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J. Med. Chem. 1998, 41, 4658-4661
Synthesis and Cytotoxicity of 2-Acetyl-4,8-dihydrobenzodithiophene-4,8-dione Derivatives Yu-Hua Chao,†,§ Sheng-Chu Kuo,*,§ Chun-Hsiung Wu,§ Chun-Yann Lee,§ Anthony Mauger,‡ I-Chen Sun,† Susan L. Morris-Natschke,† and Kuo-Hsiung Lee*,† Natural Products Laboratory, Division of Medicinal Chemistry and Natural Products, School of Pharmacy CB#7360, University of North Carolina, Chapel Hill, North Carolina 27599-7360, Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung 400, Taiwan, and Drug Synthesis and Chemistry Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 Received July 6, 1998
2-Acetyl-4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (9) and 2-acetyl-4,8-dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-dione (19), together with 10 related mono- and disubstituted derivatives, were synthesized and evaluated in vitro by NCI against eight cancer types. All compounds showed significant activity against melanoma, HL-60 leukemia, NCI-H23 nonsmall-cell lung cancer, OVCAR-3 ovarian cancer, and MDA-MB-435 and MDA-N breast cancer cell lines. Compound 11, 2-(1′-acetoxyethyl)-4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione, showed the highest overall potency (mean GI50 ) 40 nM). Many naturally occurring substituted anthraquinones1,2 and naphthoquinones3 possess cytotoxic antileukemic activities. In addition, the natural furanonaphthoquinones 14 and 24 and their synthetic analogue 33 show potent cytotoxicity against KB cells with ED50 values of 4.1, 8.2, and 1.4 µM, respectively. As part of our continuing search for potent and selective cytotoxic antitumor agents, the unsubstituted thiophene derivative naphtho[2,3-b]thiophene-4,9-dione (4),5 which is a bioisostere of the furanonaphthoquinone nucleus, also was found to be cytotoxic against KB cells with an ED50 value of 6.5 µM.6 Introduction of a lipophilic acetyl group gave 2-acetylnaphtho[2,3-b]thiophene-4,9-dione (5) with enhanced cytotoxicity (ED50 ) 1.6 µM).6 We have now extended this study to the synthesis and cytotoxic evaluation of two related series containing two thiophenerings: 4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene4,8-diones (6, 9-11, 13-15) and 4,8-dihydrobenzo[1,2b:5,4-b′]dithiophene-4,8-diones (16, 19-21, 23-25).
Scheme 1. Synthesis of Derivatives 9-11 and 13-15
Scheme 2. Synthesis of Derivatives 19-21 and 23-25
Chemistry
† § ‡
University of North Carolina. China Medical College. National Institutes of Health.
The syntheses of mono- and disubstituted compounds are outlined in Schemes 1 and 2. Syntheses of the starting materials, 4-acetoxybenzo[1,2-b:4,5-b′]dithiophene (7)7a and -[1,2-b:5,4-b′]dithiophene (17),7a have been previously described. In brief, the former was prepared in four steps from 2,3-dibromothiophene and
10.1021/jm980394t CCC: $15.00 © 1998 American Chemical Society Published on Web 10/02/1998
2-Acetyl-4,8-dihydrobenzodithiophene-4,8-diones
Journal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4659
Table 1. Cytotoxicity of 6 and 16 against Leukemia Cell Lines IC50 (µM) cell line
6
16
KB HCT-8 P-388 L-1210 A549 CAKI-1 SK-MEL-2 MCF-7
0.31 0.32
