The synthesis of pyrido [2,3-d]pyrimidine nucleosides as potential antitumor agents.
Creators: name: Rizkalla, Boshra Hanna
Publisher: name: University of Utah
Year: 2012
Subjects: Tumors
Experimental Studies
Pharmacology

description: The antitumor activity shown by 2,4-dioxopyrido[2,3-d]pyrimidine (1), 4-oxopyrido[2,3-d]pyrimidine (2) and sangivamycin (17) stimulated the synthesis of the nucleoside derivatives, 2,4-dioxo-1-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (117), 4-oxo-1-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (120) and 2,4-dioxo-8-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (122), of compound 1 and 2.  The nucleoside derivative 4-amino-6-carboxamido-8-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (13) was synthesized as sangivamycin (17) homolog.  Other related nucleoside derivatives such as 6-carboxamido-2-methylthio-4,5-dioxo-9-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (126) and 4-amino-6-carboxamido-2-methylthio-5-oxo-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine were also synthesized.  Various N-methyl derivatives of compounds 1 and 2 were synthesized to be used as model compounds for assigning the position of alkylation with the sugar on compounds 1 and 2.  2,4-dioxo-8-methylpyrido[2,3-d]pyrimidine (96), 2,4-dioxo-3-methylpyrido[2,3-d]pyrimidine (97) and 3-methyl-4-oxo-pyrido[2,3-d]pyrimidine (99) were prepared by unambiguous methods.  2,4-dioxo-8-methylpyrido[2,3-d]pyrimidine (96) was prepared by condensing ethyl 2-amino-N-methylpyridinium nicotinate with potassium cyanate.  2,4-dioxo-3-methylpyrido[2,3-d]pyrimidine (97) was prepared by condensing methyl 2-aminoicotinate with methylisocyanate in pyridine.  Heating 2-aminoicotinic acid with N-methylformamide gave 4-oxo-3-methylpyrido[2,3-d]pyrimidine (99).  The 8-methyl derivative (98) was prepared by direct methylation of 2 with methyl iodide in dimethylsulfoxide solution.  The synthesis of various pyrido[2,3-d]pyrimidine derivatives having oxo- and carbethoxy groups at position 5 and 6 respectively was carried out.  The condensation of the appropriately substituted 6-aminopyrimidine with diethyl ethoxymethylene-malonate followed by thermal cyclization afforded, 4,5-dioxo-6-carbe-thoxy-2-methylthiopyrido[2,3-d]pyrimidine (19) and 4-amino-6-carbethoxy-2-methylthio-5-oxo pyrido[2,3-d]pyrimidine (113).  Compound 113 was only obtained after protection of the 4-amino group of the intermediate diethyl N-(4-amino-2-methylthio-6-pyrimidinyl)aminomethylenemalonate (110) by acetylation. De-blocking of the 4-acetamido-6-carbethoxy-2-methylthio-5-oxop pyrido[2,3-d]pyrimidine (112) with ethanolic sodium ethoxide gave 113.  The pmr signals of the 4-amino group protons in compound 113 showed a unique geminal coupling. It is of interest that thermal cyclization of diethyl N-(4-acetamido-6-pyrimidnyl)aminomethylenemalonate gave 8-acetamido-3-carbethoxy-4-oxo pyrido[2,3-d]pyrimidine (105) ass the only product. Alkylation of trimethylsilyloxy derivatives of 1 and 2 with 2,3,5-tri-O-benzoyl bromide led to 2,4-dioxo-1-(2, 3, 5 -tri-O-benzoyl-beta-D-ribofuranosoyl) pyrido[2,3-d]pyrimidine (116) and 4-oxo-1-(2, 3, 5 -tri-O-benzoyl-beta-D-ribofuranosoyl) pyrido[2,3-d]pyrimidine (119).  The 2,4-dioxo-8-(2, 3, 5 -tri-O-benzoyl-beta-D-ribofuranosoyl) pyrido[2,3-d]pyrimidine (121) was obtained by reaction 2,4-bis(trimethylsilyloxy)pyrido[2,3-d]pyrimidine with tetra-O-acetyl-beta-D-ribofuranose in chlorobenzene in the presence of a Fridel-Crafat catalyst (AICI3).  The nucleoside derivative 4,5-dioxo-6-carboxamido-2-methylthio-8-(beta-D-ribofuranosyl) pyrido[2,3-d]pyrimidine (126) was prepared by fusion of the trimethylsilyloxy derivative of 4,5-dioxo-6-carbethosy-2-methylthiopyrido pyrido[2,3-d]pyrimidine (19) with 1,2,-3,5-tetra-O-acetyl-beta-D-ribofuranose, followed by de-blocking with liquid ammonia.  Fusion of 112 with 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose gave 4-acetamido-6-carbethoxy-2-methyl-thio-8-(2, 3, 5 -tri-O-acetyl-beta-D-ribofuranosyl) pyrido[2,3-d]pyrimidine (127) which was transformed to 4-amino-6-carboxamido-2-methylthio-5-oxo-8-(beta-D-ribofuranosyl) pyrido[2,3-d]pyrimidine by the action of liquid ammonia.  Dethiation of 127 with Raney Nickel followed by treatment with liquid ammonia afforded the sangivamycin homolog 13.  The pmr and uv spectra of these compounds and others were discussed.