Design, Synthesis and Molecular Docking of Novel Quinazolinone Hydrazide Derivatives as EGFR Inhibitors.

A series of novel quinazolinone hydrazide derivatives were designed and synthesized as EGFR inhibitors. The results indicated that most of the aimed compounds had potential anti-tumor cell proliferation and EGFR inhibitory activities. In the comprehensive analysis of all the tested compounds, the target compound 9c showed the best anti-tumor cell proliferation activity, (IC50 =1.31 µM for MCF-7, IC50 =1.89 µM for HepG2, IC50 =2.10 µM for SGC), and IC50 =0.59 µM for the EGFR inhibitory activity. Docking results showed that compound 9c could ideally insert the active site and interact with the critical amino acid residues (Val702, Lys721, Met769, Asp831) in the active site.

Recent Progress in the Development of Small Molecule c-Met Inhibitors.

C-Met, also referred to as Hepatocyte Growth Factor Receptor (HGFR), is a heterodimeric receptor tyrosine kinase. It has been determined that c-Met gene mutations, overexpression, and amplification also occur in a variety of human tumor types, and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway. Meanwhile, high c-Met expression is closely associated with poor prognosis in cancer patients. The c-Met kinase has emerged as an attractive target for developing antitumor agents. In this review, we cover the recent advances on the small molecule c-Met inhibitors discovered from 2018 until now, with a main focus on the rational design, synthesis and structureactivity relationship analysis.

Nanoscale Metal-Organic-Frameworks Coated by Biodegradable Organosilica for pH and Redox Dual Responsive Drug Release and High-Performance Anticancer Therapy.

Responsive nanocarriers with biocompatibility and precise drug releasing capability have emerged as a prospective candidate for anticancer treatment. However, the challenges imposed by the complicated preparation process and limited loading capacities have seriously impeded the development of novel multifunctional drug delivery systems. Here, we developed a novel and dual-responsive nanocarrier based on a nanoscale ZIF-8 core and an organosilica shell containing disulfide bridges in its frameworks through a facile and efficient strategy. The prepared ZIF-8@DOX@organosilica nanoparticles (ZDOS NPs) exhibited a well-defined structure and excellent doxorubicin (DOX) loading capability (41.2%) with pH and redox dual-sensitive release properties. The degradation of the organosilica shell was observed after 12 h incubation with a 10 mM reducing agent. Confocal imaging and flow cytometry analysis further proved that the nanocarriers can efficiently enter cells and complete intracellular DOX release under the low pH and high glutathione concentrations, which resulted in an enhanced cytotoxicity of DOX for cancer cells. Meanwhile, subcellular localization experiments revealed that the ZDOS NPs entered cells mainly by endocytosis and then escaped from lysosomes into the cytosol. Moreover, in vivo assays also demonstrated that the ZDOS NPs exhibited negligible systemic toxicity and significantly enhanced anticancer efficiencies compared with free DOX. In summary, our prepared pH and redox dual-responsive nanocarriers provide a potential platform for controlled release and cancer treatment.

Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents.

In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50 = 6.43-10.97 µM for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50 = 194.01 µM vs.celecoxib: IC50 = 97.87 µM for 293T cells), and excellent inhibitory activities on COX-2 (IC50 = 0.17 µM) and 5-LOX (IC50 = 0.68 µM). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10 cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.

FAK inhibitors in Cancer, a patent review.

INTRODUCTION: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes at sites of cell adhesion to the extracellular matrix (ECM) and mediates signalling events downstream of integrin engagement of the ECM. FAK is known to regulate cell survival, proliferation and migration. AREAS COVERED: FAK expression has also been shown to be up-regulated in many cancer types. Previous study also indicates that FAK-mediated signaling and functions are intrinsically involved in the progression of tumor aggressiveness, suggesting that FAK is a promising target for anticancer therapies. Small molecule FAK inhibitors have been developed and are being tested in clinical phase trials. EXPERT OPINION: These inhibitors have demonstrated to be effective by inducing tumor cell apoptosis in addition to reducing metastasis and angiogenesis. In this review, we give updates on the design, synthesis and structure-activity relationship analysis of small molecule FAK inhibitors discovered from 2015 until now. We also review the FAK inhibitors that are in clinical development and highlight the future prospects.

Synthesis and Biological Evaluation of Glycyrrhetic Acid Derivatives as Potential VEGFR2 Inhibitors.

Vascular endothelial growth factor receptor 2 (VEGFR2) has been proven to play a major role in the regulation of tumor angiogenesis. A series of novel glycyrrhetic acid derivatives were synthesized and evaluated for their VEGFR2 inhibitory activity as well as their antiproliferative properties against four cancer cell lines (MCF-7, HeLa, HepG2, and A549). In vitro biological evaluations against these human tumor cell lines indicate that most of the prepared compounds have antiproliferative activities; compound 3 a (3ß-hydroxy-30-(4-phenyl-1-piperazinyl)olean-12-ene-11,30-dione) exhibited the best inhibitory activity against MCF-7 cells, with an IC50 value of 1.08 µm. Compound 3 a also showed the most potent inhibitory activity against VEGFR2 tyrosine kinase, with an IC50 value of 0.35 µm. Docking simulations were performed with the aim of discovering the binding mode of compound 3 a, and the results indicate that 3 a could bind at the VEGFR2 active site.

Identification of novel 1-indolyl acetate-5-nitroimidazole derivatives of combretastatin A-4 as potential tubulin polymerization inhibitors.

Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a panel of human cancer cells (with IC50 values ranging from 15 to 40nM), especially HeLa cells (with IC50 values of 15nM), based on the cellular cytotoxicity assay results. Moreover, cellular mechanism studies indicated that compound 3 could induce G2/M phase arrest and apoptosis of HeLa and MCF-7 cells, which were associated with alterations in the expression of cell cycle-checkpoint related proteins (Cyclin B1, Cdc2, and P21) and a reduction in the mitochondrial membrane potential as well as alterations in the levels of apoptosis-related proteins (PARP, Caspase 9, Bcl-2, and Bax) of these cells, respectively. Importantly, in vivo studies further revealed that compound 3 could dramatically suppress HeLa cell xenograft tumour growth compared with vehicle and CA-4 phosphate (CA-4P), and no signs of toxicity were observed in these mice. Collectively, these in vitro and in vivo results indicated that compound 3 might be a promising lead compound for further development as a potential anti-cancer drug.

Recent Advances in the Design and Synthesis of c-Met Inhibitors as Anticancer Agents (2014-Present).

c-Met, also known as the surface receptor of hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase with heterodimer transmembrane. c-Met involves in the activation of several signaling pathways, most of them are implicated in aggressive cancer phenotypes. In a variety of human malignances, c-Met/HGF signaling has been found aberrant, and in many instances, has been correlated with advanced disease stage and poor prognosis. Thus, the c-Met has identified as an emerging and interesting target for cancer chemotherapy. In this review, we briefly summarize signaling pathways of c-Met, and discuss the crystal structures of representative c-Met and the binding modes with their ligands. We also present updates on the design, synthesis and structure-activity relationship analysis of c-Met inhibitors developed from 2014 till now. At last, we review the c-Met inhibitors that are in clinical development and highlight the future prospects.

Tyrosyl-tRNA synthetase inhibitors: a patent review.

INTRODUCTION: Bacterial infection has been a consistent and relentless threat to human health because of emerging resistance to existing antibiotics. Therefore, much of the research has been focused on the design of new potent antibacterial agents. Tyrosyl-tRNA synthetase (TyrRS), as a member of aminoacyl-tRNA synthetase family, could recognize the information including the coincident tRNA molecules and the amino acids' structures, which are essential in translating the coded information into protein structures in nucleic acids. Therefore, the discovery and application of tyrosyl-tRNA synthetase inhibitors might be a potential strategy to control these diseases in humans. Areas covered: This review covers 1999 to 2016 wherein several new analogues were claimed as TyrRS inhibitors based on their chemical structures. Xiao, Z.P. et al patented two Chinese patents related to TyrRS inhibitors which are included. Expert opinion: Due to the pivotal role in translation, tyrosyl-tRNA synthetase has been recognized as a promising target for a new generation of antibiotics with selectivity and specificity. However, while some of the TyrRS inhibitors showed encouraging results, there is an urgent need to develop novel TyrRS inhibitors with higher activity and selectivity. Based on the published SAR results, selective tyrosyl-tRNA synthetase inhibitors could be designed and developed as the next generation of antibacterial agents.

Evaluation of Nonpeptidic Ligand Conjugates for the Treatment of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers.

The majority of tumors contain regions of hypoxia, which cause marked phenotypic changes to resident cells. This altered gene expression often leads to increased resistance to anticancer treatments. Therefore, elimination of these resistant hypoxic cells is crucial to prevent disease recurrence. Herein, we describe the selective delivery of imaging and chemotherapeutic agents to cells expressing carbonic anhydrase IX (CA IX), a highly upregulated hypoxia receptor. These agents were conjugated to a potent divalent CA IX ligand through a hydrophilic PEG linker. These conjugates are shown to bind CA IX-expressing cells in a receptor-dependent manner in vitro with mid-nanomolar affinities and in vivo with good tumor selectivity. In a mouse xenograft tumor model using HT-29 cells, a cytotoxic tubulysin B conjugate completely inhibited tumor growth. Overall, the targeting of a hypoxia marker, such as CA IX, to selectively deliver imaging or chemotherapeutic agents may lead to better treatment options for solid, hypoxic tumors. In addition, the combination of standard chemotherapeutics that are most potent in normoxic dividing cells and drugs specifically designed to eliminate hypoxic nondividing cells may elicit a superior clinical outcome. Mol Cancer Ther; 16(3); 453-60. ©2016 AACR.

Indole-based, Antiproliferative Agents Targeting Tubulin Polymerization.

Indole is a potential lead for drug design which has been found in numerous pharmaceutically important compounds due to its medicinal properties, such as anti-tumor, anti-bacterial, anti-virus and anti-inflammatory. In the last decade, interfering with microtubule polymerization, a potential orientation to cause cell cycle arrest and apoptosis has become a promising method for cancer therapy. Thus, indole-based agents capable to modulate the microtubule assembly have gained considerable interest among scientists. This review describes the synthesis, bioactivities and SARs of indole-based agents targeting tubulin polymerization during the past decade.

Evaluation of Nonpeptidic Ligand Conjugates for SPECT Imaging of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers.

As tumors grow, vasculature is often deficient or malformed, resulting in many localized areas of hypoxia. Cells located in these hypoxic regions exhibit an altered gene expression pattern that can significantly alter resistance to conventional anticancer treatments such as ionizing radiation and chemotherapeutic drugs. A priori knowledge of the level of hypoxia within a tumor may better guide clinical care. In an effort to create a hypoxia specific imaging agent, a ligand for the tissue hypoxia marker, carbonic anhydrase IX (CA IX), was synthesized and used as a targeting ligand to deliver an attached (99m)Tc-chelating agent. Binding of the resulting conjugates to hypoxic cancer cells was first characterized in vitro. Whole animal imaging and biodistribution studies then were performed to determine tumor specificity in vivo. Several conjugates were found to bind selectively to CA IX expressing tumors in a receptor-dependent manner. We suggest that such conjugates could prove useful in identifying hypoxic cancers and/or quantitating the level of hypoxia within a tumor.

Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400).

Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents with two compounds in clinical trials. Recent metabolism studies of indotecan (LMP400) led to the discovery of the biologically active 2-hydroxylated analogue and 3-hydroxylated metabolite, thus providing strategically placed functional groups for the preparation of a variety of potential ester prodrugs of these two compounds. The current study details the design and synthesis of two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity. Many of the indenoisoquinoline prodrugs were very potent antiproliferative agents with GI50 values below 10 nM in a variety of human cancer cell lines.

Evaluation of a Carbonic Anhydrase IX-Targeted Near-Infrared Dye for Fluorescence-Guided Surgery of Hypoxic Tumors.

Proof-of-principle studies in ovarian, lung, and brain cancer patients have shown that fluorescence-guided surgery can enable removal of otherwise undetectable malignant lesions, decrease the number of cancer-positive margins, and permit identification of disease-containing lymph nodes that would have normally evaded resection. Unfortunately, the current arsenal of tumor-targeted fluorescent dyes does not permit identification of all cancers, raising the need to design new tumor-specific fluorescent dyes to illuminate the currently undetectable cancers. In an effort to design a more universal fluorescent cancer imaging agent, we have undertaken to synthesize a fluorophore that could label all hypoxic regions of tumors. We report here the synthesis, in vitro binding, and in vivo imaging of a near-infrared (NIR) fluorescent dye that is targeted to carbonic anhydrase IX (CA IX), i.e., a widely accepted marker of hypoxic tissues. The low molecular weight NIR probe, named Hypoxyfluor, is shown to bind CA IX with high affinity and accumulate rapidly and selectively in CA IX positive tumors. Because nearly all human cancers contain hypoxic regions that express CA IX abundantly, this NIR probe should facilitate surgical resection of a wide variety of solid tumors.

Discovery of a series of novel phenylpiperazine derivatives as EGFR TK inhibitors.

Human epidermal growth factor receptor (EGFR) is an important drug target that plays a fundamental role in signal transduction pathways in oncology. We report herein the discovery of a novel class of phenylpiperazine derivatives with improved potency toward EGFR. The biological activity of compound 3p as inhibitor of EGFR was further investigated both in vitro and in vivo. Notably, compound 3p exhibited an IC50 in the nanomolar range in A549 cell cultures and induced a cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice. Compoutational docking studies also showed that compound 3p has interaction with EGFR key residues in the active site.

Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9: Design, synthesis, inhibitory activity and 3D-QSAR analysis.

New series of sulfonamide derivatives containing a dihydropyrazole moieties inhibitors of MMP-2/MMP-9 were discovered using structure-based drug design. Synthesis, antitumor activity, structure-activity relationship and optimization of physicochemical properties were described. In vitro the bioassay results revealed that most target compounds showed potent inhibitory activity in the enzymatic and cellular assays. Among the compounds, compound 3i exhibited the most potent inhibitory activity with IC50 values of 0.21 µM inhibiting MMP-2 and 1.87 µM inhibiting MMP-9, comparable to the control positive compound CMT-1 (1.26 µM, 2.52 µM). Docking simulation was performed to position compound 3i into the MMP-2 active site to determine the probable binding pose. Docking simulation was further performed to position compound 3i into the MMP-2 active site to determine the probable binding model the 3D-QSAR models were built for reasonable design of MMP-2/MMP-9 inhibitors at present and in future.

Discovery of new 4-alkoxyquinazoline-based derivatives as potent VEGFR2 inhibitors.

VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty-one 4-alkoxyquinazoline-based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 nm (for VEGFR2) and 0.25 µm (for MCF-7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4ASE active site, and the result showed that compound 3h could bind well at the 4ASE active site.

Nitroimidazole derivatives: a patent review of US 2014/0141084 A1.

Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities and their recently found applications in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. The electron-deficient nitroaromatic compounds have been investigated for use in cancer treatment as chemical modifiers. In this patent (US 2014/0141084 A1), amphiphilic polymers were designed and prepared based on nitroimidazole derivatives and carboxymethyl dextran, which can be used for the hypoxia-selective release of diagnostics or drugs.

Synthesis, biological evaluation and 3D-QSAR studies of novel 5-phenyl-1H-pyrazol cinnamamide derivatives as novel antitubulin agents.

A series of novel 5-phenyl-1H-pyrazol derivatives (5a-5x) containing cinnamamide moiety were synthesized and their biological activities as potential tubulin polymerization inhibitors were evaluated. Among them, compound 5j exhibited the most potent inhibitory activity with an IC50 value of 1.02 µM for tubulin, which was superior to that of Colchicine (IC50 = 1.34 µM). Docking simulation was performed to insert compound 5j into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin inhibitory activity.

6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kα.

Twenty eight 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives were synthesized and evaluated their biological activities as PI3K inhibitors. Biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 25 exhibited the most potent and selective activity for PI3Kα, with the IC50 value of 0.016µM, an approximately 30-fold increase in comparison with LY294002, it also has an increased potency of approximately 11-fold for PI3Kß. It indicated the potential of developing 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as the new PI3Kα selective inhibitors for tumor treatment.