RESUMEN
Tocopheryl succinates (TOSs) are, in contrast to tocopherols, highly cytotoxic against many cancer cells. In this study the enzyme activity of secretory phospholipase A(2) towards various succinate-phospholipid conjugates has been investigated. The synthesis of six novel phospholipids is described, including two TOS phospholipids conjugates. The studies revealed that the TOS conjugates are poor substrates for the enzyme whereas the phospholipids with alkyl and phenyl succinate moieties were hydrolyzed by the enzyme to a high extent.
Asunto(s)
Fosfolipasas A2/metabolismo , Fosfolípidos/química , Ácido Succínico/química , Tocoferoles/química , Línea Celular Tumoral , Humanos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Especificidad por SustratoRESUMEN
Our knowledge of the biological relevance of regions of chemical space is shaped, in large part, by the synthetic accessibility of small molecules. Historically, however, chemists have explored chemical space in an exceptionally uneven and unsystematic way. We have previously demonstrated that metathesis cascade chemistry may be harnessed to yield small molecule collections with high scaffold diversity. Here, we describe the extent to which inter- and intramolecular Diels-Alder reactions, when used in conjunction with metathesis cascades, can extend the range of molecular scaffolds that are accessible. A range of metathesis substrates was prepared from combinations of two or three building blocks. Metathesis cascades were exploited to "reprogram" the molecular scaffolds. In many cases, the metathesis products were 1,3-dienes, which were potential substrates for either inter- or intramolecular Diels-Alder reactions. The synthesis and functionalisation of the products was often facilitated by fluorous tagging, for example by using a "safety-catch" linker that we have developed. It was demonstrated that, in certain cases, Diels-Alder reactions could extend the range of molecular scaffolds that may be prepared by using metathesis cascade reactions.
Asunto(s)
Compuestos Heterocíclicos/química , Estructura Molecular , CiclizaciónRESUMEN
The synthesis of two secretory phospholipase A(2) IIA sensitive 15-deoxy-Delta(12,14)-prostaglandin J(2) phospholipid conjugates is described and their biophysical and biological properties are reported. The conjugates spontaneously form particles in the liposome size region upon dispersion in an aqueous buffer and both phospholipids are hydrolyzed by phospholipase A(2), but with different conversion rates and extent of hydrolysis. The cytotoxicity was evaluated in HT-29 and Colo205 cells and the conjugates induced cell death in the presence of phospholipase A(2) and surprisingly also in the absence of the enzyme.
Asunto(s)
Fosfolípidos/química , Prostaglandina D2/análogos & derivados , Prostaglandinas/química , Apoptosis , Línea Celular Tumoral , Fosfolipasas A2 Grupo II/metabolismo , Humanos , Hidrólisis , Prostaglandina D2/químicaRESUMEN
The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. The prodrugs are degradable by secretory phospholipase A(2) IIA and have potential in liposomal drug delivery targeting tumors. We have synthesized four different retinoid phospholipid prodrugs and shown that they form particles in the liposome size region with average diameters of 94-118 nm. Upon subjection to phospholipase A(2), the lipid prodrugs were hydrolyzed, releasing cytotoxic retinoids and lysolipids. The formulated lipid prodrugs displayed IC(50) values in the range of 3-19 microM toward HT-29 and Colo205 colon cancer cells in the presence of phospholipase A(2), while no significant cell death was observed in the absence of the enzyme.
Asunto(s)
Diseño de Fármacos , Liposomas/química , Fosfolipasas A2/metabolismo , Profármacos/metabolismo , Retinoides/química , Muerte Celular , Línea Celular Tumoral , Citotoxinas , Humanos , Concentración 50 Inhibidora , Liposomas/uso terapéutico , Simulación de Dinámica Molecular , Nanopartículas , Tamaño de la Partícula , Fosfolípidos , Retinoides/uso terapéuticoRESUMEN
The synthesis and biophysical characterization of four prodrug ether phospholipid conjugates are described. The lipids are prepared from the anticancer drug chlorambucil and have C16 and C18 ether chains with phosphatidylcholine or phosphatidylglycerol headgroups. All four prodrugs have the ability to form unilamellar liposomes (86-125 nm) and are hydrolyzed by phospholipase A(2), resulting in chlorambucil release. Liposomal formulations of prodrug lipids displayed cytotoxicity toward HT-29, MT-3, and ES-2 cancer cell lines in the presence of phospholipase A(2), with IC(50) values in the 8-36 microM range.