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.     

β-Lactam derivatives as enzyme inhibitors: halogenated β-lactams and related compounds

Different modifications of the imine – acyl chloride reaction were used for the synthesis of 3-mono- and 3,3-dihalogenated 1,4-diaryl substituted β-lactams. Furthermore, these β-lactams were modified by halogen substitution either at the aryl at position 1 or at the aryl substituent at position 4, or at both positions. The influence of the halogen atoms on the reactivity of the β-lactam ring, visible by the carbonyl frequence in their IR spectra, was studied. A selection of compounds was tested as inhibitors of the serin protease porcine pancreatic elastase. No simple correlation between IR frequence and biological activity was found. Finally, the base induced rearrangement of N-benzyl β-lactams was used for the synthesis of 4,5-diaryl substituted pyrrolidinones. Correspondence: Hans-Hartwig Otto, Department of Pharmaceutical/Medicinal Chemistry (PMC), Institute of Pharmacy, Ernst-Moritz-Arndt-University, 17487 Greifswald, Germany.     

Alkylating potential of α,β-unsaturated compounds

Alkylation reactions of the nucleoside guanosine (Guo) by the α,β-unsaturated compounds (α,β-UC) acrylonitrile (AN), acrylamide (AM), acrylic acid (AA) and acrolein (AC), which can act as alkylating agents of DNA, were investigated kinetically. The following conclusions were drawn: i) The Guo alkylation mechanism by AC is different from those brought about the other α,β-UC; ii) for the first three, the following sequence of alkylating potential was found: AN > AM > AA; iii) A correlation between the chemical reactivity (alkylation rate constants) of AN, AM, and AA and their capacity to form adducts with biomarkers was found. iv) Guo alkylation reactions for AN and AM occur through Michael addition mechanisms, reversible in the first case, and irreversible in the second. The equilibrium constant for the formation of the Guo-AN adduct is K(eq) (37 °C) = 5 × 10(-4); v) The low energy barrier (≈10 kJ mol(-1)) to reverse the Guo alkylation by AN reflects the easy reversibility of this reaction and its possible correction by repair mechanisms; vi) No reaction was observed for AN, AM, and AA at pH < 8.0. In contrast, Guo alkylation by AC was observed under cellular pH conditions. The reaction rate constants for the formation of the α-OH-Guo adduct (the most genotoxic isomer), is 1.5-fold faster than that of γ-OH-Guo. vii) a correlation between the chemical reactivity of α,β-UC (alkylation rate constants) and mutagenicity was found.     

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.     

New quinoxaline derivatives as potential MT₁ and MT₂ receptor ligands

Ever since the idea arose that melatonin might promote sleep and resynchronize circadian rhythms, many research groups have centered their efforts on obtaining new melatonin receptor ligands whose pharmacophores include an aliphatic chain of variable length united to an N-alkylamide and a methoxy group (or a bioisostere), linked to a central ring. Substitution of the indole ring found in melatonin with a naphthalene or quinoline ring leads to compounds of similar affinity. The next step in this structural approximation is to introduce a quinoxaline ring (a bioisostere of the quinoline and naphthalene rings) as the central nucleus of future melatoninergic ligands.     

Discovery of a series of pyridopyrimidine derivatives as potential topoisomerase Ⅰ inhibitors

A series of new 3-benzoheterocyclic substituted pyridopyrimidines were designed and synthesized.Structures of the compounds were determined by IR,1H NMR, and elemental analyses. The antiproliferation activity of 13 novel compounds was evaluated in A549, HL-60, BGC-823 and SMMC-7721cell lines. Compounds 3, 5, 7, 8, 9, 10 showed potent inhibitory activity against the four tested cancer cell lines. These six compounds were examined for Top I inhibition at 100 mmol/L by measuring the relaxation of supercoiled DNA in plasmid pBR322. Most of the tested compounds inhibited the enzyme at this concentration. The most potent compound 9 was as potent as camptothecin.     

Synthesis of Deoxytabtoxinine-β-Lactam

Deoxytabtoxinine-β-lactam (12) was synthesized in 6 steps from 3. β-Lactam 12 does not inhibit glutamine synthetase indicating that the hydroxyl group of tabtoxinine-β-lactam (2) is necessary for inhibition of glutamine synthetase.     

β-1,2-Mannan-based glycoconjugates as potential antifungal vaccines

Phosphorylated di-, tri- and tetra-saccharides of β-1,2-mannan antigen derived from Candida albicans (C. albicans) cell wall were synthesized and covalently conjugated with keyhole limpet hemocyanin (KLH) and human serum albumin (HSA) via a bifunctional linker under mild conditions. The semi-synthetic β-1,2-mannoside–KLH conjugates were evaluated for the immunization of BALB/c mice. The ELISA results revealed that all three conjugates could elicit high levels of specific IgG antibodies and the acquired antisera could effectively identify the β-1,2-mannan epitope. Furthermore, the immunofluorescence and flow cytometry assays also uncovered that the induced antibodies, especially that obtained from immunization with β-1,2-mannotriose–KLH conjugate (1b), could bind well to fungi cell. Eventually, the structure–immunogenicity relationship analysis of β-mannan showed that the length of oligo-β-mannoses had a big impact on their immunogenicity and β-1,2-mannotriose showed the strongest immunogenicity. The results suggested the great potential of β-1,2-mannotriose–KLH conjugate as an antifungal vaccine candidate.     

An α-Lactam as an Alkilating Agent

The ‘normal’ reaction of α-lactams (aziridinones) is mcleophilic ring ening,¹ which can occur with fission of either one of the three bonds (a-b-c), depending on the reagent, to yield and acyclic addition prodnct (I,II,III).²     

β-Dicarbonyl compounds

Summary The presence of alkali suppresses the oxidative rearrangement of 2-acylcycloalkanones and favors the process of oxidative cleavage which occurs simultaneously.     

β-Dicarbonyl compounds

Summary Cases of the different chemical behavior of aliphatic and cyclic -dicarbonyl compounds have been considered. The following properties are characteristic for -diketones of the type of dihydroresorcinol: hindered Michael and C-alkylation reactions, tendency to form alkylidene-bis--diketones by the action of aldehydes, incapability of undergoing the Mannich reaction, inertness of the halogen atom of enolized 2-bromo derivatives, and the brominatioh of the enol ethers by N-bromosuccinimide in the second position.     

β-Trifluoromethyl-α-functionalized-vinyl sulfides as a potential synthetic intermediate

The β-(trifluoromethyl)vinyl sulfides on treatment with n-BuLi/TMEDA at −78 °C were readily lithiated at an α-position of the sulfanyl group, and the generated β-trifluoromethyl-α-sulfanylvinyl anions were reacted with a variety of electrophiles to give the corresponding β-trifluoromethyl-α-functionalized-vinyl sulfides 4aa-4aq in good to excellent yields. The reactivity of some products has been examined. The palladium-catalyzed cross-coupling reaction as well as homo-coupling reaction of 4af provided the corresponding products in good yields, respectively. The Diels-Alder reaction of cyclic dienes and 14 derived from 4ao provided the desired six-membered cyclic products with high endo-trifluoromethyl group selectivity.     

Novel nanoparticles composed of chitosan and β-cyclodextrin derivatives as potential insoluble drug carrier

This research was aim to develop novel cyclodextrin/chitosan(CD/CS) nanocarriers for insoluble drug delivery through the mild ionic gelation method previously developed by our lab. A series of different bcyclodextrin(β-CD) derivatives were incorporated into CS nanoparticles including hydroxypropyl-bcyclodextrin(HP-β-CD), sulphobutylether-β-cyclodextrin(SB-β-CD), and 2,6-di-O-methy-β-cyclodextrin(DM-β-CD). Various process parameters for nanoparticle preparation and their effects on physicochemical properties of CD/CS nanoparticles were investigated, such as the type of CD derivatives,CD and CS concentrations, the mass ratio of CS to TPP(CS/TPP), and p H values. In the optimal condition,CD/CS nanoparticles were obtained in the size range of 215–276 nm and with the zeta potential from30.22 m V to 35.79 m V. Moreover, the stability study showed that the incorporation of CD rendered the CD/CS nanocarriers more stable than CS nanoparticles in PBS buffer at p H 6.8. For their easy preparation and adjustable parameters in nanoparticle formation as well as the diversified hydrophobic core of CD derivatives, the novel CD/CS nanoparticles developed herein might represent an interesting and versatile drug delivery platform for a variety of poorly water-soluble drugs with different physicochemical properties.     

Design and synthesis of novel triazole derivatives containing γ-lactam as potential antifungal agents

A series of novel triazole derivatives containing γ-lactam were designed and synthesized, and their structures were confirmed by ~1H NMR,~(13)CNMR and HRMS. The in vitro antifungal activities of the target compounds were evaluated. The results showed that all of the compounds exhibited stronger activity against the six clinically important fungi tested than fluconazole. 3D and 3E showed comparative activity against the fungi tested except for Candida glabrata and Aspergillus fumigatus as voriconazole. In addition,the docking model for 2A and CYP51 was investigated.