Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-gamma-lactones as protein kinase C ligands and antitumor agents.
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.
Kang
Ji-Hye
JH
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea.
Kim
Yerim
Y
Won
Shin-Hye
SH
Park
Song-Kyu
SK
Lee
Chang Woo
CW
Kim
Hwan-Mook
HM
Lewin
Nancy E
NE
Perry
Nicholas A
NA
Pearce
Larry V
LV
Lundberg
Daniel J
DJ
Surawski
Robert J
RJ
Blumberg
Peter M
PM
Lee
Jeewoo
J
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*
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