•We prepared 2.40 nm of hexadecane-1,1-bisphosphonic acid SAM on mica.•Alkylbisphosphonate SAM covalently bound on the mica with the mode of double-tridentate attachment.•Organobisphosphonate SAM displaying a relatively excellent order and stability.

It has been postulated that one of the biggest impediments to a successful chemotherapy is the phenomena of multidrug resistance (MDR) in cancer cells. One of the main mechanisms of MDR is overexpression of the ATP-binding cassette (ABC) transporters in cancer cells which alters absorption, distribution, metabolism, and excretion of various chemotherapeutic drugs. Efforts have been made to find effective inhibitors of ABC transporters. However, none has been approved clinically. This study shows that a novel compound 3-chloro-N-(2-hydroxyphenyl)-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropanamido) benzamide (compound 7d), one of the 2-trifluoromethyl-2-hydroxypropionamide derivatives could reverse ABCG2 (BCRP)-mediated MDR. Cytotoxicity studies show that compound 7d sensitizes the ABCG2-overexpressing cells to chemotherapeutic drugs mitoxantrone and SN-38, which are well-established substrates of the ABCG2 transporter. Western blotting results indicate that compound 7d does not significantly alter the protein level of the ABCG2 transporter. Accumulation and efflux studies demonstrate that compound 7d increases intracellular accumulation of mitoxantrone by inhibiting the function of ABCG2. Overall, these findings indicate a potential use for compound 7d as an adjuvant agent for chemotherapy to inhibit the function of the clinically relevant ABC transporter and sensitize tumor cells to chemotherapeutic drugs. J. Cell. Biochem. 118: 2420-2429, 2017. © 2017 Wiley Periodicals, Inc.

Feasible interfacial engineering with bisphosphonic molecules for improving both photovoltaic performances and stability of perovskite solar cells.

Abstract Abstract: Despite the current advances in cancer drug discovery, cancer cells often develop resistance to chemotherapeutic agents leading to poor clinical outcomes. The phenomenon of multidrug resistance (MDR) is prevalent among tumor populations; wherein cancer cells are rendered resistant to structurally and mechanistically unrelated drugs. Of the several factors responsible for the development of MDR, the overexpression of ATP-binding cassette (ABC) efflux transporters poses a serious threat towards attaining a successful chemotherapeutic outcome. The second member of the G sub-family of ABC transporters (ABCG2) is one such efflux transporter that renders the cancer cells resistant to several chemotherapeutic drugs, in turn limiting their intracellular accumulation. The blockade of this efflux pump offers a strategic approach towards increasing the efficiency of chemotherapy. Here we demonstrate the biological activity of a novel N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide analog, CCTA-1650 that blocks the efflux function of ABCG2 in vitro and in vivo in a preclinical tumor xenograft nude mouse model. Cell cytotoxicity assays performed by combining the chemotherapeutic agents with CCTA-1650 at concentrations of up to 5 μM significantly increased the sensitivity of resistant cancer cells overexpressing both the wild-type and mutant variants of ABCG2. CCTA-1650 inhibits the function of the transporter by decreasing the efflux of substrate chemotherapeutic agents as evident from accumulation and efflux studies with [3H]-mitoxantrone. Furthermore CCTA-1650 at concentrations of up to 5 μM did not affect the expression of ABCG2 transporter upon treatment with CCTA-1650. In addition, CCTA-1650 increased the ATPase activity of ABCG2 in a concentration-dependent manner. CCTA-1650 also displayed inhibition of function of the ABCG2 transporter in an in vivo tumor xenograft nude mouse model. CCTA-1650 at a dose of 30 mg/kg significantly sensitized the resistant tumors to doxorubicin. This effect obtained with combining chemotherapeutic agents with an inhibitor of ABCG2 function both in vitro and in vivo demonstrates the usefulness of CCTA-1650 for the treatment of drug-resistant tumors in the clinic. Citation Format: Atish S. Patel, Tianwen Li, Nagaraju Anreddy, Yufen Zhao, Rishil J. Kathawala, Yijun Wang, Suresh V. Ambudkar, Zhe-Sheng Chen, Changmei Cheng. Design, synthesis and biological evaluation of N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide analog as a promising inhibitor of the multidrug resistance-linked ABCG2 transporter. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4419. doi:10.1158/1538-7445.AM2015-4419

Background: Human AlkB homolog 5 (Alkbh5) is an RNA demethylase that erases m(6)A modification. Results: Crystal structures of an enzymatically active Alkbh5 construct in complex with cofactors or small molecules were determined. Conclusion: Structure and activity analyses showed that Alkbh5 strongly prefers single-stranded oligos and small molecule inhibitors. Significance: The Alkbh5 structure reveals potential for structure-based design of selective inhibitors. N-6-Methylation of adenosine is the most ubiquitous and abundant modification of nucleoside in eukaryotic mRNA and long non-coding RNA. This modification plays an essential role in the regulation of mRNA translation and RNA metabolism. Recently, human AlkB homolog 5 (Alkbh5) and fat mass- and obesity-associated protein (FTO) were shown to erase this methyl modification on mRNA. Here, we report five high resolution crystal structures of the catalytic core of Alkbh5 in complex with different ligands. Compared with other AlkB proteins, Alkbh5 displays several unique structural features on top of the conserved double-stranded -helix fold typical of this protein family. Among the unique features, a distinct lid region of Alkbh5 plays a vital role in substrate recognition and catalysis. An unexpected disulfide bond between Cys-230 and Cys-267 is crucial for the selective binding of Alkbh5 to single-stranded RNA/DNA by bringing a flipping motif toward the central -helix fold. We generated a substrate binding model of Alkbh5 based on a demethylation activity assay of several structure-guided site-directed mutants. Crystallographic and biochemical studies using various analogs of -ketoglutarate revealed that the active site cavity of Alkbh5 is much smaller than that of FTO and preferentially binds small molecule inhibitors. Taken together, our findings provide a structural basis for understanding the substrate recognition specificity of Alkbh5 and offer a foundation for selective drug design against AlkB members.

The 1-azido-2-chloro-4-nitrobenzene was prepared by nucleophilic substitution between 2-chloro-4-nitro-1-(trifluoromethylsulfinyl)benzene and sodium azide, and its structure was characterized by NMR spectrum and X-ray single-crystal diffraction. It crystallizes in the monoclinic system, space group P2(1)/n, Z = 8 and M-r = 198.57. A cultivation process of the single crystal of unstable aryl azide was provided. The group of trifluoromethyl sulfinyl was found for the first time to be a new excellent leaving group of aromatic nucleophilic substitution reactions.

Cancer is a disease whose treatment is often limited due to the development of a phenomenon known as multidrug resistance (MDR). There is an immense demand for development of novel agents that can overcome the MDR in cancer. A group of transmembrane proteins called ATP-binding cassette transporters, present ubiquitously in the human body possesses a modular architecture, contributing immensely towards the development of MDR. An analysis of structural congeners among a group of compounds led to the discovery of CCTA-1523 that could selectively reverse ABCG2-mediated MDR in cancer cells in vitro and in vivo. CCTA-1523 (5 μM) sensitized the ABCG2 overexpressing cancer cells and ABCG2 transfected cells to the substrate chemotherapeutic drugs. The reversal ability of CCTA-1523 was primarily due to the inhibition of the efflux function of ABCG2; also there was no change in the protein expression or the localization of the ABCG2 in the presence of CCTA-1523. The reversal effect of CCTA-1523 was reversible. Importantly, co-administration of CCTA-1523 restored the in vivo antitumor activity of doxorubicin in ABCG2 overexpressing tumor xenografts. Taken together, our findings indicate that CCTA-1523 is a potent, selective and reversible modulator of ABCG2 that may offer therapeutic promise for multidrug- resistant malignancies.

A novel and efficient copper-catalyzed cascade method for the synthesis of quinazoline derivatives has been developed. The protocol uses readily available substituted (2-bromophenyl)methylamines and amidine hydrochlorides as the starting materials, inexpensive CuBr as the catalyst, and economical and environment friendly air as the oxidant, and the corresponding quinazoline derivatives were obtained in moderate to good yields. The procedure underwent sequential intermolecular N-arylation, intramolecular nucleophilic substitution and aerobic oxidation.

A convenient one-pot synthesis of enantiopure (R)-2-amino-3,3,3-trifluoro-2-methyl-N-phenylpropanamide derivatives has been developed. The key step in this synthetic methodology turned out to be the amide formation in which (R)-2-amino-3,3,3-trifluoro-2-methylpropanoic acid hydrochloride was simultaneously protected and activated by Vilsmeier reagent.

Our earlier research has shown that N-phenyl-2,2-dichloroacetamide analogues had much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this current study, a variety of N-arylphenyl-2,2-dichloroacetamide analogues were synthesized via Suzuki coupling reaction and their anti-cancer activity was evaluated. The results showed that N-terphenyl-2,2-dichloroacetamide analogues had satisfactory anti-cancer activity. Among them, N-(3,5-bis(benzo[d][1,3]dioxol-5-yl)phenyl)-2,2-dichloroacetamide (6 k) had an IC(50) of 2.40 μM against KB-3-1 cells, 1.04 μM against H460 cells and 1.73 μM against A549 cells.

Our earlier research has shown that mono-substituted N-phenyl-2, 2-dichloroacetamide exhibited much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this paper, a variety of multi-substituted N-phenyl-2, 2-dichloroacetamides were synthesized and biologically evaluated. The results showed that 3, 5-disubstituted N-phenyl-2, 2-dichloroacetamide analogues had satisfactory potency. Among them, N-(3, 5-diiodophenyl)-2, 2-dichloroacetamide had an IC50 of 2.84 micromol x L(-1) against non-small cell lung cancer cell line A549 and could induce cancer cell apoptosis.

Vanillin was synthesized by using 3-bromo-4-hydroxyphenylformaldehyde as raw material.The optimal reaction conditions were obtained by orthogonal parallel experiment as follows:the overall yield of target compound reached to 92.3% by using L-proline as ligand,anhydrous copper chloride as catalyst,and reaction temperature was controlled at 120 ℃.The structure of target compound was confimed by 1HNMR and 13CNMR.

A disubstituted triazine compound, namely, 2-amino-4,6-bis（diphenoxyl phosphorramide）-1,3,5-triazine, which is an inherent flame retardant monomer, was synthesized specifically, and its structure was characterized by using NMR spectrum and X-ray single-crystal diffraction. Unit cell parameters: space group P21/c, Z=4, a=8.7494（15）, b=27.518（5）, c=12.511（2）,β=109.323（16） , Z=4, V=2842.7（9）β3 , Dc=1.380 g/cm3 , F（000）=1224 and Mr=590.46. All the atoms are in the general positions.

Dicyclohexylphosphinic acid is synthesized via free radical addition reaction used diphenylphosphine and cyclohexene as the reagent,acetic acid as the solvent and di-t-butyl peroxide as the initiator,yielding 90%.The product is characterized by 1HNMR,13CNMR,31PNMR,ESI-MS.The advantages of this reaction are high yield,easy purification and mild condition.The free radical reaction mechanisms are suggested.

Carboxyl,amino,sulfhydryl derivatives of mPEG were synthesized starting from mPEG.The sructure of mPEG derivatives were confirmed by FT-IR,1HNMR and 13CNMR.

Flavonoids are important bioactive dietary compounds, which are proved to be antioxidant responsive element (ARE) activators to defend against electrophilic toxicants and oxidative stress. The activators induce ARE gene transcription through Nrf2 factor, a major transcriptional stimulator of cytoprotective genes, relieved from a Keap1 complex. In this report, based on the structures of two flavonoids, scutellarin and baicalin, which are extracted from two common Chinese plants Dengzhanhua (Erigeron breviscapus (vant) Hand-Mazz) and Huangqin (Scutellaria baicalensis Georigi), respectively, we synthesized several 8-substituted and deglucuronidated analogues and identified the ARE activation effects of these flavonoids. We found that the Baicalin, deglucurnonidated Baicalin and diaza cyclopenta derivative were more active. Their dose-dependent upregulation activities of ARE and NQO1 and induction effects of Nrf2 were testified. The results presented that these three analogues had good upregulation effects on ARE, and they could be potentially utilized in relieving oxidative stress, upon further neuroprotective tests.

A series of telbivudine 3'-O-acetyl-5'-O-phenyl-N-alkylphosphramidate derivatives have been synthesized and their structures were confirmed by EI-MS,1H NMR and 13C NMR.We evaluated their anti-HBV activity in vitro.Two compounds 6d and 6f,turned out to be more active than telbivudine.

A novel copper extractant 5-decylsalicylaldoxime is synthesized with the use of a cheap mixture by-product,5-decylsalicylaldoxime,from the petrochemical industry.The optimal condition is,n(decylphenol)∶n(magnesium)∶n(paraformaldehyde)=1∶0.65∶2.8,reaction time 5 h for the formylation reaction and n(decylphenol)∶n(hydroxylamine hydrochloride)=1∶1,reaction time 1 h for the oximation reaction.Under this condition,the yield of the desired product reaches to 75.9%(based on decylphenol) with 99.0% purity(determined by GC).The structure is elucidated by MS,NMR and EA analysis.It is indicated by the comparison with the M5640 and M5774 that the extraction performance of the product is of high copper load capability(6.36 g/L),good copper selectivity over iron(β=1 340),the extracting and stripping balance time are short,the extracting rate is more than 98% and the stripping extracting rate is more than 90% through only one stage.