Synthesis and Biological Evaluation of Antimetastatic Agents Predicated upon Dihydromotuporamine C and Its Carbocyclic Derivatives

    Authors

    A. Muth; V. Pandey; N. Kaur; M. Wason; C. Baker; X. L. Han; T. R. Johnson; D. A. Altomare;O. Phanstiel

    Comments

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    Abbreviated Journal Title

    J. Med. Chem.

    Keywords

    MULTIDIMENSIONAL MASS-SPECTROMETRY; XESTOSPONGIA-EXIGUA KIRKPATRICK; ACTIVE POLYAMINE TRANSPORTERS; HAMSTER OVARY CELLS; MOTUPORAMINES A-C; SHOTGUN LIPIDOMICS; ACID SPHINGOMYELINASE; IDENTIFICATION; ALKALOIDS; CERAMIDE; Chemistry, Medicinal

    Abstract

    The motuporamines isolated from the sea sponge Xestospongia exigua are of biological interest because of their unique antimigration and antiangiogenic properties. Key bioactive features were found to be a saturated 15-membered heterocycle and a norspermidine motif. This paper describes new analogues that modulate the cytotoxicity of this compound class and have enhanced antimigration properties. By movement of the polyamine chain outside the ring, new carbocycles were discovered that doubled the antimigration potency and reduced compound toxicity by 133-fold. Mice injected with metastatic human L3.6pl pancreatic cancer cells demonstrated significant reduction in liver metastases when treated with N-1-(3-aminopropyl)-N-3-(cyclopentadecylmethyl)propane-1,3-diamine compared with dihydromotuporamine C. Significant changes in specific ceramide populations (N16:0 and N22:1) were noted in L3.6pl cells treated with dihydromotuporamine C but not for the cyclopentadecylmethylnorspermidine derivative, which had lower toxicity. Both compounds gave increased levels of specific low molecular weight sphingomyelins, suggesting that they may act upon sphingomyelin processing enzymes.

    Journal Title

    Journal of Medicinal Chemistry

    Volume

    57

    Issue/Number

    10

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    4023

    Last Page

    4034

    WOS Identifier

    WOS:000336510100009

    ISSN

    0022-2623

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