β-Lactam derivatives as potential anti-cancer compounds

A number of 1,4-diaryl-3-methylene substituted β-lactams, the addition products obtained from their reactions with N-, S-, and C-nucleophiles, and diverse related compounds were prepared, and a selection of 43 compounds was screened in preliminary tests as anti-tumor compounds by using 4 or 5 human cancer cell lines of diverse origins. Twelve compounds were highly active against all cell lines, 6 showed low activity, 12 no activity, and 13 exhibited a selective activity against a human small cell lung carcinoma cell line. Correspondence: Hans-Hartwig Otto, Department of Pharmaceutical/Medicinal Chemistry (PMC), Institute of Pharmacy, Ernst-Moritz-Arndt-University, 17487 Greifswald, Germany.     

β-Lactam derivatives as potential anti-cancer compounds

A number of 1,4-diaryl-3-methylene substituted β-lactams, the addition products obtained from their reactions with N-, S-, and C-nucleophiles, and diverse related compounds were prepared, and a selection of 43 compounds was screened in preliminary tests as anti-tumor compounds by using 4 or 5 human cancer cell lines of diverse origins. Twelve compounds were highly active against all cell lines, 6 showed low activity, 12 no activity, and 13 exhibited a selective activity against a human small cell lung carcinoma cell line.     

Novel and versatile methodology for synthesis of β-aryl-β-mercapto ketone derivatives as potential urease inhibitors

The objective was to obtain new scaffold of compounds possessing anti-urease activity. For this new and simple method for the synthesis of β-aryl-β-mercapto ketone derivatives based on Michael addition of thiophenol to chalcones in an ionic liquid as a solvent was improved. The products were obtained in good to moderate yields with high purity and characterized by spectral and elemental analyses. The activities of synthesized compounds were investigated as new inhibitors of jack bean urease. Among 22 synthesized compounds, all of them have shown inhibitory effect in micromolar range, and the most potent one has IC₅₀ = 6 μM compared to hydroxyurea IC₅₀ = 100 μM as a reference inhibitor. A docking study was performed using Autodock 4.2 in parallel to in vitro experiments to illustrate the corresponded binding affinities as well as binding site, and involved residues in interaction. These computational results complimented the experimental inhibition activity and enabled us to report a potent urease inhibitors based on β-aryl-β-mercapto ketone scaffold.     

Quantum chemical study of α-diazocarbonyl bullvalene derivatives and related heterocyclic compounds

According to the results of PBE0/cc-pVTZ quantum chemical calculations, the equilibrium mixture of α-diazocarbonyl bullvalene derivatives (C₁₀H₈N₂O) contains an impurity of the corresponding bullvaleno-[1,2,3]oxadiazoles. The carbonyl group in the major tautomer is conjugated with the three-membered ring. The concentration of other tautomers in the equilibrium mixture of two bullvaleno[1,2,3]selenadiazoles is negligible.     

Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds

The multifaceted nature of Alzheimer's disease (AD) has led to the development of multi-targeted compounds based on the classical AD drug, tacrine, first known to inhibit the acetylcholine-degrading enzyme acetylcholinesterase (AChE). In the present work, we explore the potentiality of multimers of tacrine in this field. The synthesis using the so-called "click chemistry" and the in vitro study of the conjugates are described. Two or four copies of the tacrine molecule are "clicked" on a constrained cyclopeptide template proven to be a convenient tool for multimeric presentation. The multimers significantly inhibit self-induced amyloid fibril formation from Aβ(40) at low inhibitor to Aβ molar ratios at which the tacrine monomer is fully inactive (Thioflavin T assays and AFM observation). Moreover, they have the capacity to bind to Aβ(40) fibrils (SPR assays) while retaining the AChE inhibitory activity of the parent tacrine.     

Synthesis of 1,3-thiazoline derivatives from β-dicarbonyl compounds and phenacyl thiocyanate

Acetylacetone and ethyl acetoacetate undergo addition at the CN bond of phenacyl thiocyanate in the presence of Ni(acac)₂ to give the respective keteneN, S-acetals, which undergo smooth cyclization to afford 2-methylene-4-phenyl-1, 3-thiazoline derivatives when refluxed in THF.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1938–1940, November, 1993     

Novel synthetic acridine-based derivatives as topoisomerase Ⅰ inhibitors

Novel DNA binding agents against topoisomerases are needed for effective treatment of cancers. A series of new acridine-based derivatives 7a–7d were synthesized and their antiproliferative activity against K562 and HepG-2 cell lines were evaluated. Compound 7c with pyridin-2-yl-methanamino group substituted at the C9 position of acridine showed good antitumor activity against both cell lines. The DNA-binding affinity of compound 7c was evaluated by UV–vis absorption spectra and fluorescence emission spectra. DNA topoisomerase I mediated relaxation of plasmid pBR322 DNA was also tested. Our results suggested that compound 7c with good antitumor activity and topoisomerase I inhibition activity can be developed as a prime candidate for further chemical optimization.     

Butalene and related compounds: aromatic or antiaromatic?

Density functional theory (DFT) has been used to study the first three members of the condensed cyclobutadienoid series, butalene (3), bicyclobutadienylene (12), and dicyclobutenobutalene (20). The first is planar and is judged "aromatic" by comparisons with suitable models using both energetic and magnetic criteria. The second is nonplanar, and not aromatic, but not so antiaromatic as cyclobutadiene (11). The third is slightly more antiaromatic and best viewed as a butalene fused to two cyclobutadiene rings; its properties are the sum of aromatic and antiaromatic components, like benzocyclobutadiene. Ring-opening transition states for both 3 and 12 have been located, and these are conrotatorily twisted. The ring-opening barrier for 12 is more than twice that for 3. Ring-opening of 20 involves ring inversion as the only barrier.     

Synthesis and bioactivity of N-cyclopropanecarboxyl-N′-pyridin-2-yl thiourea derivatives and related fused ring compounds

Cyclopropanecarboxylic acid or 2,2-dimethyl cyclopropanecarboxylic acid was used as a leading compound for its biological activity.Six new N-(substituted) cyclopropanecarboxyl-N′-pyridin-2-yl thioureas were prepared.Compound 5 was obtained by oxidizing cyclization of compound 4 in the presence of bromine in chloroform solution.The structures of 4 and 5 were confirmed by ~1H NMR and elemental analysis.The preliminary biological tests indicate that compound 4b and 4e have excellent herbicidal activity,and ...     

Synthesis and biology of N-thiolated β-lactams

N-Thiolated β-lactams are an interesting new family of bioactive agents having antibacterial, antifungal, and anticancer capabilities. Our interest in these β-lactams stems from their highly unusual structure–activity profiles and selectivity toward only a few genera of pathogenic bacteria, including Staphylococcus aureus, Bacillus anthracis, and Micrococcus. Here, we provide a complete outline on our work in the discovery and ongoing development of these compounds, starting from our initial, unexpected finding of antimicrobial activity for one of the lead compounds, to a more complete understanding of their chemical and biological mode of action and potential utility as antibacterial compounds.     

Stereoselective,solid phase-based synthesis of trans 3-alkyl-substituted β-lactams as analogues of cholesterol absorption inhibitors

A straightforward solid phase-based strategy for the rapid generation of two small libraries of trans 3-alkyl-substituted β-lactams is described. For the glycine-derived library, a controlled excess of nonactivated acid chlorides was used to prevent oxazinone formation. The second library involved the attachment of Fmoc-protected p-aminophenol to Wang resin for the preparation of structurally-closed analogues of known cholesterol absorption inhibitors. This strategy allowed us to introduce diversity in the three variable positions of the β-lactam ring.     

β-lactams from esters and silylimines: A revaluation. Synthesis of N-unsubstituted 4-alkyl-β-lactams

The first preparation of enolizable silylimines is reported. The “in situ” trapping of these species with lithium enolates of esters gives rise in fairly good yields to N-unsubstituted 4-alkyl-β-lactams.     

Intramolecular ester enolate-imine cyclization reactions for the asymmetric synthesis of polycyclic β-lactams and cyclic β-amino acid derivatives

Enolates of chiral N-(α-methyl-p-methoxybenzyl)-ω-imino-esters undergo intramolecular cyclization reactions to afford (syn)-aza-anions of β-amino esters in high dr that cyclize to afford N-(α-methyl-p-methoxybenzyl)-β-lactams that can be readily deprotected to afford their corresponding cyclic NH-β-lactams, β-amino esters, or β-amino acids.     

Vibrational spectra of β-lactams—II. 1-Methyl-2-azetidinone and its deuterated compounds

The i.r. and Raman spectra of 1-methyl-2-azetidinone and its 3,3-d₂ and methyl-d₃ compounds have been recorded, and the observed bands have been assigned on the basis of the isotope effects and the normal coordinate analysis. Comparison of the CO and CN force constants between 2-azetidinone and 1-methyl-2-azetidinone indicates that, depending on amide resonance, these constants are related to each other. The solvent effects on the CO frequencies of four to seven-membered lactams have also been examined.     

Identification of cyclicsulfonamide derivatives with an acetamide group as 11β-hydroxysteroid dehydrogenase 1 inhibitors

In the continuation of our 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11β-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11β-HSD1, selectivity against 11β-HSD2, microsomal stability, good pharmacokinetic and safety profiles human ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity difference between human and mouse 11β-HSD1.     

Inclusion compounds of some water-soluble β-cyclodextrin derivatives with phenolphthalein

Cyclodextrins and some of their water-soluble derivatives form with phenolphthalein host-guest complexes whose stability depends on the structure, position, and number of substituents.Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 12, 2004, pp. 2034–2037.Original Russian Text Copyright © 2004 by Glazyrin, Grachev, Kurochkina, Nifantev.This revised version was published online in April 2005 with a corrected cover date.     

Synthesis and biological evaluation of coumarin derivatives containing oxime ester as α-glucosidase inhibitors

In this study, potent coumarin derivatives containing oxime ester 1 ～ 28 as α-glucosidase inhibitors were developed through a stepwise structure optimization, and the structure activity relationship was uncovered. Among them, compound 20 exhibited outstanding α-glucosidase inhibitory activity with IC₅₀ of 2.54 ± 0.04 μM compared to 640.57 ± 1.13 μM of Acarbose. Kinetic study ascertained that compound 20 was a reversible and uncompetitive α-glucosidase inhibitor. 3D fluorescence results showed that the interaction of compound 20 with α-glucosidase caused the changes of microenvironments and polypeptide backbone structure of α-glucosidase. CD spectra results revealed that compound 20 decreased the α-helix content and increased the β-sheet content. Molecular docking analysis indicated that compound 20 well located into the active site and mainly bind with Phe157, His239, His279, Tyr71, and Arg312 to reduce the catalytic activity of α-glucosidase.