The purpose of this proposal is to synthesize various analogues of alkyl-lysophospholipids (ALPs) to support two previously funded studies on their biochemistry and pharmacology. the two funded studies (CA-41314 and CA-43297) are designed to evaluate their potential for therapeutic application. The preliminary in vitro data that contributed to the funding of these grants was obtained on small amounts of ALP analogues that were synthesized utilizing funds from other sources. Funding now is requested to scale up the synthesis of preliminary analogues with promising in vitro activity for in vivo evaluation and to expand the preliminary structure-activity relationship study to determine which specific chemical functional groups or combination of groups contribute to the antineoplastic activity of these alkylglycerolipids. Funding of this proposal, in conjunction with our previously established collaboration with researchers at the Bowman Gray School of Medicine lipid biochemistry department, will provide a comprehensive, integrated program to design, synthesize and evaluate ALP analogues for a specific tumor-inhibitory properties. ALPs may be directly cytotoxic to tumor cells or may function as biological response modifiers, or may exhibit both effects. Several possible mechanisms have been proposed to account for the antineoplastic activity of ALPs: direct cytotoxic or cytostatic action, malignant cell differentiation and/or macrophage activation. These effects are believed to be mediated by an interaction between the compounds and the membrane. However, little effort has been made to relate activity to specific portions of the ALP molecule. Since the majority of ALPs expressing antitumor activity to date are dialkyl glycerophosphocholines, it appears advantageous to have non- hydrolyzable moieties at the sn-1 and sn-2 positions of the lipid. The analogues synthesized and tested in this study will indicate what portions of the ALP molecule are necessary for antineoplastic activity and which functional groups will enhance the tumor-inhibitory properties of the ALP molecule. Promising analogues will be more intensively investigated to optimize their antineoplastic activity while minimizing undesirable anaphylactic effects. Analogues with high radiospecific activity will be synthesized to follow their metabolism and aid in the elucidation of the mechanism of action of the ALP molecule.
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