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24 pages, 5607 KiB

Open AccessArticle

Unsymmetrically-Substituted 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione Scaffold—A Useful Tool for Bioactive Molecules Design

by Bartosz Bieszczad, Damian Garbicz, Damian Trzybiński, Marta K. Dudek, Krzysztof Woźniak, Elżbieta Grzesiuk and Adam Mieczkowski

Molecules 2020, 25(12), 2855; https://doi.org/10.3390/molecules25122855 - 20 Jun 2020

Cited by 4 | Viewed by 3239

Abstract

Unsymmetrically N-substituted and N,N’-disubstituted 5,12-dihydrodibenzo [b,f][1,4]diazocine-6,11-diones were synthesized in the new protocol. The desired modifications of the dibenzodiazocine scaffold were introduced at the stages of proper selection of building blocks as well as post-cyclization modifications with alkylation [...] Read more.

Unsymmetrically N-substituted and N,N’-disubstituted 5,12-dihydrodibenzo [b,f][1,4]diazocine-6,11-diones were synthesized in the new protocol. The desired modifications of the dibenzodiazocine scaffold were introduced at the stages of proper selection of building blocks as well as post-cyclization modifications with alkylation or acylation agents, expanding the structural diversity and possible applications of synthesized molecules. The extension of developed method resulted in the synthesis of novel: tricyclic 5,10-dihydrobenzo[b]thieno[3,4-f][1,4]diazocine-4,11-dione scaffold and fused pentacyclic framework possessing two benzodiazocine rings within its structure. Additionally, the unprecedented rearrangement of 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-diones to 2-(2-aminophenyl)isoindoline-1,3-diones was observed under the basic conditions in the presence of sodium hydride for secondary dilactams. The structures of nine synthesized products have been established by single-crystal X-ray diffraction analysis. Detailed crystallographic analysis of the investigated tri- and pentacyclic systems has shed more light on their structural features. One cell line derived from non-cancerous cells (EUFA30—human fibroblasts) and three tumor cells (U87—human primary glioblastoma, HeLa—cervix adenocarcinoma, BICR18—laryngeal squamous cell carcinoma) were used to determine the cytotoxic effect of the newly synthesized compounds. Although these compounds showed a relatively weak cytotoxic effect, the framework obtained for 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione could serve as a convenient privilege structure for the design and development of novel bioactive molecules suitable for drug design, development and optimization programs. Full article

(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)

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25 pages, 2208 KiB

Open AccessArticle

Novel Polycondensed Partly Saturated β-Carbolines Including Ferrocene Derivatives: Synthesis, DFT-Supported Structural Analysis, Mechanism of Some Diastereoselective Transformations and a Preliminary Study of their In Vitro Antiproliferative Effects

by Kinga Judit Fodor, Dániel Hutai, Tamás Jernei, Angéla Takács, Zsófia Szász, Máté Sulyok-Eiler, Veronika Harmat, Rita Oláh Szabó, Gitta Schlosser, Ferenc Hudecz, László Kőhidai and Antal Csámpai

Molecules 2020, 25(7), 1599; https://doi.org/10.3390/molecules25071599 - 31 Mar 2020

Cited by 1 | Viewed by 3443

Abstract

Use of a Pictet-Spengler reaction of tryptamine and l-tryptophan methyl ester and subsequent reduction of the nitro group followed by further cyclocondensation with aryl aldehydes and formyl–substituted carboxylic acids, including ferrocene-based components, furnished a series of diastereomeric 6-aryl-substituted 5,6,8,9,14,14b-hexahydroindolo[2′,3′:3,4]pyrido[1-c]-quinazolines and [...] Read more.

Use of a Pictet-Spengler reaction of tryptamine and l-tryptophan methyl ester and subsequent reduction of the nitro group followed by further cyclocondensation with aryl aldehydes and formyl–substituted carboxylic acids, including ferrocene-based components, furnished a series of diastereomeric 6-aryl-substituted 5,6,8,9,14,14b-hexahydroindolo[2′,3′:3,4]pyrido[1-c]-quinazolines and 5,5b,17,18-tetrahydroindolo[2′,3′:3,4]pyrido[1,2-c]isoindolo[2,1-a]quinazolin-11-(15bH)-ones with the elements of central-, planar and conformational chirality. The relative configuration and the conformations of the novel polycyclic indole derivatives were determined by ¹H- and ¹³C-NMR methods supplemented by comparative DFT analysis of the possible diastereomers. The structure of one of the pentacyclic methyl esters with defined absolute configuration “S” was also confirmed by single crystal X-ray diffraction measurement. Accounting for the characteristic substituent-dependent diastereoselective formation of the products multistep mechanisms were proposed on the basis of the results of DFT modeling. Preliminary in vitro cytotoxic assays of the products revealed moderate-to-significant antiproliferative effects against PANC-1-, COLO-205-, A-2058 and EBC-1 cell lines that proved to be highly dependent on the stereostructure and on the substitution pattern of the pending aryl substituent. Full article

(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)

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14 pages, 1484 KiB

Open AccessArticle

Synthesis of New C-3 Substituted Kynurenic Acid Derivatives

by Bálint Lőrinczi, Antal Csámpai, Ferenc Fülöp and István Szatmári

Molecules 2020, 25(4), 937; https://doi.org/10.3390/molecules25040937 - 19 Feb 2020

Cited by 16 | Viewed by 3612

Abstract

The application of kynurenic acid (KYNA) as an electron-rich aromatic system in the modified Mannich reaction has been examined. The extension possibility of the reaction was tested by using amines occurring in a number of bioactive products, such as morpholine, piperidine, or N [...] Read more.

The application of kynurenic acid (KYNA) as an electron-rich aromatic system in the modified Mannich reaction has been examined. The extension possibility of the reaction was tested by using amines occurring in a number of bioactive products, such as morpholine, piperidine, or N-methylpiperazine and aldehydes of markedly different reactivities, like formaldehyde and benzaldehyde. The influence of substituents attached to position 3 on the aminoalkylation was also investigated. Thus, reactions of 3-carbamoyl-substituted precursors with tertiary amine containing side-chains were also tested to afford new KYNA derivatives with two potential cationic centers. By means of NMR spectroscopic measurements, supported by DFT calculations, the dominant tautomer form of KYNA derivatives was also determined. Full article

(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)

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14 pages, 1138 KiB

Open AccessArticle

Synthesis and Application of 1,2-Aminoalcohols with Neoisopulegol-Based Octahydrobenzofuran Core

by Fatima Zahra Bamou, Tam Minh Le, Bettina Volford, András Szekeres and Zsolt Szakonyi

Molecules 2020, 25(1), 21; https://doi.org/10.3390/molecules25010021 - 19 Dec 2019

Cited by 8 | Viewed by 4848

Abstract

A library of 1,2-aminoalcohol derivatives with a neoisopulegol-based octahydrobenzofuran core was developed and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The allylic chlorination of (+)-neoisopulegol, derived from natural (–)-isopulegol followed by cyclization, gave the key methyleneoctahydrobenzofuran intermediate. The stereoselective [...] Read more.

A library of 1,2-aminoalcohol derivatives with a neoisopulegol-based octahydrobenzofuran core was developed and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The allylic chlorination of (+)-neoisopulegol, derived from natural (–)-isopulegol followed by cyclization, gave the key methyleneoctahydrobenzofuran intermediate. The stereoselective epoxidation of the key intermediate and subsequent oxirane ring opening with primary amines afforded the required 1,2-aminoalcohols. The ring closure of the secondary amine analogues with formaldehyde provided spiro-oxazolidine ring systems. The dihydroxylation of the methylenetetrahydrofuran moiety with OsO₄/NMO (4-methylmorpholine N-oxide) resulted in the formation of a neoisopulegol-based diol in a highly stereoselective reaction. The antimicrobial activity of both the aminoalcohol derivatives and the diol was also explored. Full article

(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)

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31 pages, 7000 KiB

Open AccessFeature PaperArticle

Synthesis, Structure and In Vitro Cytotoxic Activity of Novel Cinchona—Chalcone Hybrids with 1,4-Disubstituted- and 1,5-Disubstituted 1,2,3-Triazole Linkers

by Tamás Jernei, Cintia Duró, Antonio Dembo, Eszter Lajkó, Angéla Takács, László Kőhidai, Gitta Schlosser and Antal Csámpai

Molecules 2019, 24(22), 4077; https://doi.org/10.3390/molecules24224077 - 11 Nov 2019

Cited by 12 | Viewed by 3173

Abstract

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines [...] Read more.

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart. Full article

(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)

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10 pages, 935 KiB

Open AccessArticle

Solvent-Free C-3 Coupling of Azaindoles with Cyclic Imines

by Khadija Belasri, Ferenc Fülöp and István Szatmári

Molecules 2019, 24(19), 3578; https://doi.org/10.3390/molecules24193578 - 4 Oct 2019

Cited by 8 | Viewed by 2609

Abstract

By direct coupling 7-azaindole and cyclic imines, such as 3,4-dihydroisoquinoline, 6,7-dihydrothieno[3,2-c]pyridine, 3,4-dihydro-β-carboline, and 4,5-dihydro-3H-benz[c]azepine, new 3-substituted 7-azaindole derivatives have been synthesized. The reaction was extended to 4-azaindoles and 6-azaindoles, as electron-rich aromatic compounds. The lowest reactivity was [...] Read more.

By direct coupling 7-azaindole and cyclic imines, such as 3,4-dihydroisoquinoline, 6,7-dihydrothieno[3,2-c]pyridine, 3,4-dihydro-β-carboline, and 4,5-dihydro-3H-benz[c]azepine, new 3-substituted 7-azaindole derivatives have been synthesized. The reaction was extended to 4-azaindoles and 6-azaindoles, as electron-rich aromatic compounds. The lowest reactivity was observed in the case of C-3 substitution of 5-azaindole. In this case, the aza-Friedel-Crafts reaction took place by using 10 mol % of p-toluenesulfonic acid (p-TSA) as the catalyst. The role of the acid catalyst can be explained by the different pKa values of the azaindoles. All reactions were performed in solvent-free conditions by using both classical heating and microwave irradiation. In all cases, microwave heating proved to be more convenient to synthesize new C-3-substituted azaindole derivatives. Full article

(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)

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Review

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14 pages, 3047 KiB

Open AccessReview

Focusing on the Catalysts of the Pd- and Ni-Catalyzed Hirao Reactions

by György Keglevich, Réka Henyecz and Zoltán Mucsi

Molecules 2020, 25(17), 3897; https://doi.org/10.3390/molecules25173897 - 26 Aug 2020

Cited by 15 | Viewed by 3950

Abstract

The Hirao reaction involving the phosphinoylation or phosphonation of aryl halides by >P(O)H reagents is a P–C bond forming transformation belonging to the recently very hot topic of cross-couplings. The Pd- or Ni-catalyzed variations take place via the usual cycle including oxidative addition, [...] Read more.

The Hirao reaction involving the phosphinoylation or phosphonation of aryl halides by >P(O)H reagents is a P–C bond forming transformation belonging to the recently very hot topic of cross-couplings. The Pd- or Ni-catalyzed variations take place via the usual cycle including oxidative addition, ligand exchange, and reductive elimination. However, according to the literature, the nature of the transition metal catalysts is not unambiguous. In this feature article, the catalysts described for the Pd(OAc)₂-promoted cases are summarized, and it is concluded that the “(HOY₂P)₂Pd(0)” species (Y = aryl, alkoxy) is the real catalyst. In our model, the excess of the >P(O)H reagent served as the P-ligand. During the less studied Ni(II)-catalyzed instances the “(HOY₂P)(−OY₂P)Ni(II)Cl⁻” form was found to enter the catalytic cycle. The newest conclusions involving the exact structure of the catalysts, and the mechanism for their formation explored by us were supported by our earlier experimental data and theoretical calculations. Full article

(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)

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16 pages, 9844 KiB

Open AccessReview

Dithieno[1,4]thiazines and Bis[1]benzothieno[1,4]thiazines—Organometallic Synthesis and Functionalization of Electron Density Enriched Congeners of Phenothiazine

by Lars May and Thomas J. J. Müller

Molecules 2020, 25(9), 2180; https://doi.org/10.3390/molecules25092180 - 7 May 2020

Cited by 9 | Viewed by 3752

Abstract

This mini-review summarizes the syntheses and functionalizations of dithieno[1,4]thiazines and bis[1]benzothieno[1,4]thiazines, both electron density-enriched congeners of phenothiazines with remarkable electronic properties. Diversity-oriented, straightforward, and efficient syntheses, including versatile one-pot processes, have been developed for the anellated 1,4-thiazines as well as various functionalization for [...] Read more.

This mini-review summarizes the syntheses and functionalizations of dithieno[1,4]thiazines and bis[1]benzothieno[1,4]thiazines, both electron density-enriched congeners of phenothiazines with remarkable electronic properties. Diversity-oriented, straightforward, and efficient syntheses, including versatile one-pot processes, have been developed for the anellated 1,4-thiazines as well as various functionalization for the expansion of the π-systems. Thereby, syntheses of different regioisomers depending on the (benzo)thieno-thiazine anellation are discussed, which exert a deep impact on the electronic properties. The tunable photophysical and electrochemical properties of dithieno[1,4]thiazines and bis[1]benzothieno[1,4]thiazines outscore phenothiazines on many points and promise an enormous potential in molecular electronics and applications beyond. Full article

(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)

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