Синтезирован аналог соматостатина, обладающий гормональной и противоопухолевой активностью. Разработан оптимальный метод синтеза, позволяющий получать стандартную фармацевтическую субстанцию аналога соматостатина для доклинических и клинических исследований. Разработаны методики контроля качества, которые будут включены в проект ФСП на фармацевтическую субстанцию аналога соматостатина.
Разработана методика спектрофотометрического количественного определения тиосенса в новой лиофилизированной липосомальной лекарственной форме, содержащей лецитин - холестерин - PEG-2000-DSPE в молярном соотношении 1/0,22/0,002 и раствор сахарозы в качестве криопротектора в соотношении лецитин - криопротектор 1/2. Оценено влияние вспомогательных веществ на результаты анализа и соблюдение закона Бугера - Ламберта - Бера.
A synthesis of 3-(1H-3-indolyl)-4-(1-glycosyl-3-indolyl)furan-2,5-diones and -1H-pyrrole-2,5-diones modified with the residues of D-ribo-, D-xylo-, L-arabino-, D-galactopyranose, and D-lactose was described. Influence of the compounds prepared on DNA biosynthesis in CaOv cells was studied.
The reaction of 5'-amino-2',5'-dideoxyuridine and 5'-amino-5'-deoxy-2',3'-O-ethoxymethyliden-6- azauridine with 3-(3-indolyl)propionic or 1-nitroanthraquinon-2-carboxylic acids in THF in the presence of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) resulted in the corresponding amide derivatives. The reaction conditions of the standard procedure for the removal of the O-alkylidene protecting group turned out to be too severe for the 5'-N-acylamide derivatives of 6-azauridine. 5'-Deoxy-5'-[3-(3-indolyl)propionyl-amino]-6-azauridine was synthesized from 5'-amino-5'-deoxy-6-azauridine and 3-(3-indolyl)propionic acid in THF in the presence of EEDQ. A reaction between 5'-O-tosyl-2',3'-O-ethoxymethyliden-6-azauridine and 3-aminopropanol gave 3-(3-hydroxypropylamino)-2-(2',3'-O-ethoxymethylidene-beta- D-ribofuranosyl)-as-triazine-5(2H)-one, the structure of which was confirmed also by synthesis from O2,5'-anhydronucleoside and 3-aminopropanol followed by further chemical transformations. A reaction of 3-(3-hydroxypropylamino) derivative obtained with nicotinoyl chloride prepared in situ, or with 1-nirtoanthraquinon-2-carboxylic acid in the presence of DCC with subsequent deprotection, afforded 3-[(3-pyridin-3-ylcarboxy)propylamino]- or 3-[3-(1-nitroanthraquinon-2-carboxy)propylamino]-2-beta-D-ribof ura nosyl-as- triazine-5(2H)-one, respectively. Structures of the nucleosides prepared were examined by 1H NMR spectroscopy. 2',5'-Dideoxy-5'-[(1-nitroanthraquinon-2-carbonyl)amino]uridine at a 10(-4) M concentration was shown to inhibit thymidine incorporation into cell DNA (CE50 10(-5) M) by 72%.
The interaction of 3'-amino-2',3'-dideoxy- or 5'-amino-2',5'-dideoxy-5-substituted pyrimidine nucleosides with N-ethylmaleimide in DMF in the presence of Et3N gave two diastereomeric 2',3'-dideoxy-3'-(N-ethylsuccinimido)- or 2',5'-dideoxy-5'-(N-ethylsuccinimido)aminonucleosides in each reaction. For 3'-amino-5-trimethylsilyl- and 3'-amino-5-benzyloxymethyl-2',5'-dideoxyuridine diastereomeric 3'-(N-ethylsuccinimido)derivatives were separated by preparative TLC. Structures of synthesized analogs were confirmed by UV-, IR- and 1H-NMR spectra. It has been shown that modified nucleosides at 10(-5)-10(-4) M concentrations do not inhibit the thymidine incorporation into DNA of CaOv cells in vitro.