Regio- and stereoselective synthesis of dispirooxindole-pyrrolocarbazole hybrids via 1,3-dipolar cycloaddition reactions: Cytotoxic activity and SAR studies

Abstract

A library of novel dispiro compounds containing oxindole-pyrrolo-carbazole hybrid frame works has been synthesized in a fully regio- and stereoselective fashion by the three-component 1,3-dipolar cycloaddition of azomethineylides generated in situ from the condensation of isatins and benzylamine with 2-arylidene/heteroarylidene-2,3,4,9-tetrahydro-1H-carbazole-1-one. The structures of the compounds were established by FT-IR, H NMR,C NMR, X-ray diffraction and elemental analysis. The synthesized dispiro heterocycles have been screened for in vitro cytotoxic activity by MTT assay and displayed enviable growth inhibition on both the cancer cell lines i.e. breast cancer cell line MCF-7 and lung cancer cell line A-549. Morphological changes and apoptosis induction have been studied by inverted light microscopic, fluorescent microscopic techniques and by flow cytometry analyses. The preliminary structure activity relationships were also carried out. Data indicated that among dispiro-carbazole compounds,6-chloro-4'-(thiophen-2-yl)-5'-phenyl-3,4-dihydrodispiro[carbazole-2,3'-pyrrolo-2',3″-indole]-9(H)-1,2″-dione 7e could be exploited as a significant therapeutic drug against breast cancer as well as lung cancer cell proliferation.

Azomethine Ylides—Versatile Synthons for Pyrrolidinyl-Heterocyclic Compounds

“…Dispiro[carbazole-2,3′-pyrrolo-2′,3″-indole] derivatives of type 248 were synthesized regio- and stereoselectively by the reaction of 2-ylidene-1 H -carbazol-1-one 247 and in situ-generated azomethine ylide (formed from isatin 19 and benzylamine 57 ). Some of the obtained compounds revealed antiproliferative properties (MTT assay) via apoptosis induction against MCF7 (breast) and A-549 (lung) cancer cell lines relative to Cisplatin ( Scheme 85 ) [ 115 ].…”

Antineoplastic indole-containing compounds with potential VEGFR inhibitory properties

“…Spiroindoles occupy a unique place in heterocyclic chemistry due to the versatile bio-properties of their natural and synthetic analogs 146 (exemplied by antibacterial, antifungal, [147][148][149][150][151] antimycobacterial, [152][153][154] antiviral, 19,155 anticancer, [156][157][158][159][160] antimalarial, 161,162 anti-inammatory 163 and antihyperglycemic 164,165 ). [3 + 2]-Dipolar cycloaddition of azomethine ylides derived from isatin derivatives with a-amino acids to the exocyclic olenic linkage derived from alicycles or heterocycles is an accessible synthetic approach successfully used for the construction of various spiroindoles with regio-and stereoselectivity.…”

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…Antiproliferative properties were noticed for the synthesized agents. The most potent are those derived from 2-thienylidene-1 H -carbazole-1-ones (IC 50 = 14, 13, 15; 15, 14, 16 μM for compounds with R’ = Me, Cl, and H relative to Cisplatin; IC 50 = 9, 10 μM against MCF-7 “breast” and A-549 “lung” cancer cell lines, respectively) [ 49 ].…”