The microfilament cytoskeleton protein actin plays an important role in cell biology and affects cytokinesis, morphogenesis, and cell migration. These functions usually fail and become abnormal in cancer cells. The marine-derived macrolides latrunculins A and B, from the Red Sea sponge Negombata magnifica, are known to reversibly bind actin monomers, forming 1:1 stoichiometric complexes with G-actin, disrupting its polymerization. To identify novel therapeutic agents for effective treatment of metastatic breast cancer, several semisynthetic derivatives of latrunculin A with diverse steric, electrostatic, and hydrogen bond donor and acceptor properties were rationally prepared. Analogues were designed to modulate the binding affinity toward G-actin. Examples of these reactions are esterification, acetylation, and N-alkylation. Semisynthetic latrunculins were then tested for their ability to inhibit pyrene-conjugated actin polymerization, and subsequently assayed for their antiproliferative and anti-invasive properties against MCF7 and MDA-MB-231 cells using MTT and invasion assays, respectively.
Mohammad A. Khanfar, Diaa T. A. Youssef and Khalid A. El Sayed
Article first published online: 30 DEC 2009 | DOI: 10.1002/cmdc.200900430
ChemMedChem
Volume 5, Issue 2, pages 274–285, February 1, 2010
Negombata magnifica, a Red Sea sponge (background), is the natural source of latrunculin A. A series of latrunculin A derivatives were synthesized and tested for their ability to inhibit G-actin polymerization and breast cancer cell proliferation and invasion. Molecular modeling simulations (inset) were applied to improve the understanding of the SAR of latrunculins.
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