Discovery of N-(4-((6-(3,5- Dimethoxyphenyl)-9H-purine derivatives as irreversible covalent FGFR inhibitors.

Fibroblast growth factor receptor (FGFR) is an attractive target for cancer therapy, but existing FGFR inhibitors appear to hardly meet the demand for clinical application. Herein, a number of irreversible covalent FGFR inhibitors were designed and synthesized by selecting several five- and six-membered azaheterocycles as parent scaffold with different substituents to take over the hydrophobic region in the active pocket of FGFR proteins. Among the resulting target compounds, III-30 showed the most potent effect on enzyme activity inhibition and anti-proliferative activity against the tested cancer cell lines. Significantly, III-30 could inhibit the enzyme activity by achieving irreversible covalent binding with FGFR1 and FGFR4 proteins. It could also regulate FGFR-mediated signaling pathway and mitochondrial apoptotic pathway to promote cancer cell apoptosis and inhibit cancer cell invasion and metastasis. Moreover, III-30 had a good metabolic stability and showed relatively potent anti-tumor activity in the MDA-MB-231 xenograft tumor mice model.

Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit.

In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of XSJ-10 revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3.

A Self-Assembly-Induced Exciton Delocalization Strategy for Converting a Perylene Diimide Derivative from a Type-II to Type-I Photosensitizer.

Type-I photosensitizers have shown advantages in addressing the shortcomings of traditional oxygen-dependent type-II photosensitizers for the photodynamic therapy (PDT) of hypoxic tumors. However, developing type-I photosensitizers is yet a huge challenge because the type-II energy transfer process is much faster than the type-I electron transfer process. Herein, from the fundamental point of view, an effective approach is proposed to improve the electron transfer efficiency of the photosensitizer by lowering the internal reorganization energy and exciton binding energy via self-assembly-induced exciton delocalization. An example proof is presented by the design of a perylene diimide (PDI)-based photosensitizer (PDIMp) that can generate singlet oxygen (1O2) via a type-II energy transfer process in the monomeric state, but induce the generation of superoxide anion (O2˙-) via a type-I electron transfer process in the aggregated state. Significantly, with the addition ofcucurbit[6]uril (CB[6]), the self-assembled PDIMp can convert back to the monomeric state via host-guest complexation and consequently recover the generation of 1O2. The biological evaluations reveal that supramolecular nanoparticles (PDIMp-NPs) derived from PDIMp show superior phototherapeutic performance via synergistic type-I PDT and mild photothermal therapy (PTT) against cancer under either normoxia or hypoxia conditions.

Discovery of Efficient Hypoxia-Targeted NO Donor Compounds to Alleviate Hypoxia Cardiac Disease.

In order to obtain efficient NO donor drugs to treat hypoxic cardiac disease, a series of hypoxia-targeted NO donor compounds were prepared and screened. Among them, a representative compound H3 was found to selectively release NO under hypoxia with a higher ratio than isosorbide dinitrate (ISDN). In vitro study indicated that H3 had a strong capability of alleviating vascular dilation and reducing myocardial hypoxic injury due to its effective regulation of vascular dilatation and myocardial injury-related proteins in H9c2 cells even at low concentrations. By intraperitoneal injection or intragastric administration, in vivo animal tests revealed that H3 possessed a potent antimyocardial hypoxic injury effect superior to ISDN. These findings suggest that H3 has a better effect on alleviating hypoxic cardiac disease than the conventional drug, owing to its hypoxia-targeted release of NO.

Study on the Multimodal Anticancer Mechanism of Ru(II)/Ir(III) Complexes Bearing a Poly(ADP-ribose) Polymerase 1 Inhibitor.

A series of novel ruthenium(II) and iridium(III) complexes (Ru1-Ru3 and Ir1-Ir3) with different ancillary ligands and a PARP-1-inhibitory chelating ligand 2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazine-1-carbothioamide (L1) were designed and prepared. The target complexes were structurally characterized by NMR and ESI-MS techniques. Among them, the crystal and molecular structures of Ir1 and Ir2 were also determined by X-ray crystallography. These complexes retained the PARP-1 enzyme inhibitory effect of L1 and showed potent antiproliferative activity on the tested cancer cell lines. The ruthenium(II) complexes Ru1-Ru3 were found to be more cytotoxic than the iridium(III) complexes Ir1-Ir3. Further investigations revealed that the most active complex Ru3 induced apoptosis in MCF-7 cells by multiple modes, inclusive of inducing DNA damage, suppressing DNA damage repair, disturbing cell cycle distribution, decreasing the mitochondrial membrane potential, and increasing the intracellular reactive oxygen species levels.

Design, synthesis, and biological evaluation of a series of benzofuran[3,2-d]pyrimidine-4(3H)-one derivatives containing thiosemicarbazone analogs as novel PARP-1 inhibitors.

Poly ADP ribose polymerase-1 (PARP-1), one of the most important members of the PARP protein family, plays a crucial role in DNA damage repair, gene transcription, and apoptosis of cancer cells. In this work, benzofuran[3,2-d]pyrimidine-4(3H)-one was used as a framework to design and synthesize a series of novel PARP-1 inhibitors by introducing thiosemicarbazone or its derivatives into the scafford. Among all the target compounds, 19b and 19c were found to exhibit more potent inhibitory activity and higher selectivity against PARP-1 than Olaparib, especially the latter had an IC50 value of 0.026 µM against PARP-1 enzyme and a PARP-2/PARP-1 selectivity of 85.19-fold over Olapanib. Apart from strong cytotoxicity against the tested cancer cell lines, 19c was most sensitive to SK-OV-3 cells, with an IC50 value of 4.98 µM superior to Olaparib. Anti-cancer mechanism studies revealed that 19c could inhibit DNA single-strand breakage repair and aggravate DNA double-strand breakage by inhibiting PARP-1 activity, and promote the apoptosis of cancer cells through the mitochondrial apoptosis pathway.

Blockade of chemo-resistance to 5-FU by a CK2-targeted combination via attenuating AhR-TLS-promoted genomic instability in human colon cancer cells.

As highly expressed in several human cancers, Casein Kinase 2 (CK2) is involved in chemotherapy-induced resistance. As a new potent CK2 inhibitor, DN701 is used to overcome chemoresistance through its synergistic antitumor effect with 5-fluorouracil (5-FU). Translesion DNA synthesis (TLS) has drawn our attention because it is associated with the development of chemo-resistance and tumor recurrence. The in vitro biological properties of 5-FU-resistant colon cancer cells revealed that DN701 combined with 5-FU could overcome chemo-resistance via blocking CK2-mediated aryl hydrocarbon receptor (AhR) and TLS-induced DNA damage repair (DDR). Moreover, pharmacologic and genetic inhibitions of AhR potently reduced TLS-promoted genomic instability. The mechanistic studies showed that combined DN701 with 5-FU was investigated to inhibit CK2 expression level and AhR-TLS-REV1 pathway. Meanwhile, DN701 combined with 5-FU could reduce CK2-AhR-TLS genomic instability, thus leading to superior in vivo antitumor effect. The insights provide a rationale for combining DN701 with 5-FU as a therapeutic strategy for patients with colon cancer.

Metal-Free Hybrid Energetic Composites Based on Donor-Acceptor π-Conjugated Organic Energetic Catalysts with Enlightening the Laser Ignition Performance of Multi-Scale Ammonium Perchlorate.

Photosensitive materials, such as energetic complexes, usually have high sensitivity and cause heavy-metal pollution, whereas others, like carbon black and dye, do not contain energy, which affects energy output and mechanical properties. In this work, donor-acceptor π-conjugated energetic catalysts, denoted as D-n, are designed and synthesized. Nonmetallic hybrid energetic composites are prepared by assembling the as-synthesized catalysts into multiscale ammonium perchlorate (AP). Composites containing catalysts and APs can be successfully ignited without the involvement of metals. The new ignition mechanism is further analyzed using experimental and theoretical analyses such as UV-vis-near-infrared (NIR) spectra, electron-spin resonance spectroscopy, and energy-gap analysis. The shortest ignition delay time is 56 ms under the experimental condition of a NIR wavelength of 1064 nm and a laser power of 10 W. At the voltage of 1 kV and the electric field of 500 V mm-1 , the laser-ignition delay time of D-2/AP hybrid composite decreases from 56 to 35 ms because D-2 also exhibits organic semiconductor-like properties. D-2/AP and D-12/AP can also be used to successfully laser ignite other common energetic materials. This study can guide the development of advanced metal-free laser-ignitable energetic composites to address challenges in the field of aerospace engineering.

Design, synthesis and biological evaluation of phosphoroxy quinazoline derivatives as potential EGFRT790M/C797S inhibitors.

Owing to the urgency and importance of developing fourth-generation EGFR inhibitors that can effectively overcome C797S site mutation in NSCLC, Brigatinib was used in this work as a lead compound to modify its structure to obtain a series of phosphoroxy quinazoline derivatives. Biological study indicated that the inhibitory activity and selectivity of the target compounds on EGFRL858R/T790M/C797S/EGFRDel19/T790M/C797S enzymes and EGFRDel19/T790M/C797S overexpressed Ba/F3 cells were significantly better than those of Brigatinib. Among the target compounds, 8a exhibited the best biological activity in vitro. More importantly, 8a presented acceptable pharmacokinetic behaviors and showed potent anti-tumor efficacy in the Ba/F3-EGFRDel19/T790M/C797S subcutaneous xenograft mice model with the tumor growth inhibition value of 82.60% at a dose of 30 mg/kg. These results indicated that 8a, as a drug candidate of the novel fourth-generation EGFR small-molecule inhibitor, has high potentials to treat with NSCLC on EGFR with C797S mutation.

Naphthalene Diimide-Functionalized Half-Sandwich Ru(II) Complexes as Mitochondria-Targeted Anticancer and Antimetastatic Agents.

In this work, four naphthalene diimide (NDI)-functionalized half-sandwich Ru(II) complexes Ru1-Ru4 bearing the general formula [(η6-arene)RuII(N^N)Cl]PF6, where arene = benzene (bn), p-cymene (p-cym), 1,3,5-trimethylbenzene (tmb), and hexamethylbenzene (hmb), have been synthesized and characterized. By introducing the NDI unit into the N,N-chelating ligand of these half-sandwich complexes, the poor luminescent half-sandwich complexes are endowed with excellent emission performance. Besides, modification on the arene ligand of arene-Ru(II) complexes can influence the electron density of the metal center, resulting in great changes in the kinetic properties, catalytic activities in the oxidative conversion of NADH to NAD+, and biological activities of these compounds. Particularly, Ru4 exhibits the highest reactivity and the strongest inhibitory activity against the growth of three tested cancer cell lines. Further study revealed that Ru4 can enter cells quickly in an energy-dependent manner and preferentially accumulate in the mitochondria of MDA-MB-231 cells, inducing cell apoptosis via reactive oxygen species overproduction and mitochondrial dysfunction. Significantly, Ru4 can effectively inhibit the cell migration and invasion. Overall, the complexation with NDI and modification on the arene ligand endowed the half-sandwich Ru(II) complexes with improved spectroscopic properties and anticancer activities, highlighting their potential applications for cancer treatment.

Design of Near-Infrared-Triggered Metallo-Photosensitizers via a Self-Assembly-Induced Vibronic Decoupling Strategy.

Development of highly efficient near-infrared (NIR)-excited photosensitizers is hampered by the fast nonradiative vibrational relaxation process regulated by the energy gap law. Here, from the fundamental perspective we propose that the intermolecular coupling of well-designed photosensitizers has the potential to facilitate exciton delocalization and hence reduce the exciton-vibration coupling, thereby boosting their phototherapeutic efficacy via inhibition of the vibrational relaxation pathway. Such conceived NIR-excited metallo-photosensitizers (IrHA1 and IrHA2) were prepared and studied for experimental validation. The resulting iridium complexes exhibited a little singlet oxygen (1O2) production in the monomeric state, but produced substantially enhanced 1O2 generation efficiency via benefiting from the exciton-vibration decoupling in the self-assembly state. Particularly, IrHA2 exhibits an unprecedented high 1O2 quantum yield of 54.9% (FDA-approved NIR dye indocyanine green: ΦΔ = 0.2%) under 808 nm laser irradiation with negligible heat generation, probably attributed to the suppression of vibronic couplings from the stretching mode of the acceptor ligand. In phototherapy, IrHA2-NPs with high biocompatibility and low dark toxicity can induce substantial tumor regression with 92.9% tumor volume reduction in vivo. This self-assembly-induced vibronic decoupling strategy would offer an effective approach to the design of high-performance NIR-excited photosensitizers.

Hybrids of carbonic anhydrase and cyclooxygenase inhibitors attenuate cardiac hypoxic inflammatory injuries.

Cardiac inflammation is easily accompanied by hypoxia, while hypoxia-induced injury and microenvironmental variations limit the efficacy of common anti-inflammatory drugs. In order to effectively attenuate myocardial injury caused by hypoxic and inflammatory injury, we designed and synthesized a kind of anti-inflammatory compounds by coupling cyclooxygenase (COX) and carbonic anhydrase (CA) inhibitors, and evaluated the activity and their mechanism in vitro and in vivo. It was found that these compounds were structurally stable and had two enzymatic inhibition activities. By inhibiting the activity of overexpressed CA under hypoxia, the acidic microenvironment can be regulated to inhibit the hypoxic injury, in which the pH-dependent primary drug resistance can be overcome to improve the anti-inflammatory effect of the COX inhibitor. Consequently, this study provides a new strategy for the treatment of cardiac inflammation accompanied by hypoxia.

Design, synthesis, and biological evaluation of novel HDAC inhibitors with a 3-(benzazol-2-yl)quinoxaline framework.

A series of novel histone deacetylase (HDAC) inhibitors derived from 3-(benzazol-2-yl)quinoxaline derivatives were designed and synthesized by a pharmacophore fusion strategy. In vitro results showed that most of the synthesized compounds exhibited good anti-proliferative activity. Among them, compound 10c showed the most potent cytotoxicity, especially in HCT-116 cells with an IC50 value of 0.91 µM much superior to Vorinostat (5.66 µM). 10c was also found to induce cell apoptosis, arrest the cell cycle at G2/M phase, induce the generation of reactive oxygen species and inhibit cell invasion and migration in HCT-116 cells. Further studies revealed that 10c could up-regulate the acetylation levels of H3 and α-tubulin, exhibit significant Topo I inhibition and induce the release of related apoptotic biomarkers. These results highlight the great potential of 10c to become a promising anti-cancer HDAC inhibitor.

Circumventing drug resistance through a CK2-targeted combination via attenuating endogenous AhR-TLS-promoted genomic instability in human colorectal cancer cells.

As anchoring Casein Kinase 2 (CK2) in several human tumors, DN701 as a novel CK2 inhibitor was applied to reverse chemo-resistance via its antitumor effect synergized with oxaliplatin. Recently, translesion DNA synthesis (TLS) has attracted our attention for its association with chemo-resistance, as demonstrated by previous clinical data. The in vitro cell-based properties supported that oxaliplatin combined with DN701 could reverse drug resistance via blockading CK2-mediated aryl hydrocarbon receptor (AhR) and translesion DNA synthesis (TLS)-induced DNA damage repair. Moreover, pharmacologic or genetic inhibition on REV3L (Protein reversion less 3-like) greatly impaired TLS-induced genomic instability. Mechanistically, combination of oxaliplatin with DN701 was found to inhibit CK2 expression and AhR-TLS-REV3L axis signaling, implying the potential decrease of genomic instability. In addition, the combination of oxaliplatin with DN701 could reduce CK2-AhR-TLS-related genomic instability, leading to potent antitumor effects in vivo. Our study presents an underlying mechanism that DN701 could attenuate tumoral chemo-resistance via decaying CK2-mediated AhR and TLS genomic instability, suggesting a potential cancer chemotherapeutic modality to prolong survival in chemo-resistant patients.

Design, Synthesis, and Biological Evaluation of Histone Deacetylase Inhibitors Derived from Erianin and Its Derivatives.

Multi-target histone deacetylase (HDAC) inhibitors can be designed by introducing dominant structures of natural products to enhance activity and efficacy while avoiding the toxicity from other targets. In this study, we reported a series of novel HDAC inhibitors based on erianin and amino erianin upon pharmacophore fusion strategy. Two representative compounds, N-hydroxy-2-(2-methoxy-5- (3,4,5-trimethoxyphenethyl)phenoxy)acetamide and N-Hydroxy-8-((2-methoxy-5- (3,4,5-trimethoxyphenethyl)phenyl)amino)octanamide, possessed good inhibitory effect against five cancer cells tested (IC50 =0.30-1.29 µΜ, 0.29-1.70 µΜ) with strong HDAC inhibition, and low toxicity toward L02 cells, which were selected for subsequent biological studies in PANC-1 cells. They were also found to promote the intracellular generation of reactive oxygen species, cause DNA damage, block the cell cycle at G2/M phase, and activate the mitochondria-related apoptotic pathway to induce cell apoptosis, which are significant for the discovery of new HDAC inhibitors.

A platinum(II) complex HY1-Pt overcomes cisplatin-induced resistance and attenuates metastasis of epithelial ovarian cancer by cancer cell stemness inhibition.

Tumor recurrence, acquired resistance and metastasis have severely limited the effect of clinical treatments for epithelial ovarian cancer. Recent researches reveal that cancer stem cells play important roles in the process of cisplatin-induced resistance and cancer cell metastasis. A platinum(II) complex (HY1-Pt) owning casein kinase 2 specificity reported in our recent research was herein applied to treat cisplatin-sensitive and cisplatin-resistant epithelial ovarian cancers, respectively, anticipating to achieve high anti-tumor efficacy. HY1-Pt showed highly efficient anti-tumor effect with low toxicity for either cisplatin-sensitive or cisplatin-resistant epithelial ovarian cancer both in vitro and in vivo. Biological studies indicated that HY1-Pt as a casein kinase 2 inhibitor could effectively overcome cisplatin resistance through the signaling pathway of Wnt/ß-catenin by inhibiting expression of the signature genes of cancer stemness cells in A2780/CDDP cells. Moreover, HY1-Pt could suppress tumor migration and invasion in vitro and in vivo, further proving that HY1-Pt can be a potent novel platinum(II) agent for cisplatin-resistant epithelial ovarian cancer treatment.

A Unique Chemo-photodynamic Antitumor Approach to Suppress Hypoxia via Ultrathin Graphitic Carbon Nitride Nanosheets Supported a Platinum(IV) Prodrug.

Tumor hypoxia severely restrains the efficiency of irreversible O2-consumption photodynamic therapy. The deep hypoxia induced by photodynamic therapy can promote the level of hypoxia inducible factor 1α that participates in many tumor processes and eventually lead to poor therapeutic outcomes. Herein, a chemo-photodynamic antitumor strategy based on ultrathin graphitic carbon nitride nanosheets loaded with a hypoxia-targeting platinum(IV) prodrug is reported. Under low-intensity visible light irradiation, such integrated nanosheets effectively generate reactive oxygen species together with DNA binding platinum species to achieve enhanced antiproliferation efficacy by downregulating HIF-1α under hypoxic conditions.

Design, synthesis and anticancer evaluation of selective 2,4-disubstituted pyrimidine CDK9 inhibitors.

Specific inhibition on CDK9 has been proven to be a promising targeted cancer therapy. In this work, fourteen novel 2,4-disubstituted pyrimidine derivatives were designed and synthesized as potent and selective CDK9 inhibitors. These compounds showed broad anti-proliferative activities in various tumor cell lines, especially for PANC-1 cells with IC50 values as low as 0.08 µM. The most selective compound 8d was 84-fold selective for CDK9 over CDK2. Mechanism study indicated that 8d induced apoptosis of PANC-1 cells and arrested the cell cycle at G2/M phase in a dose-dependent manner. Decreased phosphorylation of the CTD of RNAPII at Ser-2 and downregulation of CDK9 were confirmed in PANC-1 cells. Besides, Molecular docking was also performed to gain insights into the ligand-binding interactions of 8d inside CDK9 and CDK2 binding sites. In vivo studies indicated that 8d exhibited potent anti-tumor effects in PANC-1 xenograft models without causing obvious loss of body weight. Our research suggests that compound 8d, as a potent CDK9 inhibitor, can be considered as a good lead-candidate for further development.

Hypoxia-Activated Prodrugs with Dual COX-2/CA Inhibitory Effects on Attenuating Cardiac Inflammation under Hypoxia.

Cardiac inflammation is generally accompanied by hypoxia, while myocardial injury and an abnormal microenvironment caused by hypoxia tend to suppress the efficacy of common anti-inflammatory drugs. To improve the anti-inflammatory effect under hypoxia, a hypoxia-activated prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1 was found to be activated by nitroreductase (NTR) under hypoxia to release two pharmacophores and achieve the combinatory medication intensively at the hypoxic site, better than Ind or Ace alone. When NTR activity was inhibited by Na2WO4 under hypoxia, no pharmacophores were found to release from HAP1 without exhibiting its activity. However, the efficacy of the Ind and Ace combination group (I&A) was not affected. Furthermore, HAP1 showed advantages over I&A in vivo not only in improving bioavailability but also in reducing side effects. The HAP approach turns out to inhibit cardiac inflammation efficiently and safely under hypoxia.