Synthesis and Biological Evaluation of Pyrazoles, 5,8-Isoquinolinediones, 5,8-Quinolinedions, and Furo[3,2-h]isoquinoline

Abstract

Part 1. TGF-β inhibitor have been well known for its various pharmacological activities in a number of disease states involving inflammation, angiogenesis, and immune function, including fibrosis, wound healing, Alzheimer’s disease, atherosclerosis, hypertension, restenosis, and cancer. Among many compounds, 4-ary and 4-heteroary-substituted pyrazole inhibitors recently have been reported as an important class of biologically active compounds. Therefore, in our study, we synthesized aryl- and heteroaryl- substituted pyrazole derivatives 4a-g (KEHs), 6a-f (HBs), 9 (4MHM), and 10a-f (4MHs) and evaluated for their ALK5 inhibitory activity in cell-based luciferase assays. The compounds 6d (p3TP-neo, 27 % at 30 nM) and 6f (7.2 % at 1 μM) showed potent inhibition in luciferase reporter assays using HaCat cells transiently transfected with p3TP-neo reporter construct. Part 2. The quinones have been known to be a key factor among the different classes of antitumor, antifungal, and antimalarial agents. Also, a benzofuran derivative as a novel myristoyltransferase inhibitor has been reported as antifungal agent. In our study, therefore, we synthesized isoquinoline-5,8-quinone 12 (K) derivatives, 14a-h (RSYs), 16a-f (TANGs), and 18 (KRPEA), 6,7-dichloro-2-methylquinoline-5,8-dione 20 (7b) derivative compound, 21 (7bPAA), and furo[3,2-h]isoquinoline derivatives, 17a-f (KRs), to elucidate their contribution to the antifungal activity. The in vitro antifungal activity of compounds 14a-h (RSYs) and 16a-f (TANGs) against pathogenic fungi was determined by the twofold broth dilution method. The results suggest that isoquinoline-5,8-quinone derivatives would be promising antifungal agents.;1부 TGF-β의 신호전달은 fibrosis, 심혈관 질환, 알츠하이머병, atherosclerosis, restenosis, 암, 그리고 비대성 상처와 켈로이드 등과 같은 다양한 질병에 핵심적인 병인이 된다고 밝혀졌다. 다양한 화학 구조들 가운데 특히 4-ary 와 4-heteroary-이 치환된 pyrazole 구조 화합물이 효과적인 억제 효과를 가진다고 밝혀졌다. 그리하여, 본 연구에서는 앞서 개발된 ary 와 heteroary-이 치환된 pyrazole 구조화합물과 유사한 유도체들을 [4a-g (KEHs), 6a-f (HBs), 9 (4MHM), 10a-f (4MHs)] 합성하였고, HaCat p3TP-neo assay를 통하여 ALK5 억제효과를 확인하였다. 합성한 화합물 가운데 물질 6d가 27% (30 nM), 그리고 6f가 7.2 % (1 μM) p3TP-neo activity로 앞서 다른 연구에서 발표한 억제제 못지 않음을 확인 할 수 있었다. 2부 Quinone은 항진균, 항암, 항균, 항말라리아 등 다양한 생리활성을 나타낸다. 또한 benzofuran 유도체들은 N-myristoyltransferase효소 억제제로 우수한 항진균작용을 나타낸다고 밝혀졌다. 따라서, 본 연구에서는 isoquinoline-5,8-quinone유도체 14a-h (RSYs), 16a-f (TANGs), 18 (KRPEA)과 6,7-dichloro-2-methylquinoline-5,8-dione유도체 21 (7bPAA) 그리고 furo[3,2-h]isoquinoline derivatives유도체인 17a-f (KRs)을 합성하고, 항진균 작용을 검색하였다. 14a-h (RSYs)와 16a-f (TANGs)는 대부분의 균주에서 대체적으로 fluconazole, 5-fluorocytosine과 비슷하게 좋은 효과를 나타냈다.