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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-, ...

Previously, we reported 1) a comparison of the cytotoxic effects of naturally occurring hydroxyanthraquinone derivatives, isolated from the root of Rhubarb (Rheum palmatum (Polygonaceae)) and hydroxynaphthoquinone derivatives, isolated from the roots of Lithosperumum erythrorhizon SIEB. et ZUCC. and Macrotomia euchroma (ROYLE) PAULS. (Boraginaceae), using human colorectal (HCT 116) 2) and human hepatoma (Hep G2) 3) cell lines. In addition, we prepared 1,8-di-O-alkylaloe-emodins and 15-amino-, 15-thiocyano-and 15-selenochrysophanol derivatives from aloe-emodin, which is one of hydroxyanthraquinone compounds isolated from the root of Rhubarb. A comparison of cytotoxic acivities of the derivatives using the same cancer cell lines were also reported. 4)The present study deals with preparations of chrysophanol and 18-di-O-hexylchrysophanol derivatives having various nucleic acid bases at position of 15 from aloe-emodin and 18-di-O-hexylaloe-emodin, respectively. We also synthesize napthoquinone derivatives having various nucleic acid bases, amines, and thiocyanato (-SCN), selenocyanato (-SeCN) and thioacetyl (-SAc) groups on the side chains of the naphthoquinone skeletons derived from menadione (Vitamin K 3 , 2-methylnaphthoquinone). Furthermore, we evaluate the cytotoxic effects of the synthetic derivatives using HCT 116 and Hep G2 cancer cell lines, and compare the effects with those of 5-fluorouracil (5-FU). Chemical Results and DicscussionSeveral cytotoxic compounds having purine or pyrimidine bases in the molecule, such as azathiopurine 1, 5,6) 5-fluorouracil 2 (5-FU) 7-10) and tegafur 3, 11,12) have been synthesized and used in clinical chemotherapy. In this study, syntheses of anthraquinone derivatives having nucleic acid bases (adenine, thymine, uracil or 5-FU) on the side chain of the anthraquinone skeleton were performed (Fig. 1).Firstly, anthraquinone derivatives having the nucleic acid bases at position 15 were synthesized. 1,8-Di-O-hexylaloeemodin 4, which displayed the highest cytotoxic activity of the synthesized 1,8-O-alkylaloe-emodins, 4) was selected as the starting material. The synthesis of tosylate 5 from 4 was previously reported. 13) Compound 5 was reacted with adenine 6, thymine 7, uracil 8 or 5-FU 2 in the presence of NaH in N,N-dimethylformamide (DMF) to give 9, 10, 11 and 12 in 19.5%, 27.9%, 39.7% and 55.9% yield, respectively (Fig. 2). The substituted positions of the nucleic acid bases of compounds 9-12 were confirmed from the heteronuclear multiple bond connectivity (HMBC) spectra shown in Fig. 3. In the spectrum of compound 9, correlations between the proton signals due to the methylene group (CH 2 ) on the anthraquinone residue at d 5.43 and the carbon signal at d 117.2 due to C-4 on the quinone residue and those at d 153. -2-21 Miyama, Funabashi, Chiba 274-8510, Japan. Received July 20, 2010; accepted December 14, 2010 Chrysophanol and 1,8-di-O-hexylchrysophanol derivatives having nucleic acid bases at position 5 were synthesized. Furthermore, derivatives of menadione substitu...

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