Cyclohexyl Substituents Research Articles

1,2,3-Triazole tethered β-lactam-Chalcone bifunctional hybrids: Synthesis and anticancer evaluation

The manuscript describes the synthesis of novel 1,2,3-triazole tethered β-lactam-chalcone bifunctional hybrids via click chemistry approach utilizing azide-alkyne cycloaddition reactions and their evaluation as anticancer agents against four human cancer cell lines. The presence of a cyclohexyl substituent at N-1 of β-lactam ring and methoxy substituents, preferably ortho on ring A and para on ring B on chalcones markedly improved the anticancer profiles of the synthesized scaffolds with the most potent of the test compound exhibiting an IC 50 value of <1, 67.1, <1 and 6.37 μM against A-549(lung), PC-3(prostate), THP-1(leukemia), and Caco-2(colon) cell lines, respectively.

Antiplasmodial and cytotoxicity evaluation of 3-functionalized 2-azetidinone derivatives

3-Azido-, 3-amino- and 3-(1,2,3-triazol-1-yl)-β-lactams were synthesized and evaluated for their antiplasmodial activity against four strains of Plasmodium falciparum and KB cells for their cytotoxicity profiles. The presence of a cyclohexyl substituent at N-1 and a phenyl group on the triazole ring markedly improved the activity profiles of triazole-tethered β-lactam exhibiting IC(50) values of 1.13, 1.21 and 1.00 μM against 3D7, K1 and W2 strains respectively.

Correlation between hydrocarbon flexibility and physicochemical properties for cyclohexyl-imidazolium based ionic liquids studied by 1H and 13C NMR

We have synthesized and characterized a series of cyclohexyl-imidazolium based ionic liquids incorporating a bis(trifluoromethanesulfonyl)amide anion. To reveal the characteristic features afforded by a flexible cyclohexyl substituent, the physicochemical properties including densities, shear viscosities, and thermal properties, were measured and compared with the respective n-alkyl-imidazolium ionic liquids. The cyclohexyl-imidazolium ionic liquids showed higher densities, higher shear viscosities, and higher glass transition temperatures than their acyclic counterparts. Using 1H and 13C nuclear magnetic resonance spectra, we also studied the conformational dynamics of these species.

Donor‐Functionalised Expanded Ring N‐Heterocyclic Carbenes: Highly Effective Ligands in Ir‐Catalysed Transfer Hydrogenation

AbstractThe performances of a number of RhI and IrI complexes of type [M(NHC)(COD)Cl] in the transfer hydrogenation of ketones were tested under a variety of reaction conditions, and with a variety of substrates, allowing comparison of Rh‐ and Ir‐NHC complexes, and also comparison of the influence of the NHC ligand on catalytic performance. Notably, of the RhI and IrI complexes with symmetrically substituted NHCs only those bearing cyclohexyl substituents were active, with RhI complexes of saturated 5‐, 6‐ and 7‐NHCs with N‐Mes substituents, [Rh(5,6,7‐Mes)(COD)Cl], showing no activity in transfer hydrogenation under the test conditions. RhI and IrI complexes of unsymmetrical o‐methoxyphenyl donor‐functionalised NHCs (df‐NHC) with differing carbene ring sizes were also tested in transfer hydrogenations, with the RhI complexes displaying no catalytic activity. However, the corresponding df‐NHC IrI complexes were found to be extremely effective catalysts. Catalyst tests also demonstrated the excellent stability of these complexes.

Synthesis and Anticancer Evaluation of Naphthoquinone Esters with 2′-Cyclopentyl and 2′-Cyclohexyl Substituents

Twelve novel naphthoquinone esters containing cyclopentyl and cyclohexyl substituents at C-2' of the propyl chain were synthesized by starting from 1-hydroxy-2-naphthoic acid via alkylation with cyclopentyl ester and cyclohexyl ester. They were evaluated for cytotoxicity against three cancer cell lines (human epidermoid carcinoma (KB), human cervical carcinoma (HeLa), and human hepatocellular carcinoma (HepG(2))). In comparison to naphthoquinone esters with the 2',2'-dimethyl group, the naphthoquinones with a 2'-cyclopentyl substituent showed stronger activity than those with a 2'-cyclohexyl substituent, but less than that with the 2',2'-dimethyl group. This work provides new information about the effect of 2'-position substituents on the cytotoxicity of naphthoquinone ester analogues.

Coupling of Silsesquioxane Cages in the Coordination Sphere of Erbium

AbstractA novel transformation of silsesquioxane cages in the coordination sphere of a lanthanide ion is reported. Reaction of in situ prepared (c‐C6H11)7Si7O9(OLi)3 with anhydrous ErCl3 in thf solution afforded the large heterometallic (Er/Li) metallasilsesquioxane cluster (c‐C6H11)21Si21O36(SiMe3)Er2(thf)2Li4Cl2 (2) in good yield (65 %). The molecular structure of 2 comprises several unusual features, including the coupling of two silsesquioxane cages through an –O3Si(c‐C6H11)– unit as well as trimethylsilylation of an Si–OH functionality. Due to the presence of 21 cyclohexyl substituents in the periphery of the molecule, the large cluster compound is soluble even in pentane.

Novel α-spirocyclic (alkyl)(amino)carbenes at the theoretical crossroad of flexibility and rigidity

Spirocyclic (alkyl)(amino)carbenes (CAACs) with reasonable conformations of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl substituents in the position α to the carbenic center are investigated at B3LYP/AUG-cc-pVTZ//B3LYP/6-31+G*. The singlet–triplet energy separations (∆E s−t), HOMO–LUMO energy gaps (∆E HOMO−LUMO), hydrogenation energies (∆E H), heats of methylene formation (∆E) as well as philicity indices (N and ω) of these carbenes are compared and contrasted. The highest ∆E s−t is encountered for the cyclopropyl substituted CAAC (54.2 kcal/mol), while the other ones lay in a narrow range of 48.2–51.8 kcal/mol. Assignment of the barriers for ring inversions is carried out in order to probe the “flexible steric bulk” of cyclic substituents, showing negligible differences with those of the unsubstituted rings. The calculated N and ω indices indicate that in contrast to the popular belief, CAACs appear less electrophilic than N-heteorcyclic carbenes (NHCs).

Synthesis and study of triorganostannyl esters of 3-,4- and 3,5-pyridinylimino substituted aminobenzoic acids: Crystal structures of dimorphs of aqua-trimethyltin 3-pyridinyliminobenzoate

The synthesis and the structural investigation of triorganostannyl esters of the 3- and 4-[1-pyridin-2-yl-methylidene]- and 3,5-bis-[1-pyridin-2-yl-methylidene]-benzoic acids are reported with methyl, n-butyl, cyclohexyl, phenyl and benzyl substituents on tin. The organic carboxylates may be considered as iminopyridines emerging from the condensation of the corresponding aminobenzoic acid with pyridine-2-carboxaldehyde. In this respect it is interesting to investigate their physicochemical properties since their coordination to metal centers will affect both the photophysical properties of the metal and the conformation and intermolecular interactions of the ligands. Therefore, the structure of the above triorganotin compounds is studied and discussed in relation to those of the unsubstituted benzoates as well as of the free ligands. X-ray crystallography and a coalescence of spectroscopic methods applied both in the solid state and in solution have been used in this effort.

Indole and its alkyl‐substituted derivatives protect erythrocyte and DNA against radical‐induced oxidation

The antioxidant properties of 1,2,3,4-tetra-hydrocarbazole, 6-methoxy-1,2,3,4-tetrahydrocar-bazole (MTC), 2,3-dimethylindole, 5-methoxy-2,3-dimethylindole, and indole were investigated in the case of hemolysis of human erythrocytes and oxidative damage of DNA induced by 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), respectively. The aim of this work was to explore the influence of methoxy, methyl, and cyclohexyl substituents on the antioxidant activities of indole derivatives. These indole derivatives were able to protect erythrocytes and DNA in a concentration-dependent manner. The alkyl-substituted indole can protect erythrocytes and DNA against AAPH-induced oxidation. Especially, the structural features of cyclohexyl and methoxy substituents made MTC the best antioxidant among the indole derivatives used herein. Finally, the interaction between these indole derivatives and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) radical cation and 2,2'-diphenyl-1-picrylhydrazyl, respectively, provided direct evidence for these indole derivatives to scavenge radicals and emphasized the importance of electron-donating groups for the free radical-scavenging activity of indole derivatives.

Highly Chemo‐ and Enantioselective Hydrogenation of Linear α,β‐Unsaturated Ketones

Highly chemo- and enantioselective hydrogenations of linear β,β-disubstituted enones (see scheme) have been accomplished by using iridium complexes 1 a–i bearing chiral sulfoximine-type P,N-ligands. The catalyst system preferentially hydrogenates the CC double bonds giving saturated ketones as the major products. Substrates with bulky substituents at the β-position give the best enantioselectivities. Thus, enones with isopropyl and cyclohexyl substituents afford ketones with 97 % ee (at >95 % conversion).

Copper(I) halide complexes with a sterically hindered thiourea: synthesis and crystal structures of [Cu(dchtu)2Cl] and [Cu(dchtu)2Br] (dchtu = N , N ′-dicyclohexylthiourea)

Copper(I) complexes with a sterically hindered thiourea, [Cu(dchtu)2X] (dchtu = N,N′-dicyclohexylthiourea; X=Cl 1, Br 2), were synthesized and their crystal structures were determined. Compounds 1 and 2 are isostructural orthorhombic, space group P212121. Crystallographic data for 1 : a = 13.1711(13), b = 14.2610(19), c = 15.793(2) Å, V = 2966.4(6) Å3, Z = 4. For 2 : a = 13.2628(13), b = 14.3410(19), c = 15.860(2) Å, V = 3016.5(6) Å3, Z = 4. The stoichiometry of CuX complexes with thiourea is influenced by substituents on the nitrogens. Copper(I) halides only form bis-adducts with the sterically hindered dchtu ligand even with molar excesses of dchtu due to steric hinderance of the cyclohexyl substituents. In 1 and 2, the Cu(I) is trigonally coordinated by the sulfur atoms of two monodentate N,N′-dicyclohexylthiourea ligands and one halide. The structures of the complexes are stabilized by a system of intermolecular H-bonding.

Palladium(II) aryl-amido complexes of diphosphinoazines in unsymmetrical PNP’ pincer-type configuration

Square planar palladium(II) aryl-amido complexes of diphosphinoazines in monoanionic unsymmetrical PNP’ pincer-type coordination were prepared by reactions of phenyl-, o-tolyl-, or 2,6-dimethylphenyllithium with previously described chloro-amido complexes of diphosphinoazines having isopropyl, cyclohexyl and tert-butyl substituents on phosphorus atoms. The compounds were characterized by NMR showing free rotation around metal–aryl bond in the complexes; the presence of C ipso –Pd bond was detected by two-dimensional experiments. In addition to that, crystal and molecular structure of one phenyl-amido complex, [Pd(C 6H 5){P(C 6H 11) 2CH C(Bu t )NN C(Bu t )CH 2P(C 6H 11) 2}], was determined by X-ray diffraction together with the structure of a chloro-amido complex [PdCl{PBu t 2CH C(Bu t )NN C(Bu t )CH 2PBu t 2}]. In both structures the ligand trans to the amide nitrogen is well surrounded by substituents on phosphorus atoms, the former complex showing significant interactions between two cyclohexyl hydrogen atoms and the π-system of the phenyl ring. The values od Pd–C and Pd–N bond distances in this complex are the same as those in a monodentate analog [Pd(PMe 3) 2(C 6H 5)(NHC 6H 5)] which contrasts with the different values in a similar PNP symmetrical pincer complex reported in the literature.

Inhibition of alkaline phosphatase by thioureido derivatives of methylenebisphosphonic acid

A series of thioureido derivatives of methylenebisphosphonic acid were synthesized by the reaction of aminomethylenebisphosphonic acid with the corresponding isothiocyanates, and their effect on the activity of alkaline phosphatases from bovine small intestine mucosa (BSIM) and human placenta was studied. It was found that (3-phenylthioureido)methylenebisphosphonate is approximately one order of magnitude more effective in inhibiting the activity of alkaline phosphatase from BSIM than the alkyl derivatives of thioureidomethylenebisphosphonic acid with methyl, ethyl, tert-butyl, or cyclohexyl substituents. The introduction of substituents into the benzene ring of (3-phenylthioureido)methylenebisphosphonate decreased the effect of the inhibitor on the activity of the enzyme. The affinity of (3-phenylureido)methylenebisphosphonate to the alkaline phosphatase of BSIM was also weaker as compared with the corresponding thioureidomethylenebisphosphonate. The insertion of thioureidobisphosphonates into the active site of alkaline phosphatase of human placenta by the method of molecular docking indicated that the methylenebisphosphonate residue and the substituted amino groups of the inhibitor are involved in the mechanisms of complex formation with the enzyme. It is supposed that the improvement of the inhibitory activity of (3-phenylthioureido)methylenebisphosphonate toward alkaline phosphatase of BSIM is due to the additional fixation of the phenyl substituent in the active site of the enzyme.

Conformations of β‐amino acid residues in peptides: X‐ray diffraction studies of peptides containing the achiral residue 1‐aminocyclohexaneacetic acid, β3,3Ac6c

The conformational preferences of the 3,3-disubstituted beta-amino acid residue, 1-aminocyclohexaneacetic acid (beta3,3Ac6c) have been investigated by determining the crystal structures of the parent amino acid, the hydrochloride derivative, 10 protected derivatives and di and tripeptides. The symmetrical cyclohexyl substituent at the beta-position restricts the values of the torsion angles phi (N--C(beta)) and theta (C(beta)--C(alpha)) to approximately gauche values (+/-60 degrees ). Relatively few intramolecularly hydrogen bonded conformations are observed. In the dipeptide Boc-beta(3,3)Ac6c-beta(3,3)Ac6c-NHMe a C6 hydrogen bond is observed. In Piv-Pro-beta(3,3)Ac6c-NHMe a C11 hydrogen bonded hybrid alphabeta turn is characterized. In a majority of cases the amino group occupies the axial position in the cyclohexane ring. The conformations observed are compared with crystallographically observed structures for other beta-residues, including beta(2,2)Ac6c.

Unprecedented Formation of μ-Vinylidene Complexes from Phospharuthenocene and Acyl Chloride via Activation of the C═O Double Bond

A novel reaction mode of phosphametallocenes was discovered. The phospharuthenocenes with cyclohexyl substituents at the α-positions of the η5-phospholide(s) reacted with acyl electrophiles by an initial electrophilic attack to the ruthenium to produce the μ-alkenylidene species with activation of the acyl C═O double bond and elimination of an α-hydrogen.

Electroluminescent characteristics of novel platinum–porphyrin complex

Novel platinum complex of porphyrin with methyl and cyclohexyl substituents, PtMECHP, was designed and synthesized for use as a red phosphorescent material. PtMECHP was employed as an emission dopant in the OLED and the elctro-optical characteristics were investigated. The OLED was fabricated by vacuum deposition, and the layer-structure of device was ITO/NPD/PtMECHP(10%) in CBP/BCP/Alq/LiF/Al to exhibit brightness of 53cd/m2 at 11mA/cm2 and the external quantum efficiency of 1.2% at the same current density. The maximum EL band was detected at 650nm with red phosphorescence.

Resolution of Chiral Phosphate, Phosphonate, and Phosphinate Esters by an Enantioselective Enzyme Library

An array of 16 enantiomeric pairs of chiral phosphate, phosphonate, and phosphinate esters was used to establish the breadth of the stereoselective discrimination inherent within the bacterial phosphotriesterase and 15 mutant enzymes. For each substrate, the leaving group was 4-hydroxyacetophenone while the other two groups attached to the phosphorus core consisted of an asymmetric mixture of methyl, methoxy, ethyl, ethoxy, isopropoxy, phenyl, phenoxy, cyclohexyl, and cyclohexoxy substituents. For the wild-type enzyme, the relative rates of hydrolysis for the two enantiomers ranged from 3 to 5.4 x 10(5). Various combinations of site-specific mutations within the active site were used to create modified enzymes with alterations in their enantioselective properties. For the single-site mutant enzyme, G60A, the stereoselectivity is enhanced relative to that of the wild-type enzyme by 1-3 orders of magnitude. Additional mutants were obtained where the stereoselectivity is inverted relative to the wild-type enzyme for 13 of the 16 pairs of enantiomers tested for this investigation. The most dramatic example was obtained for the hydrolysis of 4-acetylphenyl methyl phenyl phosphate. The G60A mutant preferentially hydrolyzes the SP-enantiomer by a factor of 3.7 x 10(5). The I106G/F132G/H257Y mutant preferentially hydrolyzes the RP-enantiomer by a factor of 9.7 x 10(2). This represents an enantioselective discrimination of 3.6 x 10(8) between these two mutants, with a total of only four amino acid changes. The rate differential between the two enantiomers for any given mutant enzyme is postulated to be governed by the degree of nonproductive binding within the enzyme active site and stabilization of the transition state. This hypothesis is supported by computational docking of the high-energy, pentavalent form of the substrates to modeled structures of the mutant enzyme; the energies of the docked transition-state analogues qualitatively capture the enantiomeric preferences of the various mutants for the different substrates. These results demonstrate that the catalytic properties of the wild-type phosphotriesterase can be exploited for the kinetic resolution of a wide range of phosphate, phosphonate, and phosphinate esters and that the active site of this enzyme is remarkably amenable to structural perturbations via amino acid substitution.

Chiral NMR Discrimination of Piperidines and Piperazines Using (18-Crown-6)-2,3,11,12-tetracarboxylic Acid

Enantiomeric discrimination is observed in the (1)H and (13)C NMR spectra of piperidines and piperazines in the presence of (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. The amines are protonated by the carboxylic acid groups of the crown ether to produce the corresponding ammonium and carboxylate ions. Association of the ammonium ion with the crown ether likely involves two hydrogen bonds with the crown ether oxygen atoms and an ion pair with the carboxylate anion. Methyl, hydroxymethyl, phenyl, carboxyl, pyridyl, and cyclohexyl substituent groups alpha to the nitrogen atom do not inhibit binding of the ammonium ion to the crown ether. The NMR spectra of piperidines with the stereogenic center alpha or beta to the nitrogen atom exhibit substantial enantiomeric discrimination. Dibasic substrates such as the piperizines are likely converted to their diprotonated form in the presence of the crown ether, and both nitrogen atoms appear to associate with the crown ether moiety.

N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57), a Potent Partial Agonist for the Human Histamine H1- and H2-Receptors

Both the histamine H1-receptor (H1R) and H2-receptor (H2R) exhibit pronounced species selectivity in their pharmacological properties; i.e., bulky agonists possess higher potencies and efficacies at guinea pig (gp) than at the corresponding human (h) receptor isoforms. In this study, we examined the effects of NG-acylated imidazolylpropylguanidines substituted with a single phenyl or cyclohexyl substituent on H1R and H2R species isoforms expressed in Sf9 insect cells. N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57) turned out to be the most potent hH2R agonist identified so far (EC50 of 23 nM in the GTPase assay at the hH2R-Gsalpha fusion protein expressed in Sf9 insect cells). UR-AK57 was almost a full-hH2R agonist and only slightly less potent and efficacious than at gpH2R-Gsalpha. Several NG-acylated imidazolylpropylguanidines showed similar potency at hH2R and gpH2R. Most unexpectedly, UR-AK57 exhibited moderately strong partial hH1R agonism with a potency similar to that of histamine, whereas at gpH1R, UR-AK57 was only a very weak partial agonist. Structure/activity relationship studies revealed that both the alkanoyl chain connecting the aromatic or alicyclic substituent with the guanidine moiety and the nature of the carbocycle (cyclohexyl versus phenyl ring) critically determine the pharmacological properties of this class of compounds. Collectively, our data show that gpH1R and gpH R do not necessarily exhibit preference for bulky agonists (2) compared with hH1R and hH2R, respectively, and that UR-AK57 is a promising starting point for the development of both potent and efficacious hH1R and hH2R agonists.

Organotin compounds enhance 17β-hydroxysteroid dehydrogenase type I activity in human choriocarcinoma JAr cells: Potential promotion of 17β-estradiol biosynthesis in human placenta

Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), are typical environmental contaminants and suspected endocrine-disrupting chemicals because they cause masculinization in female mollusks. However, it remains unclear whether organotin compounds also cause crucial toxicities in human sexual development and reproductive functions. We investigated the effects of 17 tin compounds on the catalytic activity and mRNA expression of 17β-hydroxysteroid dehydrogenase type I (17β-HSD I) in human choriocarcinoma JAr cells. At nontoxic concentrations, both trialkyltins with propyl, butyl or cyclohexyl substituents on the tin atom and triphenyltin (TPT) enhanced 17β-HSD I mRNA transcription and enzyme activity in a dose-dependent fashion. Although tetraalkyltin compounds such as tetrabutyltin and tributylvinyltin also increased the mRNA expression and enzyme activity of 17β-HSD I, the concentrations necessary for activation were >30–100 times greater than those for trialkyltins. Inorganic tin had no effect on the catalytic activity and mRNA expression of 17β-HSD I. Interestingly, diphenyltin and monophenyltin, which are metabolites of TPT, enhanced 17β-HSD I activity with a concomitant increase in mRNA expression, whereas dibutyltin and monobutyltin, which are metabolites of tributyltin, enhanced 17β-HSD I activity without a concomitant increase in mRNA expression. These results suggest that organotin compounds are potent stimulators of 17β-estradiol biosynthesis to enhance 17β-HSD I activity in the human placenta in vitro; the placenta represents a potential target organ for these compounds, whose endocrine-disrupting effects might be the result of local changes in 17β-estradiol concentrations in pregnant women.