Design and Synthesis of Quinoline Derivatives as Potential Cytotoxic Agents
| Autor: | Yin-Ling Wei, 魏吟玲 |
|---|---|
| Rok vydání: | 2005 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 93 The aim of this thesis is to design and synthesize quinoline derivatives as potential cytotoxic agents. Two series of target compounds, 3-phenylquinolines (7-10) and 2-phenylquinolines (11-14, 17 and 18), were prepared and evaluated for their cytotoxicity. In the preparation of 3-phenylquinolines 7-10, the required intermediates 8-nitro-3-phenylquinoline (1a) and 3-(4-methoxyphenyl)-8-nitroquinoline (1b) were obtained from 8-nitroquinoline by bromination with N-bromosuccinimide (NBS) followed by Suzuki coupling reaction. Reduction of the nitro compounds 1a,b with iron powder and subsequent reaction with appropriate benzenesulfonyl chloride, benzoyl chloride or phenyl isocyanate provided target compounds 7-10. To prepare target 8-substituted 2-phenylquinolines 11-14, o-nitroaniline was reacted with appropriate cinnamaldehyde under acidic conditions via Doebner-Miller cyclization to give the intermediates 8-nitro-2-phenylquinoline (2a) and 2-(4-methoxyphenyl)-8-nitroquinoline (2b). The intermediates 6-nitro-2-phenylquinoline (3a) and 2-(4-methoxyphenyl)-6-nitroquinoline (3b) for the synthesis of target 6-substituted 2-phenylquinolines 17 and 18 were prepared from appropriate acetophenone by treatment with Vilsmeier-Haack reagent (POCl3/DMF), followed by reaction with 2 equivalents of p-nitroaniline and subsequent cyclization at 220-250 ℃. The intermediates 2a,b and 3a,b were subjected to the same sequence of reactions as performed on 1a,b to provide target compounds 11-14, 17 and 18. All target compounds were evaluated for in vitro antiproliferative activity against five human tumor cell lines (AGS, A549, HepG2, HT-29 and PC-3) by MTT assay. Among the tested compounds, 7a-c, 8a,b, 10a,b, 11b,c, 12b, 13a,b and 14a,b demonstrated significant cytotoxicity against certain cell lines with GI50 (IC50 for PC-3) values in the low micromolar to submicromolar concentration range. The present investigation has led to the discovery of some promising cytotoxic compounds with good potency as follows: 7a, 7c, 8a and 8b (for HepG2 cell line, GI50 = 0.12, 0.18, 0.11 and 0.20 μM, respectively); 7a and 8a (for AGS cell line, GI50 = 0.73 and 1.03 μM, respectively); 11b (for HT-29 cell line, GI50 = 0.55 μM). Furthermore, as revealed from the results obtained in flow cytometry analyses, compounds 7a and 8a caused S and G2/M arrests in AGS and HepG2 cells; compounds 7c and 8b caused S and G2/M arrests and induced apoptosis in HepG2 cells; and compound 11b caused G2/M arrest and induced apoptosis in HT-29 cells. These results suggest that the designed 8-benzenesulfonamido substituted 3-phenylquinolines and 2-phenylquinolines may serve as useful lead compounds for the development of new antitumor agents. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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