Bailly Christian
Inserm UR-524, and Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Place de Verdun, 59045 Lille, France.
Curr Med Chem Anticancer Agents. 2004 Jul;4(4):363-78. doi: 10.2174/1568011043352939.
The lamellarins form a group of more than 30 polyaromatic pyrrole alkaloids, isolated from diverse marine organisms, mainly but not exclusively ascidians and sponges. These molecules fall in three structural groups, with the central pyrrole ring fused or unfused (lamellarins O-R) to adjacent aromatic rings and with the quinoline moiety containing a 5, 6-single--as in lamellarins I-L--or a double bond, as it is the case for lamellarins D and M which are both potent cytotoxic agents. The family also includes sulphated members, such as the integrase inhibitor lamellarin alpha 20-sulfate. This review presents the origin and structure of the lamellarins and summarizes the various chemical pathways which have been proposed to synthesize all lamellarins and different structurally related marine pyrrole alkaloids, including ningalins, storniamides and lukianols. The mechanisms of actions of these marine products are also discussed. Inhibition of HIV-1 integrase by lamellarin alpha 20-sulfate and human topoisomerase I by lamellarin D and Molluscum contagiosum virus topoisomerase by lamellarin H, along with other effects on nuclear proteins, provide an experimental basis indicating that DNA manipulating enzymes are important targets for the lamellarins. Some of these marine compounds exhibit cytotoxic activities against tumor cells in vitro and are insensitive to Pgp-mediated drug efflux. The structure-activity relationships are discussed. Other compounds in the series, without being strongly cytotoxic, can reverse the multidrug resistance phenotype and thus may be useful to promote the therapeutic activity of conventional cytotoxic drugs toward chemoresistant tumors. A complete description of the chemistry and pharmacological profiles of the lamellarins is presented here to shed light on this undervalued family of marine alkaloids.
片螺素是一组由30多种多芳基吡咯生物碱组成的化合物,它们从多种海洋生物中分离得到,主要但不限于海鞘和海绵。这些分子可分为三个结构组,其中心吡咯环与相邻芳环稠合或未稠合(片螺素O-R),喹啉部分含有一个5,6-单键(如片螺素I-L)或一个双键,如片螺素D和M,它们都是强效细胞毒剂。该家族还包括硫酸化成员,如整合酶抑制剂硫酸化片螺素α20。本文综述了片螺素的起源和结构,并总结了已提出的用于合成所有片螺素以及不同结构相关的海洋吡咯生物碱(包括宁加林、斯托尼亚胺和卢基阿诺尔)的各种化学途径。还讨论了这些海洋产物的作用机制。硫酸化片螺素α20对HIV-1整合酶的抑制作用、片螺素D对人拓扑异构酶I的抑制作用以及片螺素H对传染性软疣病毒拓扑异构酶的抑制作用,连同对核蛋白的其他影响,提供了一个实验基础,表明DNA操作酶是片螺素的重要靶点。其中一些海洋化合物在体外对肿瘤细胞具有细胞毒活性,并且对Pgp介导的药物外排不敏感。讨论了构效关系。该系列中的其他化合物虽然没有很强的细胞毒性,但可以逆转多药耐药表型,因此可能有助于提高传统细胞毒药物对化疗耐药肿瘤的治疗活性。本文全面描述了片螺素的化学和药理学特性,以阐明这个被低估的海洋生物碱家族。