History
Salinosporamide A was discovered by William Fenical and Paul Jensen from Scripps Institution of Oceanography in La Jolla, CA. In preliminary screening, a high percentage of the organic extracts of cultured Salinospora strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery. Salinospora strain CNB-392 was isolated from a heat-treated marine sediment sample and cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A. Although salinosporamide A shares an identical bicyclic ring structure with omuralide, it is uniquely functionalized. Salinosporamide A displayed potent in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 11 ng mL-1. This compound also displayed potent and highly selective activity in the NCI's 60-cell-line panel with a mean GI50 value (the concentration required to achieve 50% growth inhibition) of less than 10 nM and a greater than 4 log LC50 differential between resistant and susceptible cell lines. The greatest potency was observed against NCI-H226 non-small cell lung cancer, SF-539 CNS cancer, SK-MEL-28 melanoma, and MDA-MB-435 breast cancer (all with LC50 values less than 10 nM). Salinosporamide A was tested for its effects on proteasome function because of its structural relationship to omuralide. When tested against purified 20S proteasome, salinosporamide A inhibited proteasomal chymotrypsin-like proteolytic activity with an IC50 value of 1.3 nM. This compound is approximately 35 times more potent than omuralide which was tested as a positive control in the same assay. Thus, the unique functionalization of the core bicyclic ring structure of salinosporamide A appears to have resulted in a molecule that is a significantly more potent proteasome inhibitor than omuralide.
Read more about this topic: Salinosporamide A
Famous quotes containing the word history:
“The thing that struck me forcefully was the feeling of great age about the place. Standing on that old parade ground, which is now a cricket field, I could feel the dead generations crowding me. Here was the oldest settlement of freedmen in the Western world, no doubt. Men who had thrown off the bands of slavery by their own courage and ingenuity. The courage and daring of the Maroons strike like a purple beam across the history of Jamaica.”
—Zora Neale Hurston (1891–1960)
“Hence poetry is something more philosophic and of graver import than history, since its statements are rather of the nature of universals, whereas those of history are singulars.”
—Aristotle (384–322 B.C.)
“I cannot be much pleased without an appearance of truth; at least of possibility—I wish the history to be natural though the sentiments are refined; and the characters to be probable, though their behaviour is excelling.”
—Frances Burney (1752–1840)