Preparations of Anthraquinone and Naphthoquinone Derivatives and Their Cytotoxic Effects

Abstract

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...

A Potent PDK4 Inhibitor for Treatment of Heart Failure with Reduced Ejection Fraction

“…According to known methods, including the Friedel–Crafts reaction, the acetylated product 9 was synthesized from Vitamin K 3 in three steps [ 21 ]. Then, air oxidation of the methyl-ketone moiety in 9 under basic conditions produced carboxylic acid 10 in 72% yield [ 21 , 22 ] ( Scheme 2 ). Methyl esterification of 10 with HCl in MeOH, followed by oxidation with CAN, efficiently yielded the C6-methyl ester 11 .…”

Total Synthesis of Enantiopure Chabrolonaphthoquinone B Via a Stereoselective Julia-Kocienski Olefination

“…Using heteronuclear multiple bond correlation (HMBC) NMR experiments, we concluded that the acylation product corresponds to the undesired 6-regiosomer 3, in contrast to what was expected based on a similar previously reported acylation on the same substrate. 7 According to the alternative approach, β-myrcene served as the diene in a Diels−Alder reaction with bromoquinone 4 (Scheme 2B) furnishing the naphthoquinone skeleton via a three-step procedure. However, the following epoxidation of periodinane gave aldehyde 8, which was uneventfully transformed to the conjugated ketone 9 upon treatment with the required phosphonate carbanion (HWE olefination).…”

“…Menadione was converted to the corresponding dimethyl protected derivative 2 , which was subjected to a Friedel–Crafts acylation with 3-bromopropionyl chloride (Scheme A). Using heteronuclear multiple bond correlation (HMBC) NMR experiments, we concluded that the acylation product corresponds to the undesired 6-regiosomer 3 , in contrast to what was expected based on a similar previously reported acylation on the same substrate …”

“…1 H NMR (500 MHz, CDCl 3 , major isomer 6) δ: 7.97 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 6.8 (s, 1H), 2.96 (dt, J = 14.5, 7.3 Hz, 1H), 2.86 (dt, J = 14.2, 7.2 Hz, 1H), 2.74 (t, J = 6.3 Hz, 1H), 2.17 (s, 3H), 1.89 (q, J = 6.9 Hz, 2H), 1.27 (s, 3H), 1.15 (s, 3H). 13 ((2R,3R)-3-Methyl-3-(4-methylpent-3-en-1-yl)oxiran-2-yl)methanol (7). The epoxide 7 was prepared from geraniol following a known procedure.…”

Biscoumarin–pyrimidine conjugates as potent anticancer agents and binding mechanism of hit candidate with human serum albumin

“…According to the literature, it was evident that only the amine group of the thymine would undergo a substitution reaction, whereas the imide part would stay unreacted. [ 22 ] However, surprisingly, in this study, the amine and imide parts of the thymine ring were both involved in the reaction to obtain biscoumarin–pyrimidine conjugates 1a–l as the final products (Scheme 1). Hence, this study reports for the first time, as per the best of the authors' knowledge, the synthesis of such biscoumarin–pyrimidine scaffolds.…”