Propyl Substituents Research Articles

New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research.

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME—administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 μM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.

Influence of Ring Modifications on Nucleolar Stress Caused by Oxaliplatin-Like Compounds.

Oxaliplatin, a platinum compound in broad clinical use, can induce cell death through a nucleolar stress pathway rather than the canonical DNA damage response studied for other Pt(II) compounds. Previous work has found that the oxaliplatin 1,2-diaminocyclohexane (DACH) ring but not the oxalate leaving group is important to the ability to induce nucleolar stress. Here we study the influence of DACH ring substituents at the 4-position on the ability of DACH-Pt(II) compounds to cause nucleolar stress. We determine that DACH-Pt(II) compounds with 4-position methyl, ethyl, or propyl substituents induce nucleolar stress, but DACH-Pt(II) compounds with 4-isopropyl substituents do not induce nucleolar stress. This effect is independent of whether the substituent is in the axial or equatorial position relative to the trans diamines of the ligand. These results suggest that spatially sensitive interactions could be involved in the ability of platinum compounds to cause nucleolar stress.

The crystal structures of three disordered 2-substituted benzimidazole esters.

The crystal structures of three benzimidazole esters containing aryl or heterocyclic substituents at position 2 are reported, and all three exhibit disorder of mol-ecular entities. In ethyl 1-methyl-2-[4-(prop-2-yn-oxy)phen-yl]-1H-benzimidazole-5-carboxyl-ate, C20H18N2O3, (I), the prop-2-yn-1-oxyphenyl unit is disordered over two sets of atomic sites having effectively equal occupancies, 0.506 (5) and 0.494 (5). The propyl substituent in ethyl 1-propyl-2-(pyren-1-yl)-1H-benzimidazole-5-carboxyl-ate, C29H24N2O2, (II), is disordered over two sets of atomic sites having occupancies 0.601 (8) and 0.399 (8), and the ester unit in ethyl 1-methyl-2-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1H-benzimidazole-5-carboxyl-ate, C21H19ClN4O2 (III), is disordered over two sets of atomic sites having occupancies 0.645 (7) and 0.355 (7). In each of the C-H⋯π(arene) hydrogen bonds in (I), the donor and acceptor form parts of different disorder components, so that no continuous aggregation is possible. The mol-ecules of (II) are linked by a single C-H⋯O hydrogen bond into C(10) chains, which are linked into sheets by a π-π stacking inter-action, whereas those of (III) are just linked into C(13) chains, again by a single C-H⋯O hydrogen bond. Comparisons are made with the structures of some related compounds.

Synthesis of alkyl derivatives of 3,7,10-trioxo-2,4,6,8,9,11-hexaaza[3.3.3]propellane and evaluation of their biological activity

Today 3,7,10-trioxo-2,4,6,8,9,11-hexaaaza[3.3.3]propellane (THAP) has not yet received widespread re-search attention due to the complexity of the synthesis. This work is devoted to the development of a method for the THAP derivatives synthesis, as well as to the study of their biological activity in comparison with al-kyl-substituted glycolurils (subject of comparison). ТНАРwas N-alkylated to furnish novel hexaalkyl deriva-tives of ТНАРwith methyl, ethyl and propyl substituents. The conditionsfor obtaining the maximum yield of the target productwere optimizedon the base of methyl derivative. The reaction proceeded in DMSO/КОНat 75–80ºC for 13hours in a moderate yield of 56%. The ethyl and propyl derivatives of ТНАРwere synthe-sized under the same conditions. The biological activity of the obtained ТНАРalkyl derivatives and glycoluril alkyl derivatives was evaluated against Sporosarcina ureae, Bacillus pumilus, Salmonella typhimurium and Staphylococcus aureus bacteria and influenza A virus. All the samples were found to exhib-it antibacterial activity against Staphylococcus aureus.It was shown that 2,4,6,8,9,11-hexapropyl-ТНАР, di-tert-butyl-diphenyl-, di-tert-butyl-dibenzyl-, di-tert-butyl-dimethyl-and di-isopropyl-dibenzylglycoluril, have exhibited also toxicity to living cells besides antiviral activity

Chiral Recognition of Homochiral Poly (amidoamine) Dendrimers Substituted with R- and S-Glycidol by Keratinocyte (HaCaT) and Squamous Carcinoma (SCC-15) Cells In Vitro.

The generation 2 and 3 poly(amidoamine) dendrimers (PAMAM G2 and G3) were converted into N-(2,3-dihydroxy)propyl derivatives by the addition of enantiomerically pure S- and R-glycidol. The homochiral dendrimers bind to HaCaT and SCC-15 cell membranes with an R/S glycidol enantioselectivity ratio of 1.5:1, as was quantitatively determined by fluorescence microscopy and visualized by confocal microscopy. Fully substituted G2 and G3 dendrimers were equipped with 32 and 64 N-(2,3-dihydroxy)propyl residues and showed effectively radial symmetry for homochiral derivatives in 13C NMR spectrum in contrary to analogs obtained by reaction with rac-glycidol. The sub-stoichiometric derivatives of G2 and G3 were also obtained in order to characterize them spectroscopically. The homochiral dendrimers were labeled with two different fluorescent labels, fluorescein, and rhodamine B, using their isothiocyanates to react with G2 and G3 followed by the addition of S- and R-glycidol. Obtained fluorescent derivatives were deficiently filled with N-(2,3-dihydroxy)propyl substituents due to steric hindrance imposed by the attached label. Nevertheless, these derivatives were used to determine their ability to bind to the cell membrane of human keratinocytes (HaCaT) and squamous carcinoma cells (SCC-15). Confocal microscopy images obtained from cells treated with variously labeled conjugates and fluorescence analysis with fluorescence reader allowed us to conclude that R-glycidol derivatives were bound and entered the cells preferentially, with higher accumulation in cancer cells. The G3 polyamidoamine (PAMAM)-based dendrimers were taken up more efficiently than G2 derivatives. Moreover, S- and R-glycidol furnished dendrimers were highly biocompatible with no toxicity up to 300 µM concentrations, in contrast to the amine-terminated PAMAM analogs.

Synthesis and anthelmintic activity of some novel (E)-2-methyl/propyl-4-(2-(substitutedbenzylidene)hydrazinyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines

A series of some novel (E)-2-methyl/propyl-4-[(2-(substitutedbenzylidene)hydrazinyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines was synthesized and characterized by adopting an appropriate synthetic scheme. The effect of electron withdrawing and electron donating groups at the aromatic ring in presence of methyl and propyl substituents at the 2-position of the scaffold was evaluated for anthelmintic activity against adult Indian earthworms (Pheretima posthuma). Among 2-methyl-thieno[2,3-d]pyrimidine analogs, compounds with electron donating methoxy group either at para-position or at meta and para-positions of the aromatic ring showed potent anthelmintic activity at 100 μg/ml (284 and 261.8 μM concentrations) for compounds 5g and 5h with a mean paralytic time of 2.32, 2.22 min, and helminthicidal time of 22.38, 19.43 min, respectively. In contrast, the presence of electron withdrawing chloro group at ortho and para-position of the aromatic ring was found to be favorable for the anthelminthic activity of the compounds 5n and 5o (at concentration of 259.7 μM) with propyl group at the 2-position of the thieno[2,3-d]pyrimidine scaffold, exhibiting mean paralytic time of 2.5 min, 2.81 min and helminthicidal time of 21, 20.03 min, respectively. Anthelmintic activities of these four compounds 5g, 5h, 5n, and 5o (at the concentrations of 284, 261.8, 259.7, and 259.7 μM, respectively) were found to be on par with the standard drug piperazine adipate (time for paralysis and death at 6.25 and 24.5 min, respectively) at concentration of 100 μg/ml (431.03 μM). Overall, the potency of these compounds (5g, 5h, 5n, and 5o) is better than standard drug as they exhibited the same activity at 259.7–284 μM as that of a standard drug (which has shown the same activity at 431.03 μM). Further, the predicted ADME properties of all the synthesized compounds were found to be in the satisfactory ranges as predicted by SwissADME software and found to have drug-like properties. Thus, further modification of these compounds might lead to the discovery of more potent analogs.

Design and Synthesis of Novel 1a,3,4-Oxadiazole Derivatives as Cytotoxic Agents: A Combined Experimental and Docking Study

A novel series of 3,5-disubstituted-1a,3,4-oxadiazole derivatives was synthesized and screened for in vitro anticancer activity. The newly synthesized compounds were characterized by 1H, 13C NMR, IR spectroscopy and mass spectrometry. Among all the synthesized compounds, Oxaprozin derivatives containing 1,3,4-oxadiazole ring with 4-fluorobenzyl, 4-methoxybenzyl, methyl, and butyl substituents showed promising anticancer activity against HTB-57 cancer cell line, and derivatives with 4-fluorobenzyl, 4-methoxybenzyl, and propyl substituents exhibited a higher anticancer activity against a PPC-1 cell line. The possible binding mode interactions of the synthesized compounds with the key active site of the proline rich tyrosine kinase 2 Pyk2 receptor (PDB ID: 5TO8) were investigated using the AutoDock 4.2 docking protocol to find that the 1,3,4-oxadiazole Oxaprozin derivatives with methyl, ethyl, and propyl substituents had the highest binding energies (ΔG = –7.8, –7.6, and –6.8 kcal/mol, respectively) with Glu441, Leu431, Ala455, Val487, Met502, Leu556, Lys457, and Glu509.

Heterogeneous anion exchange membranes with nitrate selectivity and low electrical resistance

Selective transport of specific ions across ion-exchange membranes can be enhanced by controlling membrane properties such as hydrophobicity. Previous studies have shown that hydrophobic membranes enhance transport of ions with low hydration energy, although such membranes often have increased electrical resistance. In the present work, we study the separation of monovalent ions, specifically nitrate and chloride, using newly-designed heterogeneous anion-exchange membranes. These membranes show high selectivity for nitrate over chloride and have low electrical resistance. We use a functionalized polymeric binder (ionomer) and three ion-exchange resins with different hydrophobic groups, i.e., resins with quaternary ammonium groups and methyl, ethyl, and propyl substituents, respectively. We find that in electrolyte solutions with nitrate and chloride, nitrate over chloride selectivity in our membranes increases with increasing length of the alkyl groups. The membrane with propyl groups, i.e., which has the highest selectivity for nitrate, was further tested in electrolyte solutions containing nitrate, chloride, sulfate, and nitrate, chloride, iodate. The transport of sulfate and iodate ions across the membrane with propyl groups was 6% and 2% of the total counterions transport, respectively. For monovalent ions with similar hydrated size it is possible to report selectivity trends based on the ion hydration energy. We find that the chemical structure of the membrane can either promote or hinder the transport of ionic species.

Soluble Telechelic Polycondensation Poly(ether ketones): Synthesis and Characterization

AbstractThe present article reports the synthesis of soluble, propyl‐substituted aromatic ring telechelic polycondensation blocks having molecular weights ranging from 1800 to 6500 g mol−1 and polymolecularities of 1.3 to 1.7. Chain‐growth polycondensation is performed, and the initiator is selected through reactivity studies, using 19F nuclear magnetic resonance (NMR) measurements. Gel permeation chromatography, NMR spectroscopy, and matrix‐assisted laser desorption/ionization time of flight mass spectrometry show that blocks are terminated by a methoxy group at one end and a fluorine atom at the other. Polymers are crystalline as synthesized, as shown by X‐ray diffraction and differential scanning calorimetry, do not recrystallize once melted, and undergo solvent‐induced crystallization. Crystalline peak positions and relative intensities are different from those observed for other poly(ether ketones). The difference in crystal form is proposed to stem from packing disruption related to the presence of propyl substituents. Thermogravimetry shows a good thermal resistance up to 450 °C.

Primary Screening of Photosensitizers of the Bacteriochlorin Series for Photodynamic Therapy of Malignant Neoplasms

Primary screening of photosensitizers of the bacteriochlorin series containing aminoamide, propyl, and carbohydrate substituents was carried out; it included an assessment of spectral characteristics of these compounds, their storage stability in solution under darkened conditions and light exposure, and the study of photoinduced activity and cytotoxicity on tumor of HEp2 cells. According to the results of absorption and fluorescence analyzes, dyes with aminoamide substituents had a maximum at 754 ± 2 nm, are not stable during storage (fluorescence intensity decreased by 33–56% during a day); compounds with propyl and carbohydrate substituents absorbed in the region of 780–831 nm were characterized by stability during storage and irradiation. All PS except the dye with the carbohydrate residue in the exocycle E, exhibited photoinduced activity and lack of dark toxicity. The highest photoactivity was detected in compounds with aminoamide fragments in the macrocyclic ring (during 2 h-incubation the IC50 ranged from 17 nM to 49 nM). Taking into consideration physicochemical and biological properties, as well as technology of production and stability during storage and irradiation, O-propyloxime-N-propoxybacteriopurinimide methyl ester was chosen for further research aimed at creating a new PS generation for photodynamic therapy of malignant tumors.

New bipyridine ruthenium dye complexes with amide based ancillary ligands as sensitizers in semitransparent quasi-solid-state dye sensitized solar cells

Abstract A series of three heteroleptic ruthenium complexes containing 2,2′-bipyridine-4,4′-dicarboxamide ligands with different substituents (propyl, benzyl or 2-phenylethyl) was synthesized as possible sensitizers for dye sensitized solar cells (DSSCs). Their structure was characterized with 1H NMR and FTIR while their optical and electrochemical properties were also investigated. The observed optical differences were associated to structural properties of the three complexes and different electron donor strength of the ancillary ligands. In particular, ruthenium complex with propyl based ligand showed higher molar extinction coefficient succeeding better light harvesting. Semitransparent dye sensitized solar cells employing quasi-solid-state electrolyte and the three ruthenium complexes were constructed under the same fabrication conditions and electrically characterized under standard conditions of light irradiance (100 mW/cm2, AM 1.5). Their behavior was compared with that of commercially available ruthenium complex D907 with increased conjugation length of the ancillary ligand, in terms of current–voltage characteristic curves under simulated solar light and in the dark while electrochemical impedance spectroscopy was also used for local resistance to charge transfer across the TiO2-dye/electrolyte interface. The influence of ancillary ligands into ruthenium complexes was discussed in terms of the cells’ efficiency. A maximum overall performance of 5.0% was monitored for ruthenium complex with propyl substituent in comparison to 5.1% that was measured for semitransparent quasi-solid state devices with commercial D907.

5,5-Diphenyl-3-propylimidazolidine-2,4-dione

The asymmetric unit of the title compound, C18H18N2O2, consists of two independent molecules differing primarily in the orientation of the propyl substituent. One of the propyl groups is disordered over two positions with an occupancy ratio of 0.859 (2):0.141 (2). The two independent molecules are associated through a C—H...π(ring) interaction and sheets parallel to (011) are formed from further sets of C—H...π(ring) interactions. The sheets are connectedviainversion-related N—H...O hydrogen bonds.

Influence of Hydrophobicity on Polyelectrolyte Complexation

Polyelectrolyte complexes are a fascinating class of soft materials that can span the full spectrum of mechanical properties from low-viscosity fluids to glassy solids. This spectrum can be accessed by modulating the extent of electrostatic association in these complexes. However, to realize the full potential of polyelectrolyte complexes as functional materials, their molecular level details need to be clearly correlated with their mechanical response. The present work demonstrates that by making simple amendments to the chain architecture, it is possible to affect the salt responsiveness of polyelectrolyte complexes in a systematic manner. This is achieved by quaternizing poly(4-vinylpyridine) (QVP) with methyl, ethyl, and propyl substituents—thereby increasing the hydrophobicity with increasing side chain length—and complexing them with a common anionic polyelectrolyte, poly(styrenesulfonate). The mechanical behavior of these complexes is compared to the more hydrophilic system of poly(styrenesulfonate...

β-Amyrin Biosynthesis: Promiscuity for Steric Bulk at Position 23 in the Oxidosqualene Substrate and the Significance of Hydrophobic Interaction between the Methyl Group at Position 30 and the Binding Site.

To examine how the sterics at the 23 position of (3S)-2,3-oxidosqualene 1 influence the polycyclization cascade in β-amyrin biosynthesis, substrate analogues substituted with an ethyl group (10, 11), a hydrogen atom (12, 13), or a propyl residue (14) at the 23 position were incubated with β-amyrin synthase. The bulkier ethyl group was accepted as a substrate, leading to formation of the β-amyrin skeleton (42, 43) without truncation of the multiple cyclization reactions. Analogue 13, possessing a hydrogen atom and an ethyl group at the 23E and 23Z positions, respectively, was also converted into the β-amyrin skeleton 45. However, the analogue lacking an ethyl group at the 23Z position (12) underwent almost no conversion, strongly indicating that an alkyl group must exist at the Z position. The cyclization of the analogue with a propyl substituent at the Z position (14) was poor. Analogue 15 possessing CH2OH at the 23E position afforded a new compound 47 in a high yield as a result of trapping of the final oleanyl cation. Conversely, 16 with 23Z-CH2OH afforded novel compounds 48-50 in low yields, which resulted from the intermediary dammarenyl and baccharenyl cations. Therefore, the hydrophobic interaction between the 23Z-alkyl group and its binding site (possibly via CH/π interaction) is critical for adopting the correct chair-chair-chair-boat-boat conformation and for the full cyclization cascade.

Synthesis and photophysical studies of new benzo[a]phenoxazinium chlorides as potential antifungal agents

A set of four new benzo[a]phenoxazinium chlorides possessing ethyl, propyl, decyl and tetradecyl groups at the 9-amino function of the heterocycle along with a propyl group at the 5-amino position was efficiently synthesized. These compounds displayed fluorescence with maximum emission wavelengths of 673 and 685nm, in anhydrous ethanol and water. All the benzo[a]phenoxazines were evaluated against the yeast Saccharomyces cerevisiae in a broth microdilution assay. It was found that their antifungal activity depended on the variation in the lengths of the aliphatic chains. The highest MIC activity of 1.56μM was obtained for compound 7 comprising a di-alkylated propyl substituent at 9-amino position and a propyl chain at the 5-amino position of the heterocycle core.

1-Propyl-1H-indole-2,3-dione

In the title compound, C11H11NO2, the 1H-indole-2,3-dione unit is essentially planar, with an r.m.s. deviation of 0.0387 (13) Å. This plane makes a dihedral angle of 72.19 (17)° with the plane of the propyl substituent. In the crystal, chains propagating along thebaxis are formed through C—H...O hydrogen bonds.

A new strategy for hydrogen sulfide removal by amido-functionalized reduced graphene oxide as a novel metal-free and highly efficient nanoadsorbent

In this research, hydrogen sulfide is adsorbed on amido-functionalized reduced graphene oxide (AFRGO) as a nanoadsorbent. By the use of n-propylamine and allylamine, reduced graphene oxide (RGO) was amidated for the adsorption of hydrogen sulfide. The materials were characterized by adsorption of H2S, potentiometric titration, scanning electron microscopy (SEM), Fourier-transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) analysis. The effect of the operational conditions of 4000–6000 h−1 space velocities and 60,000 ppm H2S feed concentrations were examined on adsorption capacity. The results show that H2S feed concentration, space velocity, and functional groups of adsorbents have a major effect on H2S adsorption. It was also found that the temperature in the range of 30–70°C had a significant effect on H2S adsorption. The concentration of H2S adsorbed in 3 h by AFRGO containing allyl substituent, AFRGO containing propyl substituent, graphene oxide (GO), and reduced graphene oxide (RGO) were reported as 59,710, 59,650, 59,600, and 59,500 ppm, respectively. Hydrogen sulfide adsorption analysis showed that nanoadsorbents increase adsorption capacity of H2S.

Improving the Catalytic Performance of an Artificial Metalloenzyme by Computational Design.

Artifical metalloenzymes combine the reactivity of small molecule catalysts with the selectivity of enzymes, and new methods are required to tune the catalytic properties of these systems for an application of interest. Structure-based computational design could help to identify amino acid mutations leading to improved catalytic activity and enantioselectivity. Here we describe the application of Rosetta Design for the genetic optimization of an artificial transfer hydrogenase (ATHase hereafter), [(η(5)-Cp*)Ir(pico)Cl] ⊂ WT hCA II (Cp* = Me5C5(-)), for the asymmetric reduction of a cyclic imine, the precursor of salsolsidine. Based on a crystal structure of the ATHase, computational design afforded four hCAII variants with protein backbone-stabilizing and hydrophobic cofactor-embedding mutations. In dansylamide-competition assays, these designs showed 46-64-fold improved affinity for the iridium pianostool complex [(η(5)-Cp*)Ir(pico)Cl]. Gratifyingly, the new designs yielded a significant improvement in both activity and enantioselectivity (from 70% ee (WT hCA II) to up to 92% ee and a 4-fold increase in total turnover number) for the production of (S)-salsolidine. Introducing additional hydrophobicity in the Cp*-moiety of the Ir-catalyst provided by adding a propyl substituent on the Cp* moiety yields the most (S)-selective (96% ee) ATHase reported to date. X-ray structural data indicate that the high enantioselectivity results from embedding the piano stool moiety within the protein, consistent with the computational model.

Propyl substituted 4-arylimino-1,2,3-trihydroacridylnickel complexes: Their synthesis, characterization and catalytic behavior toward ethylene

Propyl substituted 4-arylimino-1,2,3-trihydroacridylnickel dihalide complexes were designed and prepared by metal-induced template reaction with NiCl2·6H2O or (DME)NiBr2. They were characterized by infrared spectroscopy and elemental analysis. Single crystal X-ray crystallography of representative complex Ni3 revealed a distorted trigonal bipyramidal geometry around nickel. The catalytic activities of the title nickel complexes were negatively affected by propyl substituent on their backbone when comparing with the results by unsubstituted ones. With the activation of diethylaluminium chloride, all nickel complexes exhibited moderate activity (up to 5.10 × 105 g mol−1(Ni) h−1) for ethylene oligomerization and oligomeric products ranged from C4 to C16.

Microwave-assisted synthesis of dialkylphosphinic acids and a structure–reactivity study in rare earth metal extraction

Dialkylphosphinic acids were synthesized efficiently under microwave irradiation. The extractants with ethyl or propyl substituents at the β-position showed higher separation efficiency.