- 1-Alkylcarbonyloxymethyl prodrugs of 5-fluorouracil (5-FU): Synthesis, physicochemical properties, and topical delivery of 5-FU
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1-Alkylcarbonyloxymethyl (1-ACOM) prodrugs of 5-fluorouracil (5-FU) have been synthesized and characterized by their solubilities in isopropyl myristate (S(IPM)) and pH 4.0 buffer (S(H2O)), by their partition coefficients between isopropyl myristate (IPM) and pH 4.0 buffer (K) and by their abilities to deliver total 5-FU species into (C(s)) and through (J(l)) hairless mouse skin from an IPM vehicle. All of the prodrugs were much more lipophilic (S(IPM)) than 5-FU (>60 times), and two memberS of the series (alkyl = C1 and C2, acelyl- and propionyloxymethyl) were also more soluble in water than 5-FU. The two more water-soluble members gave larger J(l) values than the other members of the series, with C2 exhibiting the best biphasic solubility and the largest J(l) value (16 times that of 5-FU). The ability of the 1-ACOM-5-FU prodrugs to deliver total 5-FU species into skin (C(s)) was greater than the delivery of 5-FU by 5-FU, except for the last two members of series (alkyl = C7 and C9, octanoyl- and decanoyl-oxymethyl). However, the ratios of normalized C(s) to J(l) for the series was less than that exhibited by 5-FU, except for C7 and C9. Also, except for C9, significant amounts of intact prodrug as percentages of total 5-FU species were found in the receptor phases during the course of the diffusion cell experiments, ranging from 55% for C1 to 12% for C7.
- Taylor, H. Elizabeth,Sloan, Kenneth B.
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- NOVEL DERIVATIVES OF CHEMOTHERAPEUTIC AGENTS AND USES THEREOF
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Novel conjugates of chemotherapeutic agents, which are designed so as to release formaldehyde or analogs thereof upon cleavage, processes of preparing same, pharmaceutical compositions containing same and methods utilizing same for treating medical conditions such as cancer, immune-mediated diseases, viral infections and diseases, bacterial infections and diseases, fungal infections and diseases, protozal infections and diseases and more, and particularly for treating such conditions which are characterized by drug resistance are provided.
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(2010/02/15)
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- Uracil derivatives
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New uracil derivatives of the general formula: STR1 wherein R1 stands for a hydrogen atom or a grouping of the formula: STR2 R2 for a hydrogen atom, an alkyl group or a phenyl group and R3 for an alkyl group or a phenyl group, with the proviso that when both R1 and R2 stand for a hydrogen atom, R3 stands for a phenyl group or a straight chain alkyl group with 3?11 carbon atoms, that when R1 stands for a hydrogen atom and R2 for methyl group, R3 stands for an alkyl group with at least 2 carbon atoms or a phenyl group, and that when R1 stands for a hydrogen atom and R3 for methyl group, R2 stands for an alkyl group with at least 2 carbon atoms or a phenyl group. These uracil derivatives are prepared by reacting 5-fluorouracil with an α-haloalkyl carboxylate or with an aldehyde diacylate or by hydrolyzing a 1,3-bis(acyloxymethyl)-5-fluorouracil with an acid or alkali. These uracil derivatives are useful as improved anti-tumor agents especially for oral administration and injection.
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