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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

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Department of Organic Chemistry, Eötvös Loránd University (ELTE) Budapest Pázmány P. sétány 1/A, H-1117 Budapest, Hungary
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MTA-ELTE Research Group of Peptide Chemistry, Budapest Pázmány P. sétány 1/A, H-1117 Budapest, Hungary
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Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
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Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Budapest Pázmány P. sétány 1/A, H-1117 Budapest, Hungary
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Department of Analytical Chemistry, Eötvös Loránd University (ELTE), Budapest, Pázmány P. sétány 1/A, H-1117 Budapest, Hungary
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Author to whom correspondence should be addressed.
Academic Editor: Maura Pellei
Molecules 2020, 25(7), 1599; https://doi.org/10.3390/molecules25071599
Received: 17 March 2020 / Revised: 27 March 2020 / Accepted: 30 March 2020 / Published: 31 March 2020
(This article belongs to the Special Issue Synthesis and Structure of Heterocyclic and Organometallic Compounds)
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. View Full-Text
Keywords: β-carboline; diastereoselectivity; conformation; ferrocene; organic synthesis; NMR spectroscopy; X-ray diffraction; DFT calculations; cytotoxic activity; structure-activity relationships β-carboline; diastereoselectivity; conformation; ferrocene; organic synthesis; NMR spectroscopy; X-ray diffraction; DFT calculations; cytotoxic activity; structure-activity relationships
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Fodor, K.J.; Hutai, D.; Jernei, T.; Takács, A.; Szász, Z.; Sulyok-Eiler, M.; Harmat, V.; Oláh Szabó, R.; Schlosser, G.; Hudecz, F.; Kőhidai, L.; Csámpai, A. 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. Molecules 2020, 25, 1599.

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