Synthesis and Cytotoxic Evaluation of Certain Pyrido[3,2-g]quinoline Derivatives
| Autor: | Shu-Yu Li, 黎淑雲 |
|---|---|
| Rok vydání: | 2007 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 95 The present report describes the synthesis and evaluation of tricyclic pyrido[3,2-g]quinoline derivatives in which an additional pyridine ring is linearly fused on the antibacterial quinoline-3-carboxylic acid. Among them, only both diethyl 4, 6- diamino -10- methylpyrido- [3,2-g]quinoline-3,7-dicarboxylate (9a) and diethyl 4,6-bis-(3-dimethyl- aminopropylamino) -10- methylpyrido[3,2-g]quinoline-3,7-dicarboxylate (9d) were able to inhibit cell proliferation of MCF-7 (Breast), NCI-H460 (Lung), and SF-268 (CNS) implying either amino or dimethylaminopropyl moiety at C-4 and C-6 positions is crucial for the antiproliferative activity of pyrido[3,2-g]quinoline derivatives. Compounds 9a – 9d were further evaluated for their activity against the growth of MCF-7 and two prostate cancer cell lines, LNCaP and PC-3. Results indicated the antiproliferative activity decreased in an order 9d > 9a >> 9b and 9c. Compound 9d was the most cytotoxic with an IC50 value of 5.63 and 3.96 ?戥M, respectively, against LNCaP and MCF-7. Flow cytometric analyses revealed that growth inhibition of LNCaP by 9d was due to cell cycle arrest in G1 phase, and followed by apoptosis. We further confirmed this 9d-induced apoptosis by Annexin V-FITC and cleavage pattern of PARP in LNCaP cells. To delineate the molecular mechanism of 9d-induced apoptosis, we examined the protein level of several cell cycle regulators including p53 and its downstream target(p21), cyclin D1, cyclin E, Rb, pRb and c-Myc. The results demonstrated that p53 was slightly increased but its target, p21, was not changed by treatment of 9d, suggesting p21 might not be a factor responsible for G1 arrest. Moreover, both cyclin D1 and cyclin E were decreased only in the presence of 80 ?戥M of 9d. In constrast, c-Myc, Rb and pRb were significantly reduced by 9d. Thus, we further examined the upstream regulators, Erk1/2 and p-Erk1/2 related to c-Myc. We found that 9d did not have the influence on Erk1/2, but it made p-Erk1/2 increase under the 5 ?戥M at 24 h. It indicated that the function of 9d to LNCaP cell cycle was probable by the effect of p-Erk1/2 on the decrease of c-Myc and then G1 arrest showed. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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