Rapid and Simple Method for Measuring Petroleum Asphaltenes by the Centrifugation Technique.

Asphaltenes are heavy constituents of crude oil which affect the flow and viscosity of crude oil. They also stabilize water-in-oil emulsions which makes the separation process of water from oil during the primary treatment processes for crude oils more difficult and costly. Measuring asphaltenes has great importance, especially for crude oil production companies. Gravimetric and spectroscopic measurement methods are the basic techniques used by international references such as ASTM and IP. A new methodology has been introduced as a modification of ASTM D6560 gravimetric methodology by using the centrifugation technique in the separation of asphaltenes for different oil samples with the API gravity change from 17.4 (oil S1) to 39.8 (oil S5). The new methodology has the advantages of consuming little time, and multiple sample processing and can be done in the field and also in the lab. Moreover, it has good repeatability, reproducibility, and working range values compared to the reference gravimetric ASTM and IP methods. The repeatability of the new method was found to be 8.0% at its maximum value (S1, has a low asphaltene content), while the minimum value was found to be 3.75% (S10, has the highest asphaltene content). It was found that the maximum reproducibility value was 17.0% for the S1 sample and the minimum was 0.0% for S9 and S10 samples.

Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation.

The tumor resistance to p53 activators posed a clinical challenge. Combination studies disclosed that concomitant administration of Bcl2 inhibitors can sensitize the tumor cells and induce apoptosis. In this study, we utilized a rapid synthetic route to synthesize two novel hybrid spirooxindole-based p53-MDM2 inhibitors endowed with Bcl2 signaling attenuation. The adducts mimic the thematic features of the chemically stable potent spiro [3H-indole-3,2'-pyrrolidin]-2(1H)-ones p53-MDM2 inhibitors, while installing a pyrrole ring via a carbonyl spacer inspired by the natural marine or synthetic products that efficiently inhibit Bcl2 family functions. A chemical insight into the two synthesized spirooxindoles including single crystal x-ray diffraction analysis unambiguously confirmed their structures. The synthesized spirooxindoles 2a and 2b were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 via MTT assay. 2b was superior to 5-fluorouracil. Mechanistically, 2b induced apoptosis-dependent anticancer effect (43%) higher than that of 5-fluorouracil (34.95%) in three studied cancer cell lines, activated p53 (47%), downregulated the Bcl2 gene (1.25-fold), and upregulated p21 (2-fold) in the treated cancer cells. Docking simulations declared the possible binding modes of the synthesized compounds within MDM2.

Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators.

Despite the achieved progress in developing efficient MDM2-p53 protein-protein interaction inhibitors (MDM2 inhibitors), the acquired resistance of tumor cells to such p53 activators posed an argument about the druggability of the pathway. Combination studies disclosed that concomitant inhibition of MDM2 and BCL2 functions can sensitize the tumor cells and synergistically induce apoptosis. Herein, we employed a rapid combinatorial approach to generate a novel series of hybrid spirooxindole-based MDM2 inhibitors (5a-s) endowed with BCL2 signaling attenuation. The adducts were designed to mimic the thematic features of the chemically stable potent spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-ones MDM2 inhibitors while installing a pyrrole ring on the core via a carbonyl spacer inspired by the natural product marinopyrrole A that efficiently inhibits BCL2 family functions by various mechanisms. NCI 60 cell-line panel screening revealed their promising broad-spectrum antiproliferative activities. The NCI-selected derivatives were screened for cytotoxic activities against normal fibroblasts, MDA-MB 231, HepG-2, and Caco-2 cells via MTT assay, subjected to mechanistic apoptosis studies for assessment of p53, BCL2, p21, and caspase 3/7 status, then evaluated for potential MDM2 inhibition utilizing MST assay. The most balanced potent and safe derivatives; 5i and 5q were more active than 5-fluorouracil, exhibited low µmrange MDM2 binding (KD=1.32and 1.72 µm, respectively), induced apoptosis-dependent anticancer activities up to 50%, activated p53 by 47-63%, downregulated the BCL2 gene to 59.8%, and reduced its protein level (13.75%) in the treated cancer cells. Further downstream p53 signaling studies revealed > 2 folds p21 upregulation and > 3 folds caspase 3/7 activation. Docking simulations displayed that the active MDM2 inhibitors resided well into the p53 binding sites of MDM2, and shared key interactions with the co-crystalized inhibitor posed by the indolinone scaffold (5i, 5p, and 5q), the halogen substituents (5r), or the installed spiro ring (5s). Finally, in silico ADMET profiling predicted acceptable drug-like properties with full accordance to Lipinski's, Veber's, and Muegge's bioavailability parameters for 5i and a single violation for 5q.

Design and synthesis of new phthalazine-based derivatives as potential EGFR inhibitors for the treatment of hepatocellular carcinoma.

Searching for new leads in the battle of cancer will never ends, we herein disclose the design and synthesis of new phthalazine derivatives and their in vitro and in vivo testing for their antiproliferative activity. Phthalazine was selected as a privilege moiety that is incorporated in a big number of anticancer drugs in clinical use or that are still under clinical or preclinical studies. We utilized the drug extension strategy to tailor the designed compounds to fit the EGFR hydrophobic sub pocket and cleft region. The designed phthalazine derivatives was synthesized by linking phthalazine moiety with 1,3,4-oxadiazole-thione and 1,2,4-triazole-thione. Alkylation and glycosylation of the new heterocyclic systems were successfully performed to be used in the drug extension. Coupling of some phthalazine derivatives with different amino acids was also performed to improve the drug selectivity. The synthesized compounds were tested for their antiproliferative activity against cancer cells both in vivo and in vitro. The in vitro activity against hepatocellular carcinoma (HepG2 cell line) ranged from 5.7 µg/mL to 43.4 µg/mL. Compounds 31a and 16 were the most active with an IC50 5.7 µg/mL and 7.09 µg/mL, respectively compared to the standard compound doxorubicin (4.0 µg/mL). In vivo, compounds 10 and 16 showed IC50 values 7.25 µg/mL and 7.5 µg/mL, respectively compared to the standard compound cisplatin (IC50 9.0 µg/mL). In silico, testing of the phthalazine derivatives showed that they are good inhibitors for EGFR. The docking studies substantiated compounds 4, 10, 16 and 31a as new lead compounds and identified Arg841 as a key residue in the cleft region for binding stronger inhibitors.

Regio- and stereoselective synthesis of new spirooxindoles via 1,3-dipolar cycloaddition reaction: Anticancer and molecular docking studies.

Owing to their structural novelty and inherent three-dimensionality, spiro scaffolds have been shown indisputable promise as chemopreventive agents. A new series of heterocycles containing spirooxindole and pyrrolidine rings were synthesized by the 1,3-dipolar cycloaddition of an azomethine ylide, which was generated in situ by the condensation of a secondary amino acid (l­proline) and dicarbonyl compounds (isatin), with dipolarophiles. This method is simple and provides diverse and biologically interesting products. The new series of compounds with a high degree of stereo- and regioselectivity were evaluated against breast cancer cell lines (MCF-7) and leukemia (K562). Among them, compound 4g was identified as the most potent with IC50 values of 15.49 ±â€¯0.04 µM, against breast cancer cell lines (MCF-7) compared to standard drug 5-Fu (IC50 = 78.28 ±â€¯0.2 µM) and compound 4i IC50 values of 13.38 ±â€¯0.14 µM against leukemia (K562) compared to standard drug 5-fluorouracil (5-FU) (IC50 = 38.58 ±â€¯0.02). The selective apoptotic effects of 4g were investigated against MCF-12 normal mammary cell and the cytotoxicity of 4g was not associated with any induction of necrosis compared to untreated cells. Molecular docking studies were investigated. From the docking data, these compounds could be act as small molecules that inhibit the MDM2-p53 interaction.

Corrosion and hydrogen evolution rate control for X-65 carbon steel based on chitosan polymeric ionic liquids: experimental and quantum chemical studies.

The corrosion performance of carbon steel was tested in four polymeric ionic liquids (PILs) that differed only in the fatty acid linked to the chitosan (CS) amine group. The measurements were implemented involved the hydrogen evolution rate (HER), gravimetric measurements, potentiodynamic polarization (PDP), electrochemical impedance spectroscopy (EIS), and quantum chemical estimations. The morphology and the elements arranged on the metal were considered by a scanning electron microscopy (SEM) system attached to an energy dispersive X-ray (EDX) system. The addition of polymeric ionic liquids hindered the rate of hydrogen generation. The order of the inhibitors efficiency was CSPTA-lauric > CSPTA-myristic > CSPTA-palmitic > CSPTA-stearic. The polarization method proved that the percentage inhibition efficiency increases with increasing the inhibitors concentration in 1 M HCl, representing a drop in the corrosion rate of carbon steel. On the other hand, the percentage inhibition decreased with the increase in temperature. Quantum chemical calculations revealed that the tested ionic liquids could react with the iron surface via electron transfer from the metal atom to ionic liquid molecule.

Synthesis of new spirooxindole-pyrrolothiazole derivatives: Anti-cancer activity and molecular docking.

The 1,3-dipolar cycloadditions of an azomethine ylide generated from isatin and thiazolidinecarboxylic acid to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded new di-spiro heterocycles incorporating pyrrolidine and oxindole rings in quantitative yields and chemo-, regio-, and stereoselectively. The newly synthesized compounds were characterized using spectroscopic techniques. Furthermore, the molecular structures of 4a, 4e, and 4n were confirmed by X-ray crystallography. These newly synthesized compounds were screened for their in vitro activity against breast cancer cell line MCF-7 and K562-leukemia. 4k was found to be the most potent compound of this series in targeting MCF-7 breast cancer cells and K562-leukemia, with IC50 values of 15.32±0.02 and 14.74±0.7µM, respectively. The molecular studies of the synthesized compounds were investigated.

Regioselective synthesis, characterization and antimicrobial evaluation of S-glycosides and S,N-diglycosides of 1,2-Dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione.

Glycosylation of 1,2-Dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide, 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride was investigated in the presence of Et3N and K2CO3 as acid scavengers. A regioselective S-glycosides were obtained by using Et3N whereas, using K2CO3 gave a mixtures of two hybrids having two glycosidic bonds. The two products of each mixture were separated and characterized as S,N(1)- and S,N(2)-bis(glycosylated) derivatives. The structures of the newly synthesized compounds were elucidated by (1)H NMR, (13)C NMR, 2D NMR and mass spectra. The compounds were screened for their antibacterial and antifungal activities. Some compounds exhibited strong inhibition activity compared with the reference drugs (chloramphenicol and baneocin).

A new synthetic access to 2-N-(glycosyl)thiosemicarbazides from 3-N-(glycosyl)oxadiazolinethiones and the regioselectivity of the glycosylation of their oxadiazolinethione precursors.

Glycosylations of 5-(1H-indol-2-yl)-1,3,4-oxadiazoline-2(3H)-thione delivered various degrees of S- and/or N-glycosides depending on the reaction conditions. S-Glycosides were obtained regiospecifically by grinding oxadiazolinethiones with acylated α-D-glycosyl halides in basic alumina, whereas 3-N-(glycosyl)oxadiazolinethiones were selectively obtained by reaction with HgCl(2) followed by heating the resultant chloromercuric salt with α-D-glycosyl halides in toluene under reflux. On using Et(3)N or K(2)CO(3) as a base, mixtures of S- (major degree) and N-glycosides (minor degree) were obtained. Pure 3-N-(glycosyl)oxadiazolinethiones can also be selectively obtained from glycosylsulfanyloxadiazoles by the thermal S→N migration of the glycosyl moiety, which is proposed to occur by a tight-ion-pair mechanism. Thermal S→N migration of the glycosyl moiety can be used for purification of mixtures of S- or N-glycosides to obtain the pure N-glycosides. The aminolysis of the respective S- or N-glycosides with ammonia in aqueous methanol served as further confirmation of their structures. While in S-glycosides the glycosyl moiety was cleaved off again, 3-N-(glycosyl)oxadiazolinethiones showed a ring opening of the oxadiazoline ring (without affecting the glycosyl moiety) to give N-(glycosyl)thiosemicarbazides. Herewith, a new synthetic access to one of the four classes of glycosylthiosemicarbazides was found. The ultimate confirmation of new structures was achieved by X-ray crystallography. Finally, action of ammonia on benzylated 3-N-(galactosyl)oxadiazolinethione unexpectedly yielded 3-N-(galactosyl)triazolinethione. This represents a new path to the conversion of glycosyloxadiazolinethiones to new glycosyltriazolinethione nucleosides, which was until now unknown.

Immunomodulatory properties of S- and N-alkylated 5-(1H-indol-2-yl)-1,3,4-oxadiazole-2(3H)-thione.

A series of S- and N-alkylated indolyloxadiazoles 2-7 were prepared. All compounds were tested for their immunomodulatory activity against T-cell proliferation, oxidative burst and cytokine analysis. Compounds 1, 2a, 2b, 2c and 2k demonstrated highly significant (P ≤ 0.005) inhibition on PHA activated T-cell proliferation with IC(50) less than 3 µg/mL concentration, while 3b exert a moderate inhibitory effect with IC(50) 8.6 µg/mL. Among all compounds of the series, only 2h was found to suppress phagocytes ROS production (IC(50) 2.4 µg/mL) in luminol-based chemiluminescence (CL) assay. Compounds 2a-k have stimulatory effect on proinflammatory cytokine predominantly IL-1ß but no effect on IL-4 and NO production indicating that these compounds might have selective inhibitory effect on T-cell proliferation. Cytotoxic effect on T-cell proliferation was tested on NIH-3T3 mouse fibroblast normal cell line. All compounds were found to be free from toxic effects up to 100 µM concentration.