苯駢[1.3.2]-1,1-雙氧雙噻唑偶極體及喹啉-4-酮衍生物之分子及細胞機制研究

Abstract

一般認為慢性發炎為癌症的傾向因子，但連結的精確機制則有待釐清。 CX9051為本實驗室確認之環氧酶-2（COX-2）及5-脂氧合酶（5-LOX）雙重抑制劑的苯駢[1.3.2]-1,1-雙氧雙噻唑偶極體衍生物，且顯示有抗發炎及抑制癌細胞增生的活性。本論文的結果證實，CX9051可以抑制脂多醣（LPS）引起的前列腺素E2 （PGE2）及腫瘤壞死因子α （TNF-α）生成，且可降低COX-2、iNOS、Akt及NF-κB蛋白質表現量及NF-κB核內外轉移。另外，CX9051可抑制前列腺癌細胞株的增生及誘發細胞凋亡，此效果被證實為是經由調控NF-κB腫瘤壞死因子及增加腫瘤相關細胞凋亡誘導配體（TRAIL）的過度表現，並活化可與粒線體引起的內在凋亡途徑有交互作用的外在凋亡訊息，進而造成癌細胞產生細胞凋亡反應。本研究中所證實CX9051具有抑制增生及抗發炎活性之結果，證明CX9051可作為抗發炎及化學預防抗癌的前導化合物。另外，此論文研究利用結構修飾原理設計一類新穎的第一型拓樸異構酶（Top I）抑制劑，其中最有效的Top I抑制劑，化合物26，為喹啉-4-酮衍生物，藉由降低Top I蛋白質表現及引起DNA單股斷裂，造成Top I毒性引起的細胞毒殺效果，進而對大腸腫瘤誘發老鼠模式也具有治療性的抗腫瘤活性效果。根據化合物26所表現的抑制Top I活性及在HT-29細胞株中誘發細胞凋亡及抑制腫瘤誘發活性等結果，提供另一前導化合物可用於發展新穎的Top I抑制劑來治療癌症。總之，本論文研究結果顯示苯駢[1.3.2]-1,1-雙氧雙噻唑偶極體及喹啉-4-酮衍生物可分別作為發展抗發炎及抗癌藥物發展的先導化合物。

While chronic inflammation is widely believed to be a predisposing factor for cancer, the exact mechanisms linking these conditions have remained elusive. CX9051, a benzo[1.3.2]dithiazolium ylide 1,1-dioxide derivative identified as a COX-2 and 5-LOX dual inhibitor in our laboratory, exhibited anti-inflammatory activity and anti-proliferation effects. Our results demonstrated that CX9051 suppressed the LPS-induced PGE2 production and TNF-α generation and attenuated the protein expression of COX-2, iNOS, Akt, and NF-κB as well as NF-κB translocation. Furthermore, CX9051 could inhibit the proliferation and induced apoptosis of prostate cancer cell lines. The effect has been shown to be mediated via the regulation of NF-κB, the induction of TRAIL and the activation of extrinsic apoptotic signaling, which cross-react the activation of mitochondria mediated intrinsic pathways, leading to the apoptosis of cancer cells. The anti-proliferation and anti-inflammatory activities of CX9051 revealed in this thesis provided a propelling evidence for CX9051 serving as a promising lead compound to provide anti- inflammatory and chemopreventive benefits. In addition, a scaffold modification approach has been employed to design a novel class of Top I inhibitor in this thesis. The most effective Top I inhibitor 26, a 3-substituted quinolin-4(1H)-one derivative, elicited its cytotoxic effects of Top I poison through Top I down-regulation, which paralleled the induction of DNA single-strand breaks and followed with curative anti-tumor activity against the colon carcinoma xenograft tumor model. According to the impressive Top I inhibitory activity, pro-apoptotic activity in HT-29 cells and in vivo xenograft inhibition activity exhibited by 26, this investigation has provided an alternative lead compound for the development of novel Top I inhibitor for the treatment of cancer. In conclusion, the results in this thesis suggested that benzo[1.3.2]dithiazolium ylide 1,1-dioxide and 3-substituted quinolin-4(1H)-one derivatives were promising leads for the development of anti-inflammatory drugs and anticancer agents, respectively.