title: Studies toward the Development of Antiproliferative Neoclerodanes from Salvinorin A.
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.
authors: †Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66045, United States.
authors: Tamara
authors: T
authors: Vasiljevik
authors: †Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66045, United States.
authors: Chad E
authors: CE
authors: Groer
authors: †Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66045, United States.
authors: Kurt
authors: K
authors: Lehner
authors: §Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Hernan
authors: H
authors: Navarro
authors: †Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66045, United States.
authors: Thomas E
authors: TE
authors: Prisinzano
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002491:Central Nervous System Agents; D045785:Diterpenes, Clerodane / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D015394:Molecular Structure; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D027544:Salvia / Q000737:chemistry
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002491:Central Nervous System Agents; D045785:Diterpenes, Clerodane; D017473:Receptors, Opioid, kappa; C090499:salvinorin A