| Description |
Lysophosphatidic acid (LPA) is an important phospholipid that mediates a variety of biologic effects. LPA induces cell proliferation, morphological changes, and has been shown to be involved in many pathophysiological processes including cancers, immunological diseases, and cardiovascular diseases and wound healing. LPA accomplishes its biological activities by acting mainly upon G-protein coupled receptors. These receptors exist in most of mammalian cells and each receptor's functions are still not clear. Thus, development of approaches to modify LPA function could have broad applicability in the control and improvement of pathophysiological conditions. LPA is present in ascites from ovarian cancer patients at very high concentrations, and it plays an essential role in regulating drug sensitivity and invasiveness of ovarian cancer cells. The development of antibodies against LPA has the potential to improve the diagnosis and treatment of ovarian cancer. In the first study, I synthesized lipid immunogens as bioconjugates with different linkers and carriers for preparation of specific antisera. A LPA/PA cross-reactive murine IgG mAb was generated, which will be useful to selectively extract LPA and PA molecular species from human serum. In a separate study, I synthesized a series of long-lived and metabolically stabilized LPA analogues. Hydroxyethoxy (HE)-substituted LPA derivatives selectively activated the LP A3 receptor, but with a potency tenfold lower than natural oleoyl LPA. A methyl thiophosphate LPA analogue, OMPT (l-oleoyl-2-O-methyl-rflc-glycero-phosphothioate), showed enantioselective responses to LPA3 receptor, and a highly potent and selective LP A3 receptor agonist (2.S)-0MPT was discovered. Among a group of thiophosphate LPA analogues with ether chains, two phosphodiesters, LQIO and LQll, were found to act as antagonists to inhibit the stimulatory effects of LPA-mediated signaling on DNA synthesis in cells. The synthesis of these compounds provides tremendous insight into how LPA receptor antagonists with high potency and less toxicity can be generated as potential therapeutics for the treatment of ovarian cancer. |
