ANTIVIRAL (RNA) ACTIVITY OF SELECTED AMARYLLIDACEAE ISOQUINOLINE CONSTITUENTS AND SYNTHESIS OF RELATED SUBSTANCES
ANTIVIRAL (RNA) ACTIVITY OF SELECTED AMARYLLIDACEAE ISOQUINOLINE CONSTITUENTS AND SYNTHESIS OF RELATED SUBSTANCES
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DOI：
10.1021/np50089a003
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发表时间：
1992-11-01
影响因子：
5.1
通讯作者：
PHELAN, MJ
中科院分区：
文献类型：
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作者：
GABRIELSEN, B;MONATH, TP;PHELAN, MJ
分离或合成了23个石蒜科异喹啉生物碱和相关的合成类似物，随后在细胞培养中评估了它们对含RNA的黄病毒(日本脑炎、黄热病和登革热病毒)、布尼亚病毒(Punta Toro病毒、沙蝇热和裂谷热病毒)、α病毒(委内瑞拉马脑脊髓炎病毒)、慢病毒(人类免疫缺陷病毒1型)和含DNA的牛痘病毒的抑制作用。Narciclasine[1]，Lycoricine[2]，pancatistatin[4]，7-deoxypancatistatin[5]，乙酸酯6-8，isonarciclasine[13a]，cis-dihyronarciclasine[14a]，反式-dihyronarciclasine[15a]，它们的7-脱氧类似物13b-15b，Lycorine 16和17，以及pretazettin[18]对所有三种黄病毒和布尼亚病毒、蓬塔多罗病毒和裂谷热病毒表现出一致的体外活性。只有7-脱氧类似物具有抗沙蝇热病毒的活性。然而，在大多数情况下，活性化合物的选择性很低，对未感染细胞的毒性(TC50)在病毒抑制浓度(IC50)的10倍以内。没有观察到对人类免疫缺陷病毒1型、委内瑞拉马脑脊髓炎病毒或牛痘病毒的活性。Pancatistatin[4]及其7-脱氧类似物5在两个小鼠日本脑炎小鼠模型中进行了评估(除其他因素外，不同的病毒剂量挑战)。在两个实验中(低LD50病毒攻击，变种I)，预防性注射4，4和6 mg/kg/天(2%乙醇/生理盐水，sc，每天一次，连续7天，第1天到+5天)使乙脑病毒感染的小鼠的存活率分别提高到100%和90%。在相同的模型中，预防性给予羟丙基纤维素中40 mg/kg/天的5(sc，每日一次，连续7天，第1天至第5天)可将乙脑病毒感染小鼠的存活率提高到80%。在第二个变种(高LD50病毒攻击)中，以6 mg/kg/天(ip，每天两次，连续9天，第1天至+7天)注射4可导致50%的存活率。在所有情况下，稀释剂处理的对照组小鼠都没有存活下来。因此，4和5在感染乙型脑炎病毒的小鼠身上表现出活性，但仅在接近毒性的浓度下表现出活性。然而，据我们所知，在日本脑炎病毒感染的小鼠模型中，这是一种罕见的化疗效果(通过干扰素诱导剂以外的物质)的证明。
A series of 23 Amaryllidaceae isoquinoline alkaloids and related synthetic analogues were isolated or synthesized and subsequently evaluated in cell culture against the RNA-containing flaviviruses (Japanese encephalitis, yellow fever, and dengue viruses), bunyaviruses (Punta Toro, sandfly fever, and Rift Valley fever viruses), alphavirus (Venezuelan equine encephalomyelitis virus), lentivirus (human immunodeficiency virus-type 1) and the DNA-containing vaccinia virus. Narciclasine [1], lycoricidine [2], pancratistatin [4], 7-deoxypancratistatin [5], and acetates 6-8, isonarciclasine [13a], cis-dihydronarciclasine [14a], trans-dihydronarciclasine [15a], their 7-deoxy analogues 13b-15b, lycorines 16 and 17, and pretazettine [18] exhibited consistent in vitro activity against all three flaviviruses and against the bunyaviruses, Punta Toro and Rift Valley fever virus. Activity against sandfly fever virus was only observed with 7-deoxy analogues. In most cases, however, selectivity of the active compounds was low, with toxicity in uninfected cells (TC50) occurring at concentrations within 10-fold that of the viral inhibitory concentrations (IC50). No activity was observed against human immunodeficiency virus-type 1, Venezuelan equine encephalomyelitis virus, or vaccinia viruses. Pancratistatin [4] and its 7-deoxy analogue 5 were evaluated in two murine Japanese encephalitis mouse models (differing in viral dose challenge, among other factors). In two experiments (low LD50 viral challenge, variant I), prophylactic administration of 4 at 4 and 6 mg/kg/day (2% EtOH/saline, sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 100% and 90%, respectively. In the same model, prophylactic administration of 5 at 40 mg/kg/day in hydroxypropylcellulose (sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 80%. In a second variant (high LD50 viral challenge), administration of 4 at 6 mg/kg/day (ip, twice daily for 9 days, day -1 to +7) resulted in a 50% survival rate. In all cases, there was no survival in the diluent-treated control mice. Thus, 4 and 5 demonstrated activity in mice infected with Japanese encephalitis virus but only at near toxic concentrations. To our knowledge, however, this represents a rare demonstration of chemotherapeutic efficacy (by a substance other than an interferon inducer) in a Japanese-encephalitis-virus-infected mouse model.