Synthesis and chiral recognition properties of two novel chiral calix[4]arene tartaric ester derivatives

Two new chiral calix[4]arene derivatives containing tartaric acid ester moieties were synthesized. The chiral calix[4]arenes are in a ‘cone’ conformation according to NMR spectroscopy. The chiral recognition capabilities of 1–4 toward the guests, 1,2-propanediol and serine methyl ester hydrochloride (SerOMe), were investigated (¹H NMR spectroscopy). The extraction properties of compounds 1 and 2 toward selected α-amino acid methyl esters were also studied.     

A study on thermal behaviors of mono ethyl ester azocalix[4]arene derivatives

In the present study, thermal stabilities of five new family of azocalix[4]arene mono ethyl ester derivatives, 4a–e, were investigated using thermogravimetry, differential thermogravimetry, and differential thermal analysis methods. It was found that all compounds showed thermal stability up to 236 °C averagely. After this temperature, decomposition of compounds starts gradually. The decomposition routes of 4a–c compounds are similar and occur with two stages. Ester alkyl groups decompose and remove from the structure in the first stage. Second stage corresponds to rest of structure decomposition. The decomposition routes of the 4d–e compounds are different from the decomposition routes of the 4a–c compounds. These compounds include halogen, and decomposition reactions realize with three and four stages respectively.     

Synthesis of optically active amino ketones from (s)-serine

The oxazoline-protected (S)-serine methyl ester 2 can be coupled with various organolithio compounds to give the corresponding ketones 4a-d in good yield without racemisation.     

Novel biotransformation of pentacyclic triterpenoid acids by Nocardia sp. NRRL 5646

Six pentacyclic triterpene acids, ursolic acid, oleanolic acid, betulinic acid, 23-hydroxybetulinic acid, glycyrrhetinic acid, and senegenin, were metabolized by the microbe Nocardia sp. NRRL 5646 to selectively furnish their corresponding 28-methyl esters. Notably, ursolic acid (1) was converted to oleanolic acid methyl ester (4) via two intermediates, oleanolic acid (2), and ursolic acid methyl ester (3), which are formed by participation of ‘retro-biosynthetic’ methyl migration from C-19 to C-20. Senegenin (11) was selectively converted to a nortriterpene methyl ester, senegenic acid methyl ester (12), via an unprecedented C-C bond cleavage. The stereochemical assignments of compounds 11 and 12 were made unambiguously for the first time using 2D NMR spectroscopy.     

A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones and pyrido[2,3-e][1,4]diazepine-2,5-diones

A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5-diones 8 and pyrido[2,3-e][1,4]diazepine-2,5-diones 9, is reported using the condensation of α-amino acid methyl ester derivatives with 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. Compounds 8 and 9 were also synthesized by peptide coupling of α-amino acid methyl ester derivatives with β-amino acids (2 or 3) followed by the cyclisation in tetrahydrofuran with sodium hydride (NaH).     

A facile and efficient synthesis of new fluoroalkylsulfonates and the corresponding tetrabutylammonium salts

A useful synthetic methodology towards new fluoroalkylsulfonates was developed. Grignard addition to an inexpensive and commercially available fluorine-containing ester, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1) gave the mono-adduct (2) as the only product in high yield. The scope and limitation of this method were thoroughly investigated and it was found that it works for most Grignard reagents except electron-poor ones. Interestingly, the resulting fluoroalkylsulfonates exhibit substituent-dependent hydration behavior due to the presence of carbonyl group in these compounds. Converting the fluoroalkylsulfonate to the acid form and then neutralizing it with tetra-n-butylammonium hydroxide gave the corresponding tetra-n-butylammonium salts, which shows good solubility in common organic solvents, some of which might be suitable for copolymerization with other hydrophobic monomers.     

Amidoalkylation of mercaptans with glyoxylic acid derivatives

The synthesis of α-alkyl mercaptohippuric acid (3a–d), N-benzyloxycarbonyl-α-methylthioglycine (3e) and their methyl esters (5a–d) by the amido-alkylation of mercaptans with α-hydroxyhippuric acid (2a), α-hydroxy-N-benzyloxycarbonylglycine (2b) and their methoxymethyl ester derivatives 4a and 4b is described. Oxidation with m-chloroperbenzoic acid afforded the corresponding sulfoxides and sulfones and treatment with N-bromosuccinimide in methanol or chlorine in carbon tetrachloride solution exchanged the sulfur containing side chain for a methoxy or a chloro group respectively. (4a, 8).     

Synthesis,evaluation and docking studies of some 4-thiazolone derivatives as effective lipoxygenase inhibitors

Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model, whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38, and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC₅₀?=?12.98 µM and IC₅₀?=?12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC₅₀?>?50 µM and, COX-2; IC₅₀?>?50 µM). The enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are promising pharmacophore for anti-inflammatory activity.     

Studies on fungal metabolites—XXXII: A renewed investigation on (−) flavoskyrin and its analogues

1-Oxo-1,2,3,4-tetrahydroanthraquinone (4a), and its 8-hydroxy-(4b) and 8-hydroxy-6- methyl (4c) derivatives were dimerized to the compounds formulated as (6a), (6b) and (6e), respectively. The structure of 6a was confirmed by X-ray crystallographic analysis.By the analogy with these dimers and NMR spectral analysis, a revised structure (7) was proposed for (?) flavoskyrin, a yellow metabolite of Penicillium islandicum NRRL 1175. A biosynthetic scheme involving Diels-Alder type cyclo-addition (π4s + π2s) was proposed for (?) flavoskyrin.     

Multistep synthesis and screening of heterocyclic tetrads containing furan,pyrazoline, thiazole and triazole (or oxadiazole) as antimicrobial and anticancer agents

In the present study novel heterocyclic tetrads containing furan, pyrazoline, thiazole and triazole (or oxadiazole) (1, 2, 3, 4a-e and 5a-e) were designed and synthesized and investigated for their antimicrobial (against selected bacteria and fungi) and anticancer potential. The molecules 4e and 5e containing 4-fluoro phenyl and 4-fluoro benzyl substituents showed promising antimicrobial (antibacterial and antifungal activities with MICs ranging between 0.5 and 8 µg/mL. Compounds 3 exhibited potent anticancer activity with an IC₅₀ value of 0.49 ± 1.45 µM against the human gastric cancer cell line (BGC-823) whereas compound 4e displayed an IC₅₀ value of 0.65 ± 0.53 µM against breast cancer (MCF-7) cell line respectively. All compounds showed selective toxicity against the cancer cell lines compared to human normal liver cell lines. Molecular docking studies of the most potent compounds (3 and 4e) against selected microbial and cancer proteins revealed the crucial binding interactions of the potent compounds with the target enzymes. Compounds 3 and 4e are promising lead molecules to be developed as potential drug candidates.     

Alkylation of 1-hydroxy-1H-[1,2,3]triazolo[4,5-e][1,2,3,4]tetrazine 5,7-dioxide

Alkylation of 1-hydroxy-1H-[1,2,3]triazolo[4,5-e][1,2,3,4]tetrazine 5,7-dioxide 1 and its silver salt 10 with different alkylating agents (diazomethane, diazoacetone, bromoacetone, α-bromoacetophenone, methyl iodide, methyl vinyl ketone) was studied. Alkylation of compound 1 with diazo compounds and salt 10 with halocompounds results predominantly in O-alkylation products, 1-alkoxy-1H-[1,2,3]triazolo[4,5-e][1,2,3,4]tetrazine 5,7-dioxides. The Michael reaction of compound 1 with methyl vinyl ketone involves the triazole nitrogen atom to give 1-(3-oxobutyl)-1H-[1,2,3]triazolo[4,5-e][1,2,3,4]tetrazine 3,4,6-trioxide. The structures of the compounds synthesized were established by ¹H, ¹³C, ¹⁴N NMR spectroscopy and mass spectrometry.     

Synthesis, separation and configuration determination of diastereoisomers of (R,S)-1-methyl-3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propyl 2,3-dideoxy-α-d-erythro-hex-2-enopyranosides

For synthesizing title compounds, first we carried out the Ferrier's rearrangement involving tri-O-acetyl-d-glucal 1 and alcohols 2a-e using Montmorillonite K-10 as a catalyst. This reaction gave diastereoisomeric mixture of 3a-e and 4a-e. Basic hydrolysis of each pair of diastereoisomeric mixture furnished title compounds 5a-e and 6a-e, which were separated very carefully over a silica gel column yielding all diastereoisomers in the pure form. One of them 5d was subjected to a single crystal X-ray analysis to determine the correct configuration at the asymmetric carbon atom of the aglycone. The methyl signals of the diastereomers helped to assign the configuration of each diastereoisomer. Molecular orbital calculations of 5d using the semi-empirical method (AM1) has been performed to compare its results with the crystallographic data. We have also determined the rotational barrier of C(8) and O(9) bond in both (R) and (S) enantiomers of compounds 5a and 6a.     

An efficient synthesis of the intrinsic fluorescent peptide labels, (S)- and (R)-(6,7-dimethoxy-4-coumaryl)alanines via asymmetric hydrogenations

The title compounds 1a,b are efficiently synthesized in high yields and with high enantioselectivity (>95% ee) by using a sequence in which the key step involves asymmetric hydrogenation of dehydroamino methyl ester 4 with Burk’s DuPHOS-based Rh(I) catalysts.     

Syntheses,crystal structures,DFT calculation and solid-state spectroscopic properties of new zincate(II) complexes with N-(4-substituted phenyl)-N'-(4-nitrophenyl)-oxamate

The electronic effects electron donating and withdrawing groups R on the properties of N-(4-R-phenyl)-N'-(4-nitrophenyl)oxamito zincate(II) complexes was investigated featuring R = Me (a), H (b), F (c), Cl (d) and Br (e). The N-(4-R-phenyl)-N'-(4-nitrophenyl)oxamide ligands 2 were synthesized by reacting ethyl 4-nitrooxanilate with the respective 4-substituted anilines. Subsequent treatment with [nBu₄N]OH and [Zn(OAc)₂(H₂O)₂] gave the respective zincate complexes [nBu₄N]₂[Zn(N-(4-nitrophenyl)-N'-(4-substituted phenyl)oxamides)₂] (3). Spectroscopic methods were used to describe compounds 2a–e and 3a–e. Single crystal X-ray diffraction analysis confirmed the formation of 3a–c in the solid state. The tetrahedral coordination sphere of the zinc (II) ion features four amide nitrogen donor atoms based on two ethanediamide ligands. The UV–Vis spectra of Complexes 3a–e display a characteristic LLCT (π → π *) band, which was confirmed by TD-DFT calculations. DFT calculations show that the Zn(II) orbitals do not contribute to the HOMO or LUMO, with the latter being primarily found on the two 4-nitrophenyl rings for compounds 3a ? e, while the HOMO-1 and HOMO are located on the 4-substituted phenyl rings. Notably, HOMO and LUMO energies and gabs do not differ significantly. Transitions from HOMO to LUMO + 1 are the most important for all ligands. The luminescence properties of solid compounds 3a ? e were also investigated at 298 K. Solid state photoluminescence studies reveal that these complexes emit strong yellow-orange luminescence at 450–600 nm with a maximum at about ～ 500 nm in the cyan region. Furthermore, the thermal stabilities of compounds 3a ? e have been investigated.     

Conformation et reactivite de derives [4.n.0] bicycliques a fonction trans—XXII : Influence d'un méthyl en position β sur les vitesses relatives des réactions d'élimination syn et anti dans la série bicyclo [4.2.0] octanique trans

Rate constants and reaction products, in different base-solvent systems, are reported for 4e-methyl 3e-tosyloxy trans bicyclo [4.2.0] octane 4 and 4a-methyl 3e-tosyloxy trans bicyclo [4.2.0] octane 5. These results are compared with these relating to the parent compound 6. The axial β-methyl increases reactivity and favours elimination with respect to competitive substitution, and equatorial β-methyl has the opposite effect. The relative reactivities of diequatorial and syn axial-equatorial eliminations determined from 4 and 5 depend mainly on the influence of the substituent. These compounds are not suitable for determining the real difference of reactivity between the two elimination process. The origin of the methyl group influence, and a scheme of the reactions which account for this behaviour, are discussed.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

Synthesis of quinoxaline-benzoxale conjugates and mesomorphic properties

A new series of non-discotic heterocyclic compounds 1a-e derived from quinoxaline was prepared and their mesomorphic properties investigated. The crystal and molecular structures of nonmesogenic 2,3-bis(3,4-didodecyloxyphenyl)quinoxaline-6-carboxylic acid 4-[(4-butoxy2-hydroxyphenylimino)methyl]phenyl ester 2a (n=4, m=12) were determined by means of X-ray structural analysis. It crystallizes in a monoclinic space group P2(1)/c, with a=21.9193(13) Å, b=8.3693(4) Å, c=30.896(2) Å, and Z=4. The molecule was considered as an elongated or tapered triangle. Both inter- and intra-molecular H-bonds were observed in the crystal lattice, which was attributed to the formation of columnar mesophase in compounds 2. The mesomorphic behavior of compounds 1-2 was studied by thermal analysis and polarized optical microscopy. All compounds 1-2 exhibited hexagonal columnar phases (Col_h), which were also confirmed by powder XRD diffractometer. A N_cell and R_ar value equal to 4.74 and 4.34 within a slice of 9.0 Å thick were obtained for 1b and 2b, indicating that a more disc-like correlated structure by two molecules lying side-by-side was formed in Col_h phases. The fluorescent properties of the compounds 1-4 in CH₃Cl were also examined.     

Ergoline derivatives—XIV : Synthesis of clavine alkaloids

The treatment of methyl lysergate with mercuric acetate in methanol yields, instead of the expected 10 - methoxy - 6 - methyl - ergoline - 8 β - carboxylic acid methyl ester (2), 10 - methoxy - 8,9 - didehydro - 6 - methyl - ergoline - 8 - carboxylic acid methyl ester (3), whose structure is demonstrated. From 3, penniclavine (14) and isosetoclavine (15) were prepared according to Scheme 1.     

Synthesis and properties of novel methanofullerenes having ethylthienyl and/or n-pentyl group for photovoltaic cells

Novel methanofullerenes 3 having ethylthienyl and/or n-pentyl groups were designed and synthesized for the purpose of developing new acceptors for an organic photovoltaic cell with higher performance than that of the [6,6]-phenyl-C₆₁-butylic acid methyl ester (PCBM) used as the standard acceptor. The electronic absorption spectra and cyclic voltammetry (CV) of 3, PCBM, and [6,6]-(thiophene-2-yl)-C₆₁-butylic acid methyl ester (ThCBM) were measured to estimate solubility and reduction potentials as characteristics of n-type semiconductor for organic photovoltaic devices. The CV measurements revealed reversible reduction waves for all of the methanofullerenes and the first reduction potentials of the n-pentyl-substituted 1-(5-ethylthiophene-2-yl)-[6,6]-methanofullerene[60] (3b) and 1-phenyl-[6,6]-methanofullerene[60] (3c) were negatively shifted compared to those of the corresponding terminal methyl ester-substituted homologues (3a and PCBM). The performances of photovoltaic devices consisting of 3b and 3c were slightly higher than those of PCBM.     

Novel metal complexes of boronated chlorin e6 for photodynamic therapy

Various structural modifications of chlorins are aimed at optimization of biomedical characteristics of these plant-derived tetrapyrrolic compounds. In particular, conjugation with boron polyhedra improves the efficacy of chlorin e₆ derivatives as antitumor photosensitizers. To obtain the compounds that may possess several clinically favorable characteristics, we synthesized a series of metal chlorin e₆ conjugates with 1-carba-closo-dodecaborate anion that contain Pd(II), Sn(IV) or Zn(II) in the coordination sphere of the chlorin macrocycle. The compounds were synthesized by alkylation of amino group in chlorin e₆ metal complexes with 1-trifluoromethanesulfonylmethyl-1-carba-closo-dodecaborate cesium. The water soluble Pd(II) complex of chlorin e₆ 13(1)-N-{2-[N-(1-carba-closo-dodecaboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester (compound 6) evoked low dark cytotoxicity; in striking contrast, 6 potently sensitized human tumor cells to illumination with monochromatic red light. Confocal microscopic studies demonstrated that photoactivation of 6 rapidly (within minutes) changed the patterns of intracellular drug distribution from diffuse cytoplasmic to clustered perinuclear. Co-localization experiments revealed that 6 associated with lysosomes in illuminated cells. These events were paralleled by alteration of mitochondrial shape, a decrease of mitochondrial transmembrane electric potential and the loss of plasma membrane impermeability for propidium iodide, the latter being a hallmark of cell necrosis. Similar mechanisms of cell photodamage were found for structurally close Pd(II) complex of chlorin with neutral carborane and for Sn(IV) chlorin conjugated with the anionic carborane. Thus, metal complexes of carboranylchlorins are efficient photosensitizers capable of triggering rapid necrosis. These compounds are promising for further development as multipotent agents in which each moiety, i.e., metal, the chlorin macrocycle and the boron substituent, as well as the entire complex, can be useful in cancer diagnostics and treatment.