title: Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1.
abstract: The natural products combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent cancer vascular disrupting agents and inhibitors of tubulin assembly (IC₅₀ = 1-2 μM). The phosphorylated prodrugs CA4P and CA1P are undergoing human clinical trials against cancer. CA1 is unique due to its incorporation of a vicinal phenol, which has afforded the opportunity to prepare both diphosphate and regioisomeric monophosphate derivatives. Here, we describe the first synthetic routes suitable for the regiospecific preparation of the CA1-monophosphates CA1MPA (8a/b) and CA1MPB (4a/b). The essential regiochemistry necessary to distinguish between the two vicinal phenolic groups was accomplished with a tosyl protecting group strategy. Each of the four monophosphate analogues (including Z and E isomers) demonstrated in vitro cytotoxicity against selected human cancer cell lines comparable to their corresponding diphosphate congeners. Furthermore, Z-CA1MPA (8a) and Z-CA1MPB (4a) were inactive as inhibitors of tubulin assembly (IC₅₀ > 40 μM), as anticipated in this pure protein assay.
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, USA.
authors: Rajendra P
authors: RP
authors: Tanpure
authors: Benson L
authors: BL
authors: Nguyen
authors: Tracy E
authors: TE
authors: Strecker
authors: Savannah
authors: S
authors: Aguirre
authors: Suman
authors: S
authors: Sharma
authors: David J
authors: DJ
authors: Chaplin
authors: Bronwyn G
authors: BG
authors: Siim
authors: Ernest
authors: E
authors: Hamel
authors: John W
authors: JW
authors: Lippert
authors: George R
authors: GR
authors: Pettit
authors: Mary Lynn
authors: ML
authors: Trawick
authors: Kevin G
authors: KG
authors: Pinney
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D012995:Solubility; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014867:Water
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D014404:Tubulin; D014867:Water; C063690:combretastatin A-1; C058728:fosbretabulin