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)

Abstract

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).

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

“…It has been previously reported that CTet formulated with γ-CD is able to inhibit proliferation of both MCF-7 and MDA-MB-231 breast cancer cell lines [21]. In this study, we confirm the dose-dependent activity of CTet in both MCF-7 (IC 50 = 1.32 ± 0.03 μM) and MDA-MB-231 (IC 50 = 1.00 ± 0.01 μM).…”

“…Solvents were Carlo Erba analytic grade. Melting point, high-performance liquid chromatography/mass spectrometry (HPLC/MS), 1 H-NMR, and 13 C-NMR were determined as in [ 21 ]. Purification of the crude material was carried out as in [ 21 ].…”

“…I3C cyclic tetrameric derivative CTet (5,6,11,12,17,18,23,24-octahydrocyclododeca[1,2- b :4,5- b' :7,8- b" :10,11- b'" ]tetraindole) (Figure 1 ) is an anticancer molecule that has been shown to exert interesting antiproliferative activity in both MCF-7 and MDA-MB-231 breast cancer cell lines [ 20 ]. Lucarini and colleagues [ 21 ] have optimized a straightforward, reproducible, and scalable CTet synthesis. Moreover, to improve bioavailability, they have optimized a formulation that is based on gamma-cyclodextrin (γ-CD) aqueous solution and that is about 10-fold more active with respect to the first preparation [ 20 ].…”

Brønsted Acid Catalyzed Bisindolization of α‐Amido Acetals: Synthesis and Anticancer Activity of Bis(indolyl)ethanamino Derivatives

“…We tested some of our compounds for cytotoxicity, including 1 , 4s , 8 , the reference parent compound DIM, and two other representative 3,3′‐bisindoles: 6,6′‐dibromo,3,3′‐diindolylmethane ( 9 )18 and the natural product 2,2‐bis(3,3′‐indolyl)propionic acid ( 10 ) (Figure 2). 13…”

“…Bis(6‐bromo‐1 H ‐indol‐3‐yl)methane (9): H 2 SO 4 (96 %, 2.6 μL) was added to a solution of 6‐bromoindole (195 mg, 0.92 mmol) and aqueous 37 % formaldehyde (37 μL, 0.49 mmol) in CH 3 OH (1 mL). The mixture was stirred at room temperature in the dark for 2 h, and concentrated in the dark to give a crude solid that was purified by flash chromatography (neutral aluminum oxide; cyclohexane/ethyl acetate, 7:3) 18. Yield: 92 mg (49 %); white solid.…”