title: Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-gamma-lactones as protein kinase C ligands and antitumor agents.
abstract: A series of DAG-lactones with polar 3-alkylidene substituents have been investigated as PKC-alpha ligands and antitumor agents. Extensive analysis of structure-activity relationships for the 3-alkylidene chain revealed that polar groups such as ether, hydroxyl, aldehyde, ester, acyloxy, and amido were tolerated with similar binding affinities and reduced lipophilicities compared to the corresponding unsubstituted alkylidene chain. Among the derivatives, compounds 5, 6 and 8 with an ether type of side chain showed high binding affinities in range of K(i)= 3-5 nM and excellent antitumor profiles, particularly against the colo205 colon cancer and the K562 leukemia cell lines.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Kang
authors.forename: Yerim
authors.initials: Y
authors.lastname: Kim
authors.forename: Shin-Hye
authors.initials: SH
authors.lastname: Won
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Lee
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Perry
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lundberg
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Surawski
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007783:Lactones / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D011493:Protein Kinase C / Q000378:metabolism*; D014631:Valerates / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C406230:(1-(hydroxymethyl)-4-(4-methyl-3-(methylethyl)pentylidene)-3-oxo-2-oxolanyl)methyl 4-methyl-3-(methylethyl)pentanoate; D000970:Antineoplastic Agents; D007783:Lactones; D008024:Ligands; D014631:Valerates; D011493:Protein Kinase C; D015107:4-Butyrolactone