interaction with TRF1 (telomeric repeat factor 1) although these two proteins share high sequence homology, indicating that their binding conformations and biological functions in telomere could be different. Our mechanistic studies showed that Curcusone C bound with TRF2 possibly through its DNA binding site causing blockage of its interaction with telomeric DNA. Further in cellular studies indicated that the interaction of TRF2 with Curcusone C could activate DNA-damage response, inhibit tumor cell proliferation, and cause cell cycle arrest, resulting in tumor cell apoptosis. Our studies showed that Curcusone C could become a promising lead compound for further development for cancer treatment. Here, TRF2 was firstly identified as a target of Curcusone C. It is likely that the anti-cancer activity of some other terpenes and terpenoids are related with their possible effect for telomere protection proteins.


Antineoplastic Agents, Phytogenic/pharmacology , DNA, Neoplasm/genetics , Diterpenes/pharmacology , Gene Expression Regulation, Neoplastic , Telomere/drug effects , Telomeric Repeat Binding Protein 2/genetics , Antineoplastic Agents, Phytogenic/isolation & purification , Binding Sites , Cell Cycle Checkpoints/drug effects , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , DNA, Neoplasm/metabolism , Diterpenes/isolation & purification , Dose-Response Relationship, Drug , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , HeLa Cells , Humans , Organ Specificity , Protein Binding , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Signal Transduction , Telomere/chemistry , Telomeric Repeat Binding Protein 1/genetics , Telomeric Repeat Binding Protein 1/metabolism , Telomeric Repeat Binding Protein 2/antagonists & inhibitors , Telomeric Repeat Binding Protein 2/metabolism
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