Synthesis and biological evaluation of antimetastatic agents predicated upon dihydromotuporamine C and its carbocyclic derivatives

Aaron Muth, Veethika Pandey, Navneet Kaur, Melissa Wason, Cheryl Baker, Xianlin Han, Teresa R. Johnson, Deborah A. Altomare, Otto Phanstiel

Research output: Contribution to journalArticle

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 N1-(3-aminopropyl)-N3- (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.

Original languageEnglish (US)
Pages (from-to)4023-4034
Number of pages12
JournalJournal of Medicinal Chemistry
Volume57
Issue number10
DOIs
StatePublished - May 22 2014
Externally publishedYes

Fingerprint

Sphingomyelins
Xestospongia
Propane
Diamines
Ceramides
Polyamines
Porifera
Pancreatic Neoplasms
Oceans and Seas
Molecular Weight
Neoplasm Metastasis
Liver
Enzymes
Population
dihydromotuporamine C
norspermidine

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and biological evaluation of antimetastatic agents predicated upon dihydromotuporamine C and its carbocyclic derivatives. / Muth, Aaron; Pandey, Veethika; Kaur, Navneet; Wason, Melissa; Baker, Cheryl; Han, Xianlin; Johnson, Teresa R.; Altomare, Deborah A.; Phanstiel, Otto.

In: Journal of Medicinal Chemistry, Vol. 57, No. 10, 22.05.2014, p. 4023-4034.

Research output: Contribution to journalArticle

Muth, A, Pandey, V, Kaur, N, Wason, M, Baker, C, Han, X, Johnson, TR, Altomare, DA & Phanstiel, O 2014, 'Synthesis and biological evaluation of antimetastatic agents predicated upon dihydromotuporamine C and its carbocyclic derivatives', Journal of Medicinal Chemistry, vol. 57, no. 10, pp. 4023-4034. https://doi.org/10.1021/jm401906v
Muth, Aaron ; Pandey, Veethika ; Kaur, Navneet ; Wason, Melissa ; Baker, Cheryl ; Han, Xianlin ; Johnson, Teresa R. ; Altomare, Deborah A. ; Phanstiel, Otto. / Synthesis and biological evaluation of antimetastatic agents predicated upon dihydromotuporamine C and its carbocyclic derivatives. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 10. pp. 4023-4034.
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