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KMID : 0043319950180060449
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Archives of Pharmacal Research
1995 Volume.18 No. 6 p.449 ~ p.453
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Synthesis of a series of cis-diamminaedichloro-platinum (II) Complexes Linked to Uracil and Uridine as Candidate An-titumor Agents
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Kim Jack-C.
Kim Mi-Hyang
Kim Seon-Hee
Choi Soon-Kyu
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Abstract
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The search for patinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichlorplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are ; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II)(3a), [N-2(2-aminoethyl)uracil-6-carboxmide]dichloroplatinum (II) (3b),[5-(2-aminorthyl)carbamoyl-2’,3’,5’,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)-carbamoyl]-2’,3’,5’,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoylu-ridine]dihloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxmide (2a) land N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes 3a and 3b were obtained through the reaction of the respective 2a and 2b ficiently introduced on the .betha.-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitfile to yield the sterospecific .betha.-anomeric 5-carboxy-2’,3’,5’-tri-O-acetyluridine (4a) and 6-carboxy-2’,3’,5’-tri-O-acetyluridine (4b), respective 5-(2-aminoethyl)carbamoyl-2’,3’,5’-tri-O-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2’,3’,5’-tri-O-acetyluridine (5b). The diamino-uridines 5a and 5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes, 6a and 6b respectively which were deacetylated into the free nucleosides, 7a and 7b by the treatment with CH/sub 3/ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).
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KEYWORD
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s-DiamminedichlOrplatinum (II), [N-(2-AminOethyl)uracil-S-carbOxamideJdichlOrOplatinum (II), [N-(2-AminOethyl)uracil-6-carbOxamideJdichlOrOplatinum (II), [5-(2-AminOethyl) carbamOyl-2’, 3’, 5’-tri-O-acetyluridineJ dichlOrOplatinum (II), [6-(2-AminOethyl)carbamOyl-2’, 3’, 5’-tri-O-acetyluridine] dichlOrOplatinum (11), [5-(2-AminOethyl)carbamOyl uridineJdichlOrOplatinum (II), [6-(2-AminOethyl)carbamOyl uridineJdichlOrOplatinum (II) (3-anOmeric S-carbOxy-2’, 3’, 5’-tri-O-acetylurid i ne, 6-carbOxy-2’, 3’, 5’-tri-O-acetylurid i ne, S-(2-AminOethyl)carbamOyl-2’, 3’, 5’tri-O-acetyluridine, 6-(2-AminOethyl)carbamOyl-2’, 3’, 5’-tri-O-acetyl)urid i ne, antitumOr activities, Human chrOnic myelOgenOus leukemia cell (K562), MOuse lymphOid neOplasma cell (P-388), MOuse mammary carcinOma cell (FM-3A)
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