To find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) was designed and synthesized. In this series, compound 7, in which the hydroxamic acid of SAHA is replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. In cancer cell growth inhibition assay, S-isobutyryl derivative 51 showed strong activity, and its potency was comparable to that of SAHA. The cancer cell growth inhibitory activity was verified to be the result of histone hyperacetylation and subsequent induction of p21(WAF1/CIP1) by Western blot analysis. Kinetical enzyme assay and molecular modeling suggest the thiol formed by enzymatic hydrolysis within the cell interacts with the zinc ion in the active site of HDACs.

The genus Millettia WEIGHT et ARN. (Leguminosae) consists of ca. 100 old world species of climbers and trees, and their seeds and other parts are in some cases known to show insecticidal and piscicidal properties.1) In previous studies 2) flavonoids, isoflavonoids and alkaloids were isolated as chemical components. M. leucantha KURZ is a lofty tree, with pinnate leaves and white flowers, growing throughout Thailand 3); however, its medicinal use is unknown. The present investigation deals with the isolation of chalcone derivatives (1, 2, 4, 6, 7, 10) including four new ones (1, 4, 7, 10) and flavones (3, 5, 8, 9, 11) from the stem bark, and their cytotoxic, antiviral and anti-inflammatory activities. Isolation of Chemical ConstituentsRepeated column chromatography (CC) of the ethanolic extract of the stem bark of M. leucantha afforded eleven products (1-11) in the order of polarity.Among them, seven compounds were identified to be known chalcones, 2Ј-hydroxy-3,4,4Ј,6Ј-tetramethoxychalcone 4,5) (2) and dihydromilletenone methyl ether 6) (6), known furanoflavones, karanjin 7,8) (3) and lanceolatin B 4-6,9) (5), and known simple flavones, desmethoxykanugin 10) (8), 3Ј,4Ј-methylenedioxy-7-methoxyflavone 6) (9), and 3Ј,4Ј-methylenedioxy-5,7-dimethoxyflavone 11) (11), by comparison with reported data. Other chalcone derivatives (1, 4, 7, 10) were found to be new ones. (Chart 1).A new chalcone 1 with molecular formula C 18 H 16 O 5 , was obtained as yellow needles. The 1 H-NMR spectrum (Table 1) showed a set of trans-olefinic protons at d 7.35 and 7.60, a methylenedioxy group at d 6.01 and two methoxy substituents at d 3.87 and 3.91, in addition to two ABX aromatic systems. In electron impact mass spectrum (EI-MS) a relatively abundant fragment peak observed at m/z 165 [2,4-(MeO) 2 C 6 H 3 -CO ϩ , 43%] indicated that two methoxy groups were located on the A ring connected to the ketonic function in a chalcone system. 12) Thus, 1 was determined to be 2Ј,4Ј-dimethoxy-3,4-methylenedioxychalcone, which has been Compound 7, b-methoxychalcone, obtained as pale yellow needles, had molecular formula C 20 H 20 O 7 . The 1 H-NMR spectrum (Table 1) showed an olefinic proton as a singlet at d 6.33 assigned to H-a. Substitution of the ketonic A ring by a methylenedioxy group was deduced by the appearance of peaks at m/z 149 (3,4-OCH 2 O-C 6 H 3 -CO ϩ , 27%) and 121 (3,4-OCH 2 O-C 6 H 3 ϩ , 20%) in EI-MS. Furthermore, a base peak (m/z 341) was reasonably assigned to be a benzopyrilium cation 13,14) produced by the loss of a methoxy group Engineering and Biotechnology; 73/1 Rama VI Road, Rajathevee, Bangkok 10400, Thailand: c Drug Research Department, R&D Division, Nippon Kayaku Co., Ltd.; 3-31-12 Shimo, Kita-ku, Tokyo 115-8588, Japan: and d Graduate School of Pharmaceutical Sciences, Chiba University; 1-33 Yayoi, Inage-ku, Chiba 263-8522, Japan. Received August 16, 2002; accepted November 19, 2002 Four new chalcone derivatives (1, 4, 7, 10) were isolated from the stem bark of Millettia leucantha KURZ (Leguminosae) along wit...

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Antiestrogen agents are commonly used to treat patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen has been the mainstay of endocrine treatment for patients with early and advanced breast cancer for many years. Following tamoxifen treatment failure, however, there are still limited options for subsequent hormonal therapy. We discovered a novel compound, NK150460, that inhibits 17β-estradiol (E2)-dependent transcription without affecting binding of E2 to ER. Against our expectations, NK150460 inhibited growth of not only most ER-positive, but also some ER-negative breast cancer cell lines, while never inhibiting growth of non-breast cancer cell lines. Cell-based screening using a random shRNA library, identified aryl hydrocarbon receptor nuclear translocator (ARNT) as a key gene involved in NK150460's antitumor mechanism. siRNAs against not only ARNT but also its counterpart aryl hydrocarbon receptor (AhR) and their target protein, CYP1A1, dramatically abrogated NK150460's growth-inhibitory activity. This suggests that the molecular cascade of AhR/ARNT plays an essential role in NK150460's antitumor mechanism. Expression of ERα was decreased by NK150460 treatment, and this was inhibited by an AhR antagonist. Unlike two other AhR agonists now undergoing clinical developmental stage, NK150460 did not induce histone H2AX phosphorylation or p53 expression, suggesting that it did not induce a DNA damage response in treated cells. Cell lines expressing epithelial markers were more sensitive to NK150460 than mesenchymal marker-expressing cells. These data indicate that NK150460 is a novel AhR agonist with selective antitumor activity against breast cancer cell lines, and its features differ from those of the other two AhR agonists.

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A concise total synthesis of 12-methoxydihydrochelerythrine (6), isolated from Bocconia integrifolia, is described. The synthesis features an efficient route to a 12-alkoxybenzo[c]phenanthridine skeleton via naphthoquinone monooxime 11 as a key compound. Starting from 7-methoxy-2-methylbenzo[b]furan (9), 3-aryl-1-tetralone 10 was synthesised, followed by aromatisation to 3-aryl-1-naphthol 17. After oxidative cleavage of the furan ring, basic nitrosation of naphthol 22 gave the naphthoquinone 11. The benzo[c]phenanthridine skeleton was formed by reductive cyclisation of 11. Deoxygenation of the lactam moiety in 23 afforded nor-base 32 and methylation of 32 under reductive conditions gave the target dihydro base 6 (23 steps from benzofuran 9 in 10% overall yield). The corresponding quaternary base 7 showed moderate anti-tumour activity against cancer cell lines; on NCI-H460: IC50 4.5 microM and on MDA-MB-231: IC50 1.2 microM. Introduction of a methoxy group into the 12-position of the benzo[c]phenanthridine skeleton could cause enhanced activity against MDA-MB-231 by comparison of 7 with chelerythrine (35) (IC50 5.3 microM).