1-取代基異喹啉之衍生物的合成及其生物活性之探討

異喹啉 (isoquinolines) 存在於自然物中，由於有廣泛的生物效應而引起極大的研究興趣，1-(2-硝基苯基)-3,4-二氫異喹啉[1-(2-nitrophenyl)isoquinolines]於中等條件下以氯化亞錫還原得5,6-二氫吲唑[3, 2-a]異喹啉 (5,6-dihydroindazolo[3,2-a]isoquinolines 4a-i)。其反應機構被提出，抗腫瘤活性也作評估。除此之外，苯氧烷胺基 (Phenoxyalkylamino) 部分，是α-阻斷 (α-blocker) 的主要結構，而許多苯甲基異喹啉 (benzylisoquimoline) 基石的生物鹼在阻斷Ca+2進出上有極佳的功能。因此，所合成1,2,3,4-四氫異喹啉 (1,2,3,4-THIQs 5a-c, 5f, 5p) 另外再與1-溴-2-苯氧乙烷 (1-bromo-2-phenoxyethane) 作用合成十三種新的化合物N-苯氧乙基-1-取代基異喹啉 (N-phenoxyethyl-1-(substituted)isoquinolines 6a-c, 6f, 6p, 7a-c, 7f) 探討其α-阻斷的活性。另外一方面，由1-(2-胺基苯基)-1,2,3,4-四氫異喹啉 (5a-5o) 與K2PtCl4反應合成十五種順二氯鉑鉑錯合物 (8a-8o)。這些化合物以人類的四個腫瘤細胞株來測試其活性並探討在抗腫瘤活性上的結構活性相關聯。所有化合物對乳癌 (MCF-7) 細胞株皆有不錯的活性。大部分的化合物對結腸癌 (WiDr) 細胞株也有不錯的活性，8c及8f除外。化合物8j 及 8o 對肝癌 (Hepa59T/VGH) 細胞株，顯示較佳的活性。C-6位置具推電子基 (MeO) 似乎會使抗腫瘤活性減弱，於苯胺環上之C-4位置具氯取代基使抗腫瘤活性增加。反式效應在控制此類錯合物的安定性上，佔最重要的因素。

關鍵字

異喹啉生物活性；鉑錯合物；反式效應

並列摘要

Isoquinoline alkaloids are interested due to their widespread occurrence in nature and broad biological effects. A series of 1-(2-nitro phenyl)-3,4-dihydroisoquinolines were reduced under very mild reaction conditions in the presence of Tin(Ⅱ) chloride dihydrate (SnCl2.2H2O) to give 5,6-dihydroindazolo[3,2-a]isoquinolines 4a-i. A mechanism for this reaction is proposed and their antitumor activity was evaluated. Besides, phenoxyalkylamino moiety is known to be the mother structure of α-blockers and many benzylisoquimoline- based alkaloids exhibitd excellent antagonistic activity on Ca+2-channel. In this dissertation, thirteen new N-phenoxyethyl -1-(substituted)isoquinolines (6a-c, 6f, 6p, 7a-c, 7f) were synthesized by treatment of 1,2,3,4-THIQs (5a-c, 5f, 5p) with 1-bromo-2-phenoxyethane. Their α-blocking activity will be tested. On the other hand, fifteen cis-dichloroplatinum complexes (8a-8o) were synthesized by treatment of 1-(2-aminophenyl)-1,2,3,4-THIQs (5a-5o) with K2PtCl4. The antitumor activity of these compounds was examined against four different human tumor cell lines. Their structure-activity relationships for antitumor activity were reported. All of these compounds exhibited activity against MCF-7 cell line and showed good activity against WiDr cell line except 8c and 8f. On the other hand, compounds 8j and 8o are more active than the other compounds against Hepa59T/VGH cell line. The electron-donating group at the 6-position of isoquinoline ring seems to decrease the antitumor activity and the chloro substituent at the C-4 position of the aniline ring shown the highest potency. The “trans influence” dominates the control of the stability of [1-(2-aminophenyl)-1,2,3,4- THIQ]dichloroplatinums(Ⅱ).