Arch. Pharm. Chem. Life Sci. 2009, 342, 165 – 172 J. Chen et al. 165 Full Paper Synthesis and In-vitro Antitumor Activities of Some Mannich Bases of 9-Alkyl-1,2,3,4-tetrahydrocarbazole-1-ones Jing Chen 1 , Jianshu Lou 2 , Tao Liu 1 , Ru Wu 2 , Xiaowu Dong 1 , Qiaojun He 2 , Bo Yang 2 , and Yongzhou Hu 1 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China. 2 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China. A novel series of 2-substituted aminomethyl-9-alkyl-1,2,3,4-tetrahydrocarbazole-1-ones 5a – q was synthesized via aminomethylation of 9-alkyl-1,2,3,4-tetrahydrocarbazole-1-ones 4a – e with hydrochlorides of the respective amines 6a – m. The structures of these newly synthesized com- pounds were characterized by 1 H-NMR, MS, and elemental analysis. All the compounds were tested for their cytotoxic activity in vitro against four human tumor cell lines including human non-small lung cancer cells (A549), human gastric adenocarcinoma (SGC), human colon cancer cell (HCT116), human myeoloid leukemia cells (K562), and one multi-drug resistant subline (KB- VCR). Most compounds showed moderate to potent cytotoxic activity against the tested cell lines. Preliminary mechanism research indicated that the most promising compound, 2-diethyl- aminomethyl-9-methyl-1,2,3,4-tetrahydrocarbazole-1-one 5c, exhibited a potential inhibitory effect against microtubule. Keywords: 9-Alkyl-1,2,3,4-tetrahydrocarbazole-1-ones / Antitumor activity / Mannich bases / Microtubules / Received: September 23, 2008; accepted: October 22, 2008 DOI 10.1002/ardp.200800179 Introduction Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an impor- tant target for anticancer therapy [1]. A number of natu- rally occurring compounds exhibited their anticancer properties by interfering with microtubules, resulting in mitotic arrest, such as paclitaxel [2], which promotes the microtubulin polymerization, while colchicine [3], com- bretastatin A 4 (CA 4) [4], and vinca alkaloids [1] inhibit the microtubulin polymerization. Because the antitubu- lin-chemotherapy drugs had problems with toxicity and drug resistance, scientists had been actively exploring new antitubulin agents. A variety of synthetic small mol- ecules such as BPR0L075, NSC 676693 were reported as inhibitors of tubulin polymerization [4 – 9]. Structurally, they involved various heteroaromatic cores including indole, benzothiophene [10], benzofuran [11], imidazole [12], thiazole [13], and oxadiazoline [14] moieties. A num- ber of indole-based compounds, for example 2-aroylin- doles [15], 3-aroylindoles [16], 3-aroyl-2-phenylindoles [11], 3-arylthioindoles [17], and indolyl-3-glyoxamides [18], had shown strong antiproliferative and antitubulin activity, and some of them are being developed. 1,2,3,4-Tetrahydrocarbazole-1-ones, also including a indole structure, were known for a long times and many synthesis methods were published [19, 20]. They were reported to possess many biological activities, such as antitumor activity [21], HIV integrase inhibition [22], pro- longed analgesic activity [23], heat shock protein 90 (Hsp90) inhibition [24], mitogen-activated protein kinase- activated protein kinase-2 (MAPKAP-k2) inhibition [25], antibacterial and antifungal activities [26]. Moreover, they had been increasingly important intermediates in the syntheses of various biological active heterocyclic Correspondence: Yongzhou Hu, ZJU-ENS Joint laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China. E-mail: huyz@zju.edu.cn Fax: + 86 571 8820-8460 i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim