Latrunculin A and its C-17-O-carbamates inhibit prostate tumor cell invasion and HIF-1 activation in breast tumor cells.

Abstract

The marine-derived macrolides latrunculins A ( 1) and B, from the Red Sea sponge Negombata magnifica, have been found to reversibly bind actin monomers, forming a 1:1 complex with G-actin and disrupting its polymerization. The microfilament protein actin is responsible for several essential functions within the cell such as cytokinesis and cell migration. One of the main binding pharmacophores of 1 to G-actin was identified as the C-17 lactol hydroxyl moiety that binds arginine 210 NH. Latrunculin A-17- O-carbamates 2- 6 were prepared by reaction with the corresponding isocyanates. Latrunculin A ( 1) and carbamates 4- 6 displayed potent anti-invasive activity against the human highly metastatic human prostate cancer PC-3M cells in a Matrigel assay at a concentration range of 50 nM to 1 microM. Latrunculin A ( 1, 500 nM) decreased the disaggregation and cell migration of PC-3M-CT+ spheroids by 3-fold. Carbamates 4 and 5 were 2.5- and 5-fold more active than 1, respectively, in this assay with less actin binding affinity. Latrunculin A ( 1, IC 50 6.7 microM) and its 17- O-[ N-(benzyl)carbamate ( 6, IC 50 29 microM) suppress hypoxia-induced HIF-1 activation in T47D breast tumor cells.

• Authors: Khalid A El Sayed, Mohammad A Khanfar, Hassan M Shallal, A Muralidharan, Bhushan Awate, Diaa T A Youssef, Yang Liu, Yu-Dong Zhou, Dale G Nagle, Girish Shah
• Journal: Journal of natural products (J Nat Prod) Vol. 71 Issue 3 Pg. 396-402 (Mar 2008) ISSN: 0163-3864 [Print] United States
• PMID: 18298079 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Carbamates
• Hypoxia-Inducible Factor 1
• Thiazolidines
• latrunculin B
• latrunculin A

Topics

• Animals
• Breast Neoplasms (drug therapy)
• Bridged Bicyclo Compounds, Heterocyclic (chemistry, pharmacology)
• Carbamates (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Hypoxia-Inducible Factor 1 (antagonists & inhibitors)
• Male
• Molecular Structure
• Porifera (chemistry)
• Prostatic Neoplasms (drug therapy)
• Thiazolidines (chemistry, pharmacology)