br Cite this article as LV Yi
Cite this article as: LV Yi, SO Kwok-Fai, WONG Nai-Kei, XIAO Jia. Anti-cancer activities of S-allylmercaptocysteine from
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Anti-cancer activity of m-carborane-containing trimethoxyphenyl derivatives through tubulin polymerization inhibition
Asako Kaisea, Yasuyuki Endoa, , Kiminori Ohtab,
a Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan b School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Tubulin polymerization inhibition Trimethoxyphenyl moiety
m-Carborane-containing compound 1a was identified as a cell growth inhibitor from a random screening of a boron compound library. As 1a is a mixture of diastereomers due to the presence of two chiral carbons, we designed achiral derivatives 2–4 and studied the structure-activity relationships of the methoxy groups on the benzene ring. 3,4,5-Trimethoxybenzyl derivative 2a and 3,4,5-trimethoxybenzoyl derivative 3a showed more potent anti-cancer activity against the human breast cancer cell line MDA-MB-453 than lead compound 1a. Compound 3a inhibited tubulin polymerization in a dose-dependent manner.
The trimethoxyphenyl moiety is included in the structures of many natural products and low-molecular-weight bioactive compounds.1 In the binding mechanism of these compounds to target proteins, the tri-methoxyphenyl moiety binds to some amino A 61603 residues through π stacking and hydrogen bond formation. Moreover, the trimethox-yphenyl moiety can fit into a small hydrophobic pocket because it has hydrophobic-hydrophilic balance. Colchicine (COL, Fig. 1), a tubulin polymerization inhibitor, has a trimethoxyphenyl moiety that forms hydrogen bonds with Val238 and Cys241 of the main chain located in the hydrophobic pocket of β-tubulin.2 Combretastatin A-4 (CA-4, Fig. 1) binds to the colchicine binding site of β -tubulin and also inhibits tu-bulin polymerization.3 The trimethoxyphenyl group of CA-4 is buried deeper in the hydrophobic pocket than that of colchicine, although no hydrogen bonds are formed.3
Dicarba-closo-dodecaborane (carborane) exhibits remarkable thermal and chemical stability, has high hydrophobicity, and contains an icosahedral geometry.4 Based on these properties, various carborane derivatives have been prepared in medicinal5 and material chemistry.6 Carboranes have also been prepared as a boron carrier for boron neu-tron capture therapy (BNCT) because of their high boron contents.7 We have synthesized various carborane derivatives for use as nuclear re-ceptor ligands,8 bio-functional compounds,9 and optical materials,10 and these have been consolidated as a boron compound library. A
random screening of the boron compound library revealed that com-pound 1a, which is a mixture of diastereomers, inhibited cell growth of the human breast cancer cell line MDA-MB-453 (GI50 = 8.6 μ) (Fig. 1). This result inspired us to develop novel m-carborane-containing tri-methoxyphenyl bioactive compounds.
Screening-hit compound 1a has two chiral carbon atoms, and it is difficult to synthesize the diastereomers selectively. Moreover, they are not separable by column chromatography on silica gel. Therefore, we designed several achiral derivatives, including dibenzyl- (2), dibenzoyl-(3), and diaryl- (4) m-carboranes (Fig. 2). Furthermore, to investigate the effects of the number and the substitution position of methoxy groups in 1a on the anticancer activity, various methoxy derivatives were designed using the dibenzyl derivative 2. Here, we describe the synthesis of target compounds 2–4, their cell growth inhibitory activ-ities against MDA-MB-453 cells, and the tubulin polymerization in-hibitory activity of selected compounds 2a and 3a.
2. Results and discussion
Scheme 1 summarizes the synthesis of benzyl (2) and benzoyl (3) derivatives. The Li salt of m-carborane (5), which was prepared by treatment with n-BuLi, was reacted with various benzaldehydes to give corresponding dihydroxy derivatives 1a–d. The benzylic hydroxyl
E-mail addresses: [email protected] (Y. Endo), [email protected] (K. Ohta).
Available online 10 February 2019
Fig. 1. Chemical structures of colchicine, combretastatin A-4, and 1a.
Fig. 2. Chemical structures of target compounds 2–4.
GI50 values of m-carborane derivatives 1–4 against human breast cancer cell line, MDA-MB-453.
groups of 1a–d were removed by treatment with triethylsilane in the presence of trifluoroacetic acid or BF3-OEt to give benzyl derivatives 2a–d.11 Benzoyl derivative 3a was obtained by the oxidation of both hydroxyl groups in 1a with Dess-Martin periodinane.12 The tert-bu-tyldimethylsilyl (TBS) group of 2d was deprotected with tetra-n-buty-lammonium fluoride (TBAF) to give 2e. 4-Nitrobenzyl derivative 2f, which has no methoxy group, was synthesized by the reaction of the Li salt of 5 with 4-nitrobenzylbromide.