Semisynthetic Latrunculin Derivatives as Inhibitors of Metastatic Breast Cancer: Biological Evaluations,Preliminary Structure–Activity Relationship and Molecular Modeling Studies |
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Authors: | Mohammad A Khanfar Diaa T A Youssef Prof Khalid A El Sayed Prof |
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Affiliation: | 1. Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201 (USA), Fax: (+1)?318‐342‐1737;2. Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522 (Egypt) |
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Abstract: | 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. |
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Keywords: | actin antitumor agents cancer latrunculin A structure– activity relationships |
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