2. Result and discussion
The synthesis of (À)-jorumycin and its analogs basically follows the synthetic route we employed in our total synthesis of (À)-renieramycin G and its analogs, which used L-tyrosine as the chiral starting material.12a Intermediate compound 1 was obtained after a multi-step transformation from L-tyrosine as done before. Reduction of compound 1 with LiAlH4 in THF, followed by cyanation
renieramycin M, which was isolated from the Thai sponge Xesto-
spongia sp. Both of them showed very potent cytotoxic activity against a panel of human tumor cell lines.4 Although there have
material via 21 steps. These analogues, along with (À)-jorumycin itself, were evaluated in vitro for cy-
totoxicity against HCT-8, BEL-7402, Ketr3, A2780, MCF-7, A549, BGC-823, Hela, HELF, and KB cells. The
IC50 values of the cytotoxicity of most of these analogs were at the level of nM, which was similar to that of (À)-jorumycin. Among these analogs including (À)-jorumycin, hippuric acid ester derivative 23 ex-
Fig. 1. Structures of Et-743, jorumycin and renieramycin M.
* Corresponding author. Tel.: þ86 10 63165253; fax: þ86 10 63017757; e-mail address: liuzhanzhu@ (Z. Liu).
O
OH
OR 3
hibited the most potent and broad-spectrum cytotoxic activity against the ten cell lines with an average
IC50 of 2.12 nM.
Ó 2012 Elsevier Ltd. All rights reserved.
All of the compounds including (À)-jorumycin were tested against 10 human tumor cell lines including HCT-8, BEL-7402, Ketr3, A2780, MCF-7, A549, BGC-823, Hela, HELF, and KB. The results are summarized in Table 1. It can be seen from the screening
With compound 4 in hand, (À)-jorumycin was easily prepared according to the literature method.5 The spectral data of the synthesized product was fully consistent with that of the natural product (Scheme 2).
more, although there were several reports on the structureeactivity relationship studies of other isoquinoline alkaloids, none has been reported on that of (À)-jorumycin.6e11
been several reports on the total synthetic studies of these two
natural products, only R. M. Williams’ group and Zhu’s group have finished the total synthesis of (À)-Jorumycin up to now.5 Further-
1. Introduction
Isoquinoline marine alkaloids belong to a family of natural products consisting of about sixty members, which have interesting biological activities including cytotoxicity and antimicrobial activity.1 Among these natural products, Ecteinascidin 743 (Et-743), an exceedingly potent antitumor compound, which was isolated from the marine tunicate Ecteinascidia turbinate, has received marketing authorization from the European commission for the treatment of advanced soft-tissue sarcomas2 (Fig. 1).
with KCN or TMSCN afforded amino nitrile 2 in a yield of 86% after chromatography. The subsequent oxidation of 2 with air in the presence of salcomine gave bisquinone 3. Finally, 15 analogues with a variety of side chains at C-22 were prepared in 70e85% yields through the condensation of 3 with a series of carboxylic acids. All the compounds were characterized by their HRMS, 1H and 13C NMR (Scheme 1).
Keywords: (À)-Jorumycin Tetrahydroisoquinoline Synthesis Cytotoxicity
abstract
(À)-Jorumycin and its 15 C-22 analogues were prepared employing L-tyrosine as the chiral starting
article info
Article history: Received 8 December 2011 Received in revised form 19 January 2012 Accepted 7 February 2012 Available online 13 February 2012
(À)-Jorumycin, which is structurally related to the renieramycins, the ecteinascidins and the saframycins, was isolated from the mantle and mucus of the pacific nudibranch jorunna funebris.3 In particular the structure of jorumycin is very similar to that of
As the continuation of our study on isoquinoline natural products,12 we now report the total synthesis and the cytotoxic activities of (À)-jorumycin and its analogues.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2012.02.016
2760
W. Liu et al. / Tetrahedron 68 (2012) 2759e2764
Tetrahedron 68 (2012) 2759e2764
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: /locate/tet
Total synthesis and cytotoxicity of (À)-jorumycin and its analogues
Wei Liu a, Xiangwei Liao a, Wenfang Dong a, Zheng Yan b, Nan Wang b, Zhanzhu Liu a,b,*