Macrocyclic condensation products of indole and simple aldehydes

Bergman, Jan; Högberg, Sverker; Lindström, Jan-Olof

doi:10.1016/s0040-4020(01)92912-6

Cited by 45 publications

(18 citation statements)

References 10 publications

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“…The synthesis of pure CTet was carried out by modifying Bergman et al .’s procedure [ 33 ]. When we applied this protocol, we repeatedly obtained results not congruent with the reported ones.…”

Section: Resultsmentioning

confidence: 99%

“…Bergman’s protocol was modified by prolonging reaction time, due to the presence of the starting material in the mixture after one hour, and by purifying the crude by two rapid passages through short aluminum oxide columns. CTet was finally obtained with a purity higher than 99% by recrystallization from acetone, rather than pyridine [ 33 ] and DMSO [ 34 ], to facilitate solvent removal. The protocol proved to be scalable, in that it was possible to run it using up to 150 mmol of indole (17.5 g); these experiments gave yields and CTr / CTet ratios comparable with those reported on a lower scale (amounts of reagents higher than those reported were not used) ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…The methods reported in the literature for the preparation of CTet are three. The first involves the one-pot reaction of indole and formaldehyde in acidic methanol, and is in principle advantageous [ 33 ]. The second is in fact aimed at obtaining CTr and affords CTet as a by-product in low yield after recrystallization with DMSO; this method, employing gramine as a source in a basic environment of the presumed 3-methylene indolenine intermediate, is practical and efficient but not all its reagents could be utilized on a large scale synthesis because of their toxicity [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of a γ-Cyclodextrin-based Formulation of the Anticancer Agent 5,6,11,12,17,18,23,24- Octahydrocyclododeca[1,2-b:4,5-b’:7,8-b’’:10,11-b’’’]tetraindole (CTet)

et al. 2010

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5,6,11,12,17,18,23,24-octahydrocyclododeca[1,2-b:4,5-b’:7,8-b’’:10,11-b’’’]tetraindole (CTet), an indole-3-carbinol (I3C) metabolite endowed with anticancer properties, is poorly soluble in the solvents most frequently used in biological tests. This study indicates that the use of γ-cyclodextrin (γ-CD) avoids this problem. Formulated with γ-CD CTet is a potent inhibitor of DNA synthesis in both estrogen receptor positive (MCF-7) and estrogen receptor negative (MDA-MB-231) human breast cell lines (IC50 = 1.20 ± 0.04 μM and 1.0 ± 0.1 μM, respectively).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of a γ-Cyclodextrin-based Formulation of the Anticancer Agent 5,6,11,12,17,18,23,24- Octahydrocyclododeca[1,2-b:4,5-b’:7,8-b’’:10,11-b’’’]tetraindole (CTet)

et al. 2010

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“…Recently, Lucarini and colleagues [ 21 ] proposed a straightforward synthesis of CTet, but this method, as well as the others reported in the literature [ 20 , 37 , 38 ], is not sufficiently advantageous. In this paper, we describe a new synthesis involving 2,3'-DIM homo-coupling in the presence of formaldehyde in acidic medium.…”

Section: Discussionmentioning

confidence: 99%

The indole-3-carbinol cyclic tetrameric derivative CTet inhibits cell proliferation via overexpression of p21/CDKN1A in both estrogen receptor-positive and triple-negative breast cancer cell lines

et al. 2011

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IntroductionIndole-3-carbinol (I3C), an autolysis product of glucosinolates present in cruciferous vegetables, and its dimeric derivative (3,3'-DIM) have been indicated as promising agents in preventing the development and progression of breast cancer. We have recently shown that I3C cyclic tetrameric derivative CTet formulated in γ-cyclodextrin (γ-CD) efficiently inhibited cellular proliferation in breast cancer cell lines. This study aims to analyze the mechanisms involved in the in vitro inhibition of cell proliferation and to evaluate the in vivo antitumor activity of CTet in a xenograft study.MethodsEstrogen receptor-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines were exposed to CTet to evaluate cell cycle perturbation (propidium iodide staining and cytofluorimetric acquisition), induction of autophagic morphological features (co-localization of LC3b autophagosome marker and LAMP2a lysosome marker by immunofluorescence) and changes in protein expression (immunoblot and microarray-based gene expression analyses). To test the in vivo efficacy of CTet, female athymic nude mice inoculated with MCF-7 cells were i.p. treated with 5 mg/kg/day of CTet for five days/week for two weeks and the tumor mass was externally monitored.ResultsCTet induced accumulation in G2/M phase without evidence of apoptotic response induction in both cell lines tested. In triple-negative MDA-MB-231 the autophagic lysosomal activity was significantly up-regulated after exposure to 4 μM of CTet for 8 hours, while the highest CTet concentration was necessary to observe autophagic features in MCF-7 cells. The inhibition of Akt activity and p53-independent p21/CDKN1A and GADD45A overexpression were identified as the main molecular events responsible for CTet activity in MCF-7 and p53-mutant MDA-MB-231 cells. In vivo, CTet administration was able to significantly inhibit the growth of MCF-7 xenotransplanted into nude mice, without adverse effect on body weight or on haematological parameters.ConclusionsOur data support CTet formulated with γ-CD as a promising and injectable anticancer agent for both hormone-responsive and triple-negative breast tumors.

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“…Reaction of 3-hydroxymethyl-1-methylindole [3][4][5] with a catalytic amount of p-toluenesulfonic acid in dichloromethane gives a simple indolocyclotriveratrylene. [6] Similar but more complex cyclotriveratrylenes can also be generated from other N-substituted hydroxymethylindoles and also those derived from activated indoles. [7] Given the formation of indolocyclotriveratrylenes 2 from N-substituted hydroxymethylindoles 1, it was considered that the reactions of bis-hydroxymethylindole systems 3 containing two indole rings joined by linkers through their nitrogen atoms might lead to the formation of cylindrical structures 4 capable of selectively attracting small molecules (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%