Preparation of 1,8-Di-O-alkylaloe-emodins and 15-Amino-, 15-Thiocyano-, and 15-Selenocyanochrysophanol Derivatives from Aloe-Emodin and Studying Their Cytotoxic Effects

Abstract

Previously, we reported that when the cytotoxic effects of 4Ј-O-alkylaloenin derivatives (from methyl to hexadecyl) derived from aloenin (1) are compared, the longer the alkyl chain of the 4Ј-O-alkylaloenin derivatives, the greater is the enhancement in the cytotoxic effects on human colorectal (HCT 116) and human hepatoma (Hep G2) cancer cell lines.1) Furthermore, we reported that pseudodiosgenone derivatives having various amino groups, thiocyano (SCN), and selenocyano (SeCN) groups at the 26 position derived from diosgenin (2) exhibited the potent cytotoxic activities against the same cancer cell lines, 2) while compounds 1 and 2 have not been known to exhibit cytotoxic activity yet. In our preliminary investigation, these compounds also showed no marked cytotoxicity in less than 500 mM of the IC 50 valuethe concentration at which 50% of the cells are inhibited from growing. However, from the both above-mentioned reports, it is evident that a compound that possessed an alkyl chain with an appropriate length or that introduced appropriate substituents such as amino, thiocyano, and selecocyano groups in the molecule seemed to exhibit potent cytotoxic activity.In the present study, we investigate the preparation of 1,8-di-O-alkylaloe-emodins and 15-amino-, 15-thiocyano-, and 15-selenocyanochrysophanol derivatives from aloe-emodin (3) which has been known to have several pharmacological activities such as cytotoxic activity, [3][4][5] antifungal activity, 6) antibacterial activity, 7) and so on, and further we evaluate the cytotoxic effects of the synthetic derivatives on HCT 116 and Hep G2 cancer cell lines. Results and DiscussionAloe-emodin 3 is an anthraquinone derivative isolated from many Chinese herbal medicines such as Aloe arborensces MILL. var. natalensis BERGER (Liliaceae), 8,9) Rheum palumatum L. (Poligonaceae), 10,11) Cassia tora L. (Leguminosae), 12) and so on. This anthraquinone derivative has two phenolic hydroxyl groups at the 1 and 8 positions and one aliphatic hydroxyl group at the 15 position. In this study, the alkylations of the phenolic hydroxyl groups and the substitution reactions with various amino groups and thiocyano and selenocyano groups at the 15 position of 3 were performed to compare their cytotoxic activities. First, several alkyl derivatives were prepared from 3. The methylation of 3 with dimethylsulfate in the presence of K 2 CO 3 was done according to the method reported by Ross and Mitali. 13) to give 1,8-di-O-methylaloe-emodin 4 in a 61.6% yield. Other alkylations were performed according to the method of MacTough et al. 14) Compound 3 was reacted with propyl iodide, hexyl bromide, dodecyl iodide, and octadecyl iodide in the presence of K 2 CO 3 to give 1, Sciences, Josai International University; 1 Gumyo, Togane, Chiba 283-8555, Japan: and c Faculty of Pharmaceutical Sciences, Himeji Dokkyo University; 7-2-1 Kami Ohno, Himeji, Hyogo 670-8524, Japan. Received November 9, 2007; accepted February 6, 2008 1,8-Di-O-alkylaloe-emodin derivatives (namely, methyl-, propyl-, ...

Preparations of Anthraquinone and Naphthoquinone Derivatives and Their Cytotoxic Effects

“…The organic extracts were successively washed with brine and water, dried over absolute MgSO 4 , and then filtered.…”

“…The organic extracts were successively washed with brine and water, dried over absolute MgSO 4 , and then filtered. The filtrate was evaporated to give a residue, which was subjected to silica gel column chromatography (a gradient of 0-10% MeOH in CHCl 3 ) to afford compound 14 (20.2 mg, 18.1% yield) as yellowish needles (mp more than 300°C The same reaction and procedure using 13 (41.0 mg, 0.12 mmol), 7 (32.0 mg, 0.25 mmol) and NaH (14.0 mg, 0.58 mmol) as described for the preparation of 14 gave compound 15 (26.6 mg, 57.0% yield) as yellowish needles (mp more than 300°C 1 mmol) in MeOH (250 ml).…”

“…1,8-Dihydroxyl anthraquinone derivatives having nucleic acid bases were synthesized as follows. 15-Bromochrysophanol 13 4) was reacted with adenine 6, thymine 7, uracil 8 or 5-FU 2 in the presence of NaH in DMF to give compounds 14, 15, 16 and 17 in 18.1%, 57.0%, 68.2% and 45.9% yield, respectively (Fig. 4).…”

“…Compound 20 was oxidized with KMnO 4 in aqueous pyridine to give compound 21 in 32.3% yield, and then reduced with LiAlH 4 to obtain alcohol 22 (57.1% yield). The alcohol was then reacted with CBr 4 and PPh 3 in ether to give compound 19 (50.3% yield) (Fig. 6).…”

“…Compound 24 was successively treated with KOH, 16) reduced with LiAlH 4 and brominated with CBr 4 and PPh 3 to give 25, 26 and 23, in 43.5%, 64.7% and 65.8% yield, respectively. Bromide 19 was reacted with adenine, thymine, uracil and 5-fluorouracil in the presence of NaH in DMF to give compounds 27, 28, 29 and 30 in 28.3%, 53.7%, 41.9% and 54.7% yield, respectively (Fig.…”