摘要
苯并萘啶类生物碱具有广泛的生物活性,如抗菌、抗病毒、抗肿瘤等等。尤其是自2009年以来,发现该类化合物可作为小分子免疫增效剂而对免疫应答起到刺激和调节作用,从而引起了广泛关注。
2010年,上海交通大学徐岷涓课题组从红树林沉积物中的Streptomyces albogriseolus中提取分离得到了一种新型骨架结构的苯并萘啶类生物碱,经光谱分析,推测其结构为1-N-甲基-3-氨甲基-[N-丁酸-3-(9-甲基-8-丙烯酰-7-酮)-酰胺]-苯并[f][1,7]萘啶-2-酮。这是首次发现该种骨架结构的苯并萘啶类生物碱。然而,由于该化合物分离得到的量微,其侧链3’位的绝对构型未能确定,并且也没能对其进行生物活性测试。因此,为了进一步验证其结构、确定3’位绝对构型并得到足够量的化合物进行生物活性测试,我们对其进行了全合成研究。
我们以商业上便宜易得的吲哚醌为起始原料,经15步反应,以1.6%的总收率首次完成了该天然产物的全合成。合成产物与天然产物的1H NMR谱、13C NMR谱、HRESI-MS谱及比旋光度均一致。由此,我们进一步验证了该苯并萘啶类生物碱的结构,并确定其3’位绝对构型为S构型。
细胞毒活性筛选结果显示：该苯并萘啶类生物碱对AGS(胃腺癌细胞株),3AO(卵巢癌细胞株),Skdbip(卵巢癌细胞株),97H(肝癌细胞株)及LM3(肝癌细胞株)无明显抑制作用,而对HGC-27(胃癌细胞株)具有中等程度的抑制作用。
贝前列素钠是一种PGI2类似物,但其结构较PGI2更为稳定,半衰期较长,且口服有效,是常用的抗血小板凝集药之一,目前临床上常用于改善慢性动脉闭塞性疾病引起的溃疡、间歇性跛行、疼痛和冷感等症状。
目前关于其不对称合成研究已有多篇文献报道,其难点主要在于环戊并[b]苯并呋喃骨架结构的合成。而目前所采取的合成策略主要是利用手性拆分或手性控制的不对称合成反应。前者昂贵的手性拆分剂,极大地提高了其合成成本,而后者多步手性控制的不对称合成反应路线较长,合成效率较低。为了寻找一条更为简便的合成路线,我们对其关键中间体进行了不对称合成研究。
我们以商业上易得的(-)-Corey内酯二醇为原料,分别经烷基化、RCM环合及环己二烯的芳构化等7步反应,成功地构建了Beraprost结构中的环戊并[b]苯并呋喃骨架结构,以40%的总收率实现了Beraprost的关键中间体的合成,为贝前列素及其相关结构类似物的合成提供了一个新的方法。
吡咯并喹啉类生物碱因其良好的生物活性、新颖的结构及全合成研究的挑战性,引起了广泛关注。其中,Ammosamide B及Lymphostin更是成为近几年国内外研究的热点。Ammosamide B是由W.Fenical课题组于2009年从海洋链霉菌属CNR-698中提取分离得到的,并发现其具有良好的抗肿瘤活性；]ymphostin是由H. Nagata课题组于1997年从Streptomyces sp. KY11783中提取分离得到的,并且发现它具有良好的抑制淋巴细胞特异性蛋白质酪氨酸激酶和磷脂酰肌醇3-激酶的作用,是一种潜在的免疫抑制剂,而最近又发现Lymphostin对mTOR(哺乳动物雷帕霉素靶蛋白)具有良好的抑制活性,因而开展对于这类天然产物的合成研究具有较高的理论价值和实际意义。
由于Ammosamide B和Lymphostin均具有良好的生物活性,其药理活性研究也处于初级阶段,而且其合成研究也具有一定挑战性,因此,我们对其进行了合成研究。
我们以商业上易得的1,5-二氟-2,4-二硝基苯为原料,经Doebner-Von Miller反应构建出了喹啉环骨架,并在此基础上找到了一条快速构建吡咯并喹啉结构骨架的合成路线,为Ammosamide B及Lymphostin的合成提供了便利,也为它们的结构改造奠定了基础。
Benzonaphthyridines have drawn widespread concern due to their chemical reactivity and biological properties, e.g. anti-bacterial, anti-fungal and anti-cancer bioactivities. Especially since2009, benzonaphthyridines were found to be small molecule immune potentiators capable of stimulating or modulating an immune response and developed as vaccines against herorrhagic fever virus, e.g., Ebola virus.
A novel benzonaphthyridine alkaloid was first isolated from a mangrove-derived S. albogriseolus by Xu in2010, which possesses a fused tricyclic heteroaromatic system, and belongs to diazaphenathrene family. Based on extensive NMR data analysis, mass fragment analysis and calculation of13C NMR shifts, its structure was determined to be1-N-methy1-3-methylamino-[N-butanoic acid-3'-(9'-methyl-8'-propen-7'-one)-amide]-benzo[f][1,7]naphthyridine-2-one. It is the first known natural product with the framework. However, its absolute configuration of3'in the side chain still remained unclear due to its insufficient supply. In order to fully elucidate the structure of this natural product and overcome the problem of minor amount, the total synthesis of the benzonaphthyridine could offer us the opportunity for confirming the stereoconfiguration and reproducing such compounds in large amount for biotest and further medicinal research.
In conclusion, we have for the first time accomplished the total synthesis of the noval benzonaphthyridine alkaloid with an overall yield of1.6%in15steps from isatin. The spectroscopic data (1H and13C NMR) and specific rotation of the synthetic material were in good agreement with those of the natural product. And finally by using commercially available L-glutamic acid derivative as chiral pool, the absolute configuration of benzonaphthyridine alkaloid was assigned as3'S.
In primary cytotoxicity test, this noval benzonaphthyridine alkaloid showed no inhibitory effects against AGS,3AO, Skdbip,97H, LM3at concentrations of45μg/ml. But it proved to be moderately active against HGC-27at a concentration of45μg/ml and inhibited the proliferation significantly.
Beraprost sodium is an orally active PGI2analogue, which is more stable than the PGI2and has longer half-life. It has been one of the commonly used antiplatelet drugs, and was commonly used in the treatment of intermittent claudication, pain and cold flu symptoms which was caused by chronic arterial occlusive disease.
There were several articles on its asymmetric synthesis have been published, and the main difficulty lies in asymmetric synthesis of cyclopenta[b]benzofuran-5-butyric acid skeleton structure. At present, the use of chiral resolution and asymmetric reaction is adopted as the normal asymmetric synthesis strategy. However, the former greatly increases the cost of its synthesis due to the expensive chiral resolving agents, while the latter possesses low synthesis efficiency for the multi-step asymmetric reactions. In order to find a more efficient synthetic route, we attempted to conduct the asymmetric synthesis of Beraprost.
We have accomplished the formal synthesis of Beraprost with an overall yield of40%in7steps from (-)-Corey lactone diol. The synthesis involves the use of RCM cyclization and aromatization of cyclohexadiene.
Pyrroloquinoline alkaloids have been studied as both synthetic targets to develop new methodologies and biological activities to discover new drugs. Recently, ammosamide B and lymphostin have been isolated as significant bioactive compounds. Ammosamide B was isolated from the marine Streptomyces strain CNR-698, and interest in it has been stimulated by its cytotoxicities in cancer cell cultures. Lymphostin was isolated from a culture broth of Streptomyces sp. KY11783. Lymphostin has been shown to inhibit both lymphocyte kinase and phosphatidylino-sitol3-kinase, and recently, it has been found to be a potent mTOR inhibitor.
The biological activity, along with ammosamide B and lymphostin's c, inspired us to synthesize them.
We have already constructed the quinoline skeleton during Doebner-Von Miller reaction from1,5-difluoro-2,4-dinitrobenzene, and found an efficient method to synthesize tricyclic pyrroloquinoline skeleton for ammosamide B and lymphostin, which lays a foundation for the total synthesis and structural modification of them.
引文
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