AMINOOXYLIPIDS FOR THE CONSTRUCTION OF SELF-ASSEMBLING LIPOSOMAL SYSTEMS ENABLING THEIR SUBSEQUENT MODIFICATION BY BIOLOGICALLY FUNCTIONAL MOLECULES

摘要

New aminooxylipids of general formula (I), wherein n1 = 5-30 and X is polymethylene linker of the general formula (II) where n2 = 2 -10, or X is polyethylene glycol linker of the general formula (III), wherein n3 = 1-14, are provided. A method of preparation of the aminooxylipids of general formula (I) characterized in that the acylation of N-tert-butoxycarbonyl-polymethylenediamine {(CH3)3C-0-(C=0)-HN-(CH2)n-N H2, n = 2 -13}, or N-tert- butoxycarbonyl-polyethyleglycoldiamine {(CH3)3C-0-(C=0)-HN-(CH2)2-[0-(CH2)]n-0-(CH2)2NH2, n = 1-14} with in position C(2) symmetrically branched fatty acids of general formula (IV), wherein n1 = 5-30, in the presence of condensation reagent, or from acid of general formula (IV) derived acylchloride of general formula (V) wherein n1 = 5-30, produces N-Boc-aminolipids of general formula (VI), wherein n1 = 5-30 a X is polymethylene linker of the general formula (II) or X is polyethylene glycol linker of the general formula (III). These are converted by debocylation to aminolipids of general formula (VII), wherein n1 = 5-30 and X is polymethylene linker of the general formula (II) or X is polyethylene glycol linker of the general formula (III). By their condensation with N-terf-butoxycarbonyl-aminooxyacetic acid in the presence of condensation reagent, N-Boc-aminooxylipids of general formula (VIII), where in n1 = 5- 30 and X is polymethylene linker of the general formula (II) or X is polyethylene glycol linker of the general formula (III), are obtained, which by debocylation afford aminooxylipids of general formula (I). Acylchlorides of general formula (V) are prepared by reaction of acid of general formula (IV) with oxalylchloride in the presence of catalytic amount of N, N-dimethylformamide in organic aprotic solvent. The use of nontoxic aminooxylipids of the general formula I for construction of nontoxic self-assembly liposomal carriers of therapeutics presenting aminooxy groups and so-called "post-liposomal" modification of these carriers with biologically functional molecules using oxime ligation technique (binding counterparts: aminooxy group and aldehyde or ketone group).