Interrogating the Bioactive Pharmacophore of the Latrunculin Chemotype by Investigating the Metabolites of Two Taxonomically Unrelated Sponges

被引:35
作者
Amagata, Taro [1 ]
Johnson, Tyler A. [1 ,2 ]
Cichewicz, Robert H. [1 ]
Tenney, Karen [1 ]
Mooberry, Susan L. [3 ]
Media, Joseph [4 ]
Edelstein, Matthew [4 ]
Valeriote, Frederick A. [4 ]
Crews, Phillip [1 ,2 ]
机构
[1] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA
[2] Univ Calif Santa Cruz, Dept Ocean Sci, Santa Cruz, CA 95064 USA
[3] SW Fdn Biomed Res, San Antonio, TX 78245 USA
[4] Henry Ford Hosp, Dept Internal Med, Div Hematol & Oncol, Detroit, MI 48202 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1021/jm8008585
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
This study involved a campaign to isolate and study additional latrunculin analogues from two taxonomically unrelated sponges, Cacospongia mycoffiensis and Negombata magnifica. A total of 13 latrunculin analogues were obtained by four different ways, reisolation (1-4), our repository (5, 6), new derivatives (7-12), and a synthetic analogue (7a). The structures of the new metabolites were elucidated on the basis of a combination of comprehensive 1D and 2D NMR analysis, application of DFT calculations, and the preparation of acetonide derivative 7a. The cytotoxicities against both murine and human cancer cell lines observed for 1, 2, 7, 7a, 8, 9, and 12 were significant, and the IC50 range was 0.5-10 mu M. Among the cytotoxic derivatives, compound 9 did not exhibit microfilament-disrupting activity at 5 mu M. The implications of this observation and the value of further therapeutic study on key latrunculin derivatives are discussed.
引用
收藏
页码:7234 / 7242
页数:9
相关论文
共 36 条
[1]   Latrunculin with a highly oxidized thiazolidinone ring: Structure assignment and actin docking [J].
Ahmed, Safwat A. ;
Odde, Srinivas ;
Daga, Pankaj R. ;
Bowling, John J. ;
Mesbah, Mostafa K. ;
Youssef, Diaa T. ;
Khalifa, Sherief I. ;
Doerksen, Robert J. ;
Hamann, Mark T. .
ORGANIC LETTERS, 2007, 9 (23) :4773-4776
[2]  
AMAGATA T, UNPUB
[3]  
[Anonymous], SPART 06
[4]   High rates of actin filament turnover in budding yeast and roles for actin in establishment and maintenance of cell polarity revealed using the actin inhibitor latrunculin-A [J].
Ayscough, KR ;
Stryker, J ;
Pokala, N ;
Sanders, M ;
Crews, P ;
Drubin, DG .
JOURNAL OF CELL BIOLOGY, 1997, 137 (02) :399-416
[5]  
BLASBERGER D, 1989, LIEBIGS ANN CHEM, V117, P1
[6]  
Cone M, 1987, FEBS LETT, V213, P316
[7]   MYCOTHIAZOLE, A POLYKETIDE HETEROCYCLE FROM A MARINE SPONGE [J].
CREWS, P ;
KAKOU, Y ;
QUINOA, E .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (13) :4365-4368
[8]   Total syntheses of the actin-binding macrolides latrunculin A, B, C, M, S and 16-epi-latrunculin B [J].
Fuerstner, Alois ;
De Souza, Dominic ;
Turet, Laurent ;
Fenster, Michael D. B. ;
Parra-Rapado, Liliana ;
Wirtz, Conny ;
Mynott, Richard ;
Lehmann, Christian W. .
CHEMISTRY-A EUROPEAN JOURNAL, 2007, 13 (01) :115-134
[9]   Catalysis-based total synthesis of latrunculin B [J].
Fürstner, A ;
De Souza, D ;
Parra-Rapado, L ;
Jensen, JT .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2003, 42 (43) :5358-5360
[10]   Epothilons A and B: Antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria) - Production, physico-chemical and biological properties [J].
Gerth, K ;
Bedorf, N ;
Hofle, G ;
Irschik, H ;
Reichenbach, H .
JOURNAL OF ANTIBIOTICS, 1996, 49 (06) :560-563