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J Nat Prod. 2014 Aug 22;77(8):1817-24. doi: 10.1021/np5002048. Epub 2014 Jul 30.

Studies toward the Development of Antiproliferative Neoclerodanes from Salvinorin A.

Author information

1
†Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66045, United States.
2
§Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.

Abstract

The success rate for central nervous system (CNS) drug candidates in the clinic is relatively low compared to the industry average across other therapeutic areas. Penetration through the blood-brain barrier (BBB) to reach the therapeutic target is a major obstacle in development. The rapid CNS penetration of salvinorin A has suggested that the neoclerodane nucleus offers an excellent scaffold for developing antiproliferative compounds that enter the CNS. The Liebeskind-Srogl reaction was used as the main carbon-carbon bond-forming step toward the synthesis of quinone-containing salvinorin A analogues. Quinone-containing salvinorin A analogues were shown to have antiproliferative activity against the MCF7 breast cancer cell line, but show no significant activity at the κ-opioid receptors. In an in vitro model of BBB penetration, quinone-containing salvinorin A analogues were shown to passively diffuse across the cell monolayer. The analogues, however, are substrates of P-glycoprotein, and thus further modification of the molecules is needed to reduce the affinity for the efflux transporter.

PMID:
25075762
PMCID:
PMC4143179
DOI:
10.1021/np5002048
[Indexed for MEDLINE]
Free PMC Article
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