TY - JOUR
T1 - Alkyl lysophosphatidic acid and fluoromethylene phosphonate analogs as metabolically-stabilized agonists for LPA receptors
AU - Xu, Yong
AU - Tanaka, Masayuki
AU - Arai, Hiroyuki
AU - Aoki, Junken
AU - Prestwich, Glenn D.
N1 - Funding Information:
We thank the Human Frontier Science Program (RG0073-2000B) and the NIH (HL070231) for support at the University of Utah and the College of Pharmacy at University of Tokyo.
PY - 2004/11/1
Y1 - 2004/11/1
N2 - We describe an efficient method for the synthesis of alkyl lysophosphatidic acid (LPA) analogs as well as alkyl LPA mono- and difluoromethylene phosphonate analogs. Each alkyl LPA analog was evaluated for subtype-specific LPA receptor agonist activity using a cell migration assay for LPA 1 activation in cancer cells and an intracellular calcium mobilization assay for LPA 2 and LPA 3 activation. Alkyl LPAs induced pronounced cell migration activity with equivalent or higher potency than sn-1-oleoyl LPA, while the alkyl LPA fluoromethylene phosphonates proved to be less potent agonists in this assay. However, each alkyl LPA analog activated Ca 2+ release by activation of LPA 2 and LPA 3 receptors. Interestingly, the absolute configuration of the sn-2 hydroxyl group of the alkyl LPA analogs was not recognized by any of the three LPA receptors. The use of alkyl LPA analogs further expands the scope of structure-activity studies, which will better define LPA-LPA receptor interactions.
AB - We describe an efficient method for the synthesis of alkyl lysophosphatidic acid (LPA) analogs as well as alkyl LPA mono- and difluoromethylene phosphonate analogs. Each alkyl LPA analog was evaluated for subtype-specific LPA receptor agonist activity using a cell migration assay for LPA 1 activation in cancer cells and an intracellular calcium mobilization assay for LPA 2 and LPA 3 activation. Alkyl LPAs induced pronounced cell migration activity with equivalent or higher potency than sn-1-oleoyl LPA, while the alkyl LPA fluoromethylene phosphonates proved to be less potent agonists in this assay. However, each alkyl LPA analog activated Ca 2+ release by activation of LPA 2 and LPA 3 receptors. Interestingly, the absolute configuration of the sn-2 hydroxyl group of the alkyl LPA analogs was not recognized by any of the three LPA receptors. The use of alkyl LPA analogs further expands the scope of structure-activity studies, which will better define LPA-LPA receptor interactions.
KW - Alkyl LPA
KW - Cell migration
KW - Epoxide ring opening
KW - Fluorinated alkyl LPA analogues
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U2 - 10.1016/j.bmcl.2004.08.019
DO - 10.1016/j.bmcl.2004.08.019
M3 - Article
C2 - 15454220
AN - SCOPUS:5344244761
VL - 14
SP - 5323
EP - 5328
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 21
ER -
