R1 Position Research Articles

Yellow–green luminescence of four-coordinate copper(I) complexes bearing N–heterocyclic carbene (NHC) ligands: Synthesis, photophysical and computational studies

The synthesis and photophysical investigation of a series of six copper(I) complexes bearing benzimidazolylidene–type N–heterocyclic carbene (NHC) ligands with different groups are reported. Their photophysical properties can be tuned by adjusting the groups at the R1/R2 positions of the pyridine ring. The lowest-lying metal–to–ligand (MLCT) absorption bands at 325–437 nm can be observed for all the complexes. Upon excitation with UV light all the complexes emit bright yellow-green light (λem = 540–573 nm) with higher emission quantum yields of 21.1–55.6% and excited state lifetimes on the microsecond scale (τ = 30.6–62.1 μs) in PMMA films. The substituents (R2 = COCH3, F, Br, CH3, or OCH3) on R2–position of the pyridine ring were shown to have effects on the emission wavelengths of these complexes, while the introduction of R1 substituents (R1 = CH3) shows negligible effects on the emission wavelength but allow the enhancement of photoluminescence quantum yield (Φ) of the complexes. Additionally, the electronic properties, absorption and emission profiles of these complexes were further explored using DFT/TDDFT methods.

Design, synthesis, and biological evaluation of potent 1,2,3,4-tetrahydroisoquinoline derivatives as anticancer agents targeting NF-κB signaling pathway

The multifunctional transcription factor, nuclear factor-κB (NF-κB), is broadly involved in multiple human diseases, such as cancer and chronic inflammation, through abnormal modulations of the NF-κB signaling cascades. In patients with several types of cancer diseases, NF-κB is excessively activated, which could result in the stimulation of proliferation and/or suppression of apoptosis. Herein, we present a new series of 1,2,3,4-tetrahydroisoquinoline derivatives with good anticancer activities against various human cancer cell lines, which are rationally designed based on our novel NF-κB inhibitors. The SAR studies demonstrated that compound 5d with a methoxy group at the R3 position exhibits the most anti-proliferative activity with GI50 values, ranging 1.591 to 2.281 μM. Similar to KL-1156, the compound 5d (HSR1304) blocked NF-κB nuclear translocation step in LPS-stimulated MDA-MB-231 cells, probably leading to cytotoxic potency against tumor cells. Together with known potent NF-κB inhibitors containing diverse core heterocyclic moieties, the 1,2,3,4-tetrahydroisoquinoline derivatives can provide structural diversity, enhancing a potential for the development of a novel class of anticancer drugs.

Effects of Substituents on the Molecular Structure and Redox Behavior of Uranyl(V/VI) Complexes with N3O2-Donating Schiff Base Ligands.

Uranyl(VI) complexes with pentadentate N3O2-donating Schiff base ligands having various substituents at the ortho (R1) and/or para (R2) positions on phenolate moieties, R1,R2-Mesaldien2-, were synthesized and thoroughly characterized by 1H nuclear magnetic resonance, infrared, elemental analysis, and single-crystal X-ray diffraction. Molecular structures of UO2(R1,R2-Mesaldien) are more or less affected by the electron-donating or -withdrawing nature of the substituents. The redox behavior of all UO2(R1,R2-Mesaldien) complexes was investigated to understand how substituents introduced onto the ligand affect the redox behavior of these uranyl(VI) complexes. As a result, the redox potentials of UO2(R1,R2-Mesaldien) in dimethyl sulfoxide increased from -1.590 to -1.213 V with an increase in the electron-withdrawing nature of the substituents at the R1 and R2 positions. The spectroelectrochemical measurements and theoretical calculation [density functional theory (DFT) and time-dependent DFT calculations] revealed that the center U6+ of each UO2(R1,R2-Mesaldien) complex undergoes one-electron reduction to afford the corresponding uranyl(V) complex, [UO2(R1,R2-Mesaldien)]-, regardless of the difference in the substituents. Consequently, the redox active center of uranyl(VI) complexes seems not to be governed by the redox potentials but to be determined by whether the LUMO is centered on a U 5f orbital or on one π* orbital of a surrounding ligand.

BODIPY-DERIVATIVES AS PHOTOSENSITIZERS IN PHOTODYNAMIC THERAPY: THE RELATIONSHIP BETWEEN ELECTRONIC PROPERTIES AND LIGHT ABSORPTION EFFICIENCY

In this study, the structural and electronic properties of BODIPY and its twelve derivates, including meso-amino, meso-alkoxy, meso-phenyl, meso-alkyl and other compounds, were investigated using an accurate and broadly parametrized self-consistent tight-binding quantum chemical method named GFN2-xTB. The influence of the substituent groups on the geometrical parameters, the HOMOLUMO gap, and electronic properties of BODIPYs was analyzed. The obtained results have shown that the presence of substituents at the R2 position did not significantly change the structural parameters of BODIPY. The electron-acceptor or electron-donor substituents in the meso-position have different effects on the electronic parameters of the molecules. A correlation between the global electrophilicity index and the HOMO-LUMO gap was found. Among the studied systems, the BODIPY-derivative with a -NO2 group at the meso-position was evaluated as the most promising candidate for photosensitizers in PDT.

Anti-chronic myeloid leukemia activity and quantitative structure-activity relationship of novel thiazole aminobenzamide derivatives

The anti-chronic myeloid leukemia activity of thiazole aminobenzamide derivatives in vitro was tested by a methanethiosulfonate (MTS)-based viability assay method, and the result showed that some compounds exhibited good inhibitory activities against human chronic myeloid leukemia cell line K562, imatinib-resistant strain K562/R and T135I mutant cell line BaF3-ABL-BCR-T315I. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to analyze the relationship between the structure of thiazole aminobenzamide derivatives and the inhibition of K562/R cell activity. In CoMFA, Q2 was 0.899 and R2 was 0.963; in CoMSIA, Q2 and R2 were 0.840 and 0.903, respectively. These data indicated that the selected test set showed suitable external predictive ability. Combined with the contour map results, we further analyzed the three-dimensional quantitative structure (3D-QSAR) model. The results demonstrated that in the backbone of the thiazole aminobenzamide derivative, the substitution of a small group at R1 position, or the introduction of a hydrophilic group at R2 position, or the introduction of a large-volume amino acid at R3 position may be beneficial to improve the anti-CML activity of the compound.

Novel daidzein molecules exhibited anti-prostate cancer activity through nuclear receptor ERβ modulation, in vitro and in vivo studies

Eight novel ERβ selective daidzein analogues (NCE1-8) were synthesized and their anti-cancer activity was evaluated by in vitro and in vivo methods. Cytotoxicity study, Receptor binding studies, Luciferase assay, cMYC & Cyclin D1 expression and Caspase 3, 8 & 9 activities were measured to ascertain the anticancer activity and mechanism. Uterotropic, anti-androgenic and anti-tumour activities were performed in rodents. The results revealed that NCEs produced anti-prostate cancer activity in DU145, LNCaP and PC3 cell lines and 50% more active than genistein. NCEs was significantly down-regulated cMYC & Cyclin D1 genes and elevated caspase 3 & 9 levels and did not show any difference in uterotropic, anti-androgenic activities. The tumour weight was also reduced. The NCE 1 and 2 have shown ERβ selectivity in receptor binding studies. Daidzein with methyl substitution at R or R1 position exhibited more ERβ selectivity and could be considered as lead molecules for anti-prostate cancer activity.

Understanding the influence of lipid bilayers and ligand molecules in determining the conformational dynamics of somatostatin receptor 2

Somatostatin receptor 2 (SSTR2) is a G-protein coupled receptor (GPCR) that controls numerous cellular processes including cell-to-cell signaling. In this study, we report how the lipid and ligand molecules influence the conformational dynamics of the membrane-bound SSTR2. Molecular simulations of different holo and apoenzyme complexes of SSTR2 in the presence and absence of a lipid bilayer were performed, observed, and correlated with previously reported studies. We identified the important SSTR2 residues that take part in the formation of the SSTR2-ligand complex. On analyzing the molecular simulation trajectories, we identified that the residue D3.32 is crucial in determining the bioactive conformation of SSTR2 ligands in the binding site. Based on the results, we suggest that designing a novel SSTR2 ligand with an H-bond donor group at the R1 position, and hydrophobic groups at R2 and R3 might have higher activity and SSTR2-selectivity. We analyzed the simulated systems to identify other important structural features involved in SSTR2-ligand binding and to observe the different conformational changes that occur in the protein after the ligand binding. Additionally, we studied the conformational dynamics of N- and C-terminal regions of SSTR2 in the presence and absence of the lipid bilayer. Both the systems were compared to understand the influence of lipid molecules in the formation of secondary structural domains by these extracellular regions. The comparative study revealed that the secondary structural elements formed by C-terminal residues in presence of lipid molecules is crucial for the functioning of SSTR2. Our study results highlight the structural complexities involved in the functioning of SSTR upon binding with the ligands in the presence and absence of lipid bilayer, which is essential for designing novel drug targets.

Benzothiazole Amides as TRPC3/6 Inhibitors for Gastric Cancer Treatment

Transient receptor potential canonical channel 6 (TRPC6) has been implicated in many kinds of malignant tumors, but very few potent TRPC6 antagonists are available. In this study, a benzothiazole amide derivative 1a was discovered as a TRPC6 activator in a cell-based high-throughput screening. A series of benzothiazole amide derivatives were designed and synthesized. The docking analyses indicated that the conformations of the compounds bound to TRPC6 determined the agonistic or antagonistic activity of the compounds against TRPC6, and compound 1s with the tetrahydronaphthalene group in R1 position fit well into the binding pocket of the antagonist-bound conformation of TRPC6. Compound 1s showed an inhibitory potency order of TRPC3 (IC50 3.3 ± 0.13 μM) ≈ C6 (IC50 4.2 ± 0.1 μM) > C7 with good anti-gastric cancer activity in a micromolecular range against AGS and MKN-45, respectively. In addition, 1s inhibited the invasion and migration of MKN-45 cells in vitro.

Electronic structure and first hyperpolarizability of triple helicene compounds

Density functional theory (DFT) investigations on the reported triple helicene and four new substituted compounds are employed to aid in the design of nonlinear optical (NLO) materials with large first hyperpolarizability βHRS. The influences of different substituents were analyzed in terms of geometric and optoelectronic parameters such as energy gap, UV–vis absorption spectra, and electronic absorption energies. The investigation shows that the combination insertion of the donor unit and acceptor unit, especially the combination introduction of NH2 units at the R1 and R2 positions and NO2 units at the R3 and R4 positions, effectively reduces the band gap, makes the FMOs obvious spatial charge separation, broadens the absorption spectrum and produces a larger red shift, and obtains a larger βHRS value. Considering their strong NLO response, the studied compounds have the probability to be candidates used as excellent second-order NLO materials.

Identification of new 3-phenyl-1H-indole-2-carbohydrazide derivatives and their structure–activity relationships as potent tubulin inhibitors and anticancer agents: A combined in silico, in vitro and synthetic study

Virtual screening of commercially available molecular entities by using CDRUG, structure-based virtual screening, and similarity identified eight new derivatives of 3-phenyl-1H-indole-2-carbohydrazide with anti-proliferative activities. The molecules were tested experimentally for inhibition of tubulin polymerisation, which revealed furan-3-ylmethylene-3-phenyl-1H-indole-2-carbohydrazide (27a) as the most potent candidate. Molecule 27a was able to induce G2/M phase arrest in A549 cell line, similar to other tubulin inhibitors. Synthetic modifications of 27a were focussed on small substitutions on the furan ring, halogenation at R1 position and alteration of furyl connectivity. Derivatives 27b, 27d and 27i exhibited the strongest tubulin inhibition activities and were comparable to 27a. Bromine substitution at R1 position showed most prominent anticancer activities; derivatives 27b-27d displayed the strongest activities against HuCCA-1 cell line and were more potent than doxorubicin and the parent molecule 27a with IC50 values <0.5 μM. Notably, 27b with a 5-methoxy substitution on furan displayed the strongest activity against HepG2 cell line (IC50 = 0.34 µM), while 27d displayed stronger activity against A549 cell line (IC50 = 0.43 µM) compared to doxorubicin and 27a. Fluorine substitutions at the R1 position tended to show more modest anti-tubulin and anticancer activities, and change of 2-furyl to 3-furyl was tolerable. The new derivatives, thiophenyl 26, displayed the strongest activity against A549 cell line (IC50 = 0.19 µM), while 1-phenylethylidene 21b and 21c exhibited more modest anticancer activities with unclear mechanisms of action; 26 and 21c demonstrated G2/M phase arrest, but showed weak tubulin inhibitory properties. Molecular docking suggests the series inhibit tubulin at the colchicine site, in agreement with the experimental findings. The calculated molecular descriptors indicated that the molecules obey Lipinski’s rule which suggests the molecules are drug-like structures.

Push-pull effect on the charge transport characteristics in V-shaped organic semiconductor materials

With the goal to tune charge transport and electronic properties of 4,6-di(thiophen-2-yl)pyrimidine (DTP) structure, seven novel V-shaped organic semiconductor compounds were designed by nitrogen doping, oligocenes π-bridge incorporations and push-pull strategy. Primarily, 4,6-bis-thiazol-2-yl-pyrimidine (1) was designed by nitrogen atoms doping in DTP. Then push-pull system named 1DA was designed by substituting –N(CH3)2 at R1 and R2, while –CF3 at R3 and R4 positions of 1. Moreover, various semiconducting materials (2DA-6DA) with tuned properties were designed from 1DA by fusing benzene, naphthalene, anthracene, tetracene and pentacene at both ends. The density functional theory (DFT) and time-dependent DFT were adopted for optimizing the ground and excited state structures, correspondingly. We investigated frontier molecular orbitals, photo-stability, electron injection, electron affinity (EA), ionization energies (IE) and reorganization energies. The push-pull and π-bridge elongation strategies ominously raise EA while diminish IE values, which may lead to decrease the electron and hole injection obstruction. Besides, donors–acceptors and oligocenes at both ends meaningfully drop the electron reorganization energy values as compared to normally used n-type material, i.e., tris(8-hydroxyquinolinato)aluminium (mer-Alq3). These results revealed that newly designed materials 4DA-6DA would be proficient to be used in n-type semiconductor devices.

A TD-DFT molecular screening for fluorescence probe based on excited-state intramolecular proton transfer of 2’-hydroxychalcone derivatives

A systematic screening of fluorescence probe based on excited-state intramolecular proton transfer (ESIPT) of 2’-hydroxychalcone (2HC) derivatives with different electron donating (EDG) and electron withdrawing (EWG) groups at para position of phenol moiety (R1) and para position of the connected benzene ring to carbonyl (R2) of 2HC has been carried out by the best method of choice at ωB97XD/6-311++G(d,p) level. Seven selected 2HC derivatives with OH donor having mono-substitution with –NMe2 at R1 position or di-substitution with –NMe2 at R1 position and EDG (Me, OMe, NMe2) or EWG (Br, Cl, F) at R2 position have passed all required parameters (photophysical parameters, kinetic and thermodynamic parameters). Whereas, seven selected 2HC derivatives with NH donor having the same substituents as the 2HC derivatives with OH donor have passed photophysical parameters but failed kinetic and thermodynamic parameters due to high PT barrier and endothermic reaction. To ensure the effective ESIPT occurrence, a hydrogen atom on the amine group of NH donor derivatives is replaced with a tosyl (Ts) group, providing the Ts-substituted NH donor derivatives. The Ts substituent helps strengthening the intramolecular hydrogen bond, leading to low PT barrier with exothermic reaction thus facilitating ESIPT process. The systematically screening procedure from this theoretical calculation is beneficial for the design of fluorescent molecular probes utilizing the ESIPT process.

Structure-Guided Discovery of Silicon-Containing Subnanomolar Inhibitor of Hydroxyphenylpyruvate Dioxygenase as a Potential Herbicide.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been recognized as one of the most promising targets in the field of herbicide innovation considering the severity of weed resistance currently. In a persistent effort to develop effective HPPD-inhibiting herbicides, a structure-guided strategy was carried out to perform the structural optimization for triketone-quinazoline-2,4-diones, a novel HPPD inhibitor scaffold first discovered in our lab. Herein, starting from the crystal structure of Arabidopsis thaliana (At)HPPD complexed with 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(o-tolyl)quinazoline-2,4(1H,3H)-dione (MBQ), three subseries of quinazoline-2,4-dione derivatives were designed and prepared by optimizing the hydrophobic interactions between the side chain of the core structure at the R1 position and the hydrophobic pocket at the active site entrance of AtHPPD. 6-(2-Hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(3-(trimethylsilyl)prop-2-yn-1-yl)quinazoline-2,4(1H,3H)-dione (60) with the best inhibitory activity against AtHPPD was identified to be the first subnanomolar-range AtHPPD inhibitor (Ki = 0.86 nM), which significantly outperformed that of the lead compound MBQ (Ki = 8.2 nM). Further determination of the crystal structure of AtHPPD in complex with compound 60 (1.85 Å) and the binding energy calculation provided a molecular basis for the understanding of its high efficiency. Additionally, the greenhouse assay indicated that 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-propylquinazoline-2,4(1H,3H)-dione (28) and compound 60 showed acceptable crop safety against peanut and good herbicidal activity with a broad spectrum. Moreover, compound 28 also showed superior selectivity for wheat at the dosage of 120 g ai/ha and favorable herbicidal efficacy toward the gramineous weeds at the dosage of as low as 30 g ai/ha. We believe that compounds 28 and 60 have promising prospects as new herbicide candidates for wheat and peanut fields.

Enzymatic Preparation and Structure-activity Relationship of Sesaminol.

As a valuable natural antioxidant, sesaminol can be used in food and medicine industries, but it is trace in sesame seeds and oil, and it is feasible to prepare sesaminol from sesaminol triglucoside (STG) which is abundant in defatted sesame cake. Therefore, in order to establish an effective enzymatic preparation method and elucidate the antioxidant structure-activity relationship of sesaminol, a suitable glycosidase for preparing sesaminol from STG were screened, enzymatic hydrolysis was optimized by single-factor test and response surface methodology, and finally, the structure-activity relationship of sesaminol was illustrated by comparative molecular field analysis (CoMFA). These results suggested that β-galactosidase was the optimal glycosidase for enzymatic hydrolysis of STG to prepare sesaminol. Under the optimal conditions of a reaction temperature of 50°C, reaction time of 4.0 h, pH of 5.5, substrate concentration of 1.0 mg/mL, and enzyme dosage of 20 mg/mL, the conversion rate of sesaminol was 98.88±0.67%. Sesaminol displayed excellent antioxidant ability in 2,2-diphenyl-1-picrylhydrazyl (DPPH, IC50 = 0.0011 mg/mL), 2,2'-azinobis-(3-ethyl-benzothiazoline-6-sulfonate) (ABTS, IC50 = 0.0021 mg/mL) radical scavenging activities and Ferric reducing antioxidant power (FRAP, 103.2998 mol/g) compared to other sesaminol derivatives. According to －log (IC50 of DPPH) and －log (IC50 of ABTS), CoMFA models were successfully established based on Q2 >0.5 (QDPPH 2 = 0.558, QABTS 2 = 0.534). The active site of sesaminol tended to be located on the hydroxyl group of the benzene ring (R1 position). A positive correlation between the bulky and positively charged groups at the 1H, 3H-furo [3, 4-c] furan group, the small, negatively charged groups at the R1 position and the antioxidant activity of sesaminol. This study provides an effective method to prepare sesaminol, reveals the structure-activity relationship of sesaminol and provides theoretical basis to design the novel compound.

Predicting the potential toxicity of 26 components in Cassiae semen using in silico and in vitro approaches

Cassiae semen are dried and ripe seeds of Cassia obtusifolia L. or Cassia tora L. (Fabaceae) and have been made into roasted tea or used as a traditional medicine in Asian countries. However, it was reported to result in liver and renal toxicity. The components of Cassiae semen that induce hepatotoxicity or nephrotoxicity remain unknown. In the present study, we evaluate the potential toxicity of 26 newly isolated compounds from Cassiae semen using quantitative structure–activity relationship (QSAR) methods and co-culture of hepatic and renal cell approaches, and we aim to illustrate the relationship between the structural characteristics and cytotoxicity by general linear models (GLMs). Both the QSAR models and co-culture of hepatic and renal cell systems predicted that 6 compounds were potentially hepatotoxic, 10 compounds were potentially nephrotoxic, and specific anthraquinones and anthraquinone-glucosides were potential toxicants in Cassiae semen. Specific groups such as –OH and –OCH3 at the R1, R2, R3, and R7 positions influenced the cytotoxicity.

Regional Variations in Diagnostic Radiology Residency Stipends Are Accentuated When Correlated With Cost of Living.

To determine and compare the relative value of diagnostic radiology resident stipends when adjusted for regional cost of living. The ACGME database was queried for a list of accredited allopathic diagnostic radiology residency programs for academic year 2017-2018. Stipend information for R1 positions (post-graduate year 2) was identified through each program's website. Data was grouped and analyzed by city, state, and geographical region. Stipends were then correlated with the 2017 annual region-specific average cost of living index (COLI). There were 194 programs identified, of which 118 (60.8%) were analyzed after exclusions for lack of stipend or correspondingCOLI data. The average annual stipend was $57,161±$4,242 (range, $49,547-$72,000). The COLI-adjusted value was$51,357±$9,927 (range, $26,915-$68,827). The average difference between stipend and cost-ofliving adjusted value was -$5,804±$12,610 (range, -$40,953-$10,958), corresponding to an average -9.1% stipend value loss (range, -58.1%-21.7%, P=.00000004). Value loss in large metropolitan cities was as high as 53.8%. Financial issues are one of the biggest challenges faced by trainees and have been correlated with increased stress as well as poor academic performance. The pressures of debt can also play a significant role in ultimate subspecialty career choice. Discrepancies between resident stipends, which are not adjusted based on the local COLI, are exacerbated by large regional variations in cost of living. Residency applicants should not discount regional cost of living when deciding where to train, and training programs should consider cost of living when setting stipend levels for their trainees.

Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer.

Inositol trisphosphate receptor (IP3R) mediated Ca+2 signaling is essential in determining the cell fate by regulating numerous cellular processes, including cell division and cell death. Despite extensive studies about the characterization of IP3R in cancer, the underlying molecular mechanism initiating the cell proliferation and apoptosis remained enigmatic. Moreover, in cancer, the modulation of IP3R in downstream signaling pathways, which control oncogenesis and cancer progression, is not well characterized. Here, we constructed a biological regulatory network (BRN), and describe the remodeling of IP3R mediated Ca2+ signaling as a central key that controls the cellular processes in cancer. Moreover, we summarize how the inhibition of IP3R affects the deregulated cell proliferation and cell death in cancer cells and results in the initiation of pro-survival responses in resistance of cell death in normal cells. Further, we also investigated the role of stereo-specificity of IP3 molecule and its analogs in binding with the IP3 receptor. Molecular docking simulations showed that the hydroxyl group at R6 position along with the phosphate group at R5 position in ‘R’ conformation is more favorable for IP3 interactions. Additionally, Arg-266 and Arg-510 showed π–π and hydrogen bond interactions and Ser-278 forms hydrogen bond interactions with the IP3 binding site. Thus, they are identified as crucial for the binding of antagonists.

Synthetic Spirocyclohexadienones as New Anti-Migratory Compounds in Triple- Negative Breast Cancer Cell Migration.

Triple-negative BC is the most aggressive type of breast cancer and its lack of responsiveness to conventional therapies requires screening of new chemical entities. Anti-migratory compounds are promising to treat metastatic cancer since they inhibit one of the main steps of the metastatic cascade. Spirocyclic compounds are non-conventional structures used as building blocks for the synthesis of biologically active molecules and considered interesting structures in the search for new targets in cancer research. Here, we evaluated the potential of eight synthetic spirocyclohexadienones as cell migration inhibitors. The anti-migratory ability of compounds was tested by wound healing and Boyden chamber approaches. Experiments in tubulin were performed by fluorescence and tubulin polymerization techniques. Finally, compounds were submitted to cell proliferation inhibition and flow cytometry assays to explore the mechanism by which they inhibit cell migration. Four compounds inhibited cell migration significantly. Analogs containing the 3,4,5-trimethoxyphenil ring at R1 position were the most potent and, thus, selected for additional experiments. Tubulin polymerization and fluorescence assays highlighted a possible binding of spirocyclohexadienones in the colchicine binding site; however, these compounds did not affect the cell cycle to the same extent as colchicine. Cell proliferation was affected and, notably, the most potent analogs induced apoptosis of tumor cells, suggesting a different mechanism by which they inhibit cell migration. We presented, for the first time, a series of eight synthetic spirocyclohexadienones with the ability to inhibit TNBC cell migration. These compounds represent a new category to be explored as anticancer agents.

Synthesis and Antitumor Activity Evaluation of Cyclometalated 2H-Indazole Ruthenium(II) and Iridium(III) Complexes.

In this work, a series of novel C-N cyclometalated 2H-indazole Ru(II) and Ir(III) complexes were synthesized, wherein chelating ligands with substituents like H, and isopropyl group in the R4 position of the phenyl ring of the 2H-indazole chelating ligand are present. The cytotoxicity of Ru(II) and Ir(III) complexes has been evaluated against different human cancer cell lines (HeLa, MCF-7, and A549) in a concentration-dependent manner. The new iridium complex with isopropyl substituent in the phenyl ring of the 2H-indazole moiety showed good cytotoxic activity against MCF-7 cells with an IC50 value 3.5 μM. The complex also exhibited cytotoxicity comparable to that of cisplatin. The ability of this compound inducing apoptosis was tested by nuclear condensation, cell membrane blebbing and caspase 3/7 activation. Further, this iridium complex is capable of inhibiting cancer cell migration when tested in MCF-7 cell line. Subsequently, we have studied the DNA binding and protein binding ability of the newly synthesized iridium complex.

Biological evaluation and SAR analysis of novel covalent inhibitors against fructose-1,6-bisphosphatase

Fructose-1,6-bisphosphatase (FBPase) is an attractive target for affecting the GNG pathway. In our previous study, the C128 site of FBPase has been identified as a new allosteric site, where several nitrovinyl compounds can bind to inhibit FBPase activity. Herein, a series of nitrostyrene derivatives were further synthesized, and their inhibitory activities against FBPase were investigated in vitro. Most of the prepared nitrostyrene compounds exhibit potent FBPase inhibition (IC50 < 10 μM). Specifically, when the substituents of F, Cl, OCH3, CF3, OH, COOH, or 2-nitrovinyl were installed at the R2 (meta-) position of the benzene ring, the FBPase inhibitory activities of the resulting compounds increased 4.5–55 folds compared to those compounds with the same groups at the R1 (para-) position. In addition, the preferred substituents at the R3 position were Cl or Br, thus compound HS36 exhibited the most potent inhibitory activity (IC50 = 0.15 μM). The molecular docking and site-directed mutation suggest that C128 and N125 are essential for the binding of HS36 and FBPase, which is consistent with the C128-N125-S123 allosteric inhibition mechanism. The reaction enthalpy calculations show that the order of the reactions of compounds with thiol groups at the R3 position is Cl > H > CH3. CoMSIA analysis is consistent with our proposed binding mode. The effect of compounds HS12 and HS36 on glucose production in primary mouse hepatocytes were further evaluated, showing that the inhibition was 71% and 41% at 100 μM, respectively.