Soon-Kyu Choi

SYNTHESIS OF 2,4-DISUBSTITUTED NORTROPINONE DERIVATIVES BY ALDOL CONDENSATION

2,4-Disubstituted nortropinone derivatives 2, with anticipated anticonvulsant activity, were synthesized by the reaction of N-substituted nortropinones, ethanol, 5N-NaOH, and aromatic aldehydes (R1CHO).

Synthesis and antitumor evaluation ofcis-(1,2-diaminoethane) dichloroplatinum (II) complexes linked to 5- and 6-methyleneuracil and-uridine analogues

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diamine] dichloroplatinum (II) (3b), {[N-(2′,3′,5′-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamine}dichloroplatinum (II) (6a), {[N-(2′,3′,5′-tri-O-acetyl) uridine-6-yl-methyl]ethane-1,2-diamine}dichloroplatinum (II) (6b), [N-(uridine-5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl- methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)amino] methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatiate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4a) and 6-chloromethyl-2′,3′,5′-tri-O-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)amino]methyl-2′,3′,5′-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-2′,3′,5′-tri-O-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH3ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.

Potential antitumor α-methylene-γ-butyrolactone-bearing nucleic acid base. 3. Synthesis of 5′-Methyl-5′-[(6-substituted-9H-purin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans

Search for a new α-methylene-γ-butyrolactone-bearing 6-substituted purine as a potental antitumor agent has led to synthesize seven, hitherto unreported, 5′-Methyl-5′-[(6-substituted-9H-purin-9-yl)methyl]-2′-oxo-3′ methylenetetrahydrofurans (H, Cl, I, CH3, NH2, SH, >C=O) (6a-g). These include 5′-Methyl-5′-[(9H-purin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans (6a), 5′-Methyl-5′-[(6-chloro-9H-purin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans (6b), 5′-Methyl-5′-[(6-iodo-9H-purin-9-yl) methyl]-2′-oxo-3′-methylenetetrahydrofurans (6c), 5′-Methyl-5′-[(6-methyl-9H-purin-9-yl) methyl]-2′-oxo-3′-methylenetetrahydrofurans (6d), 5′-Methyl-5′-[(9H-adenin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans (6e), 5′-Methyl-5′-[(6-mercapto-9H-purin-9-yl) methyl]-2′-oxo-3′-methylenetetrahydrofurans (6f) and 5′-Methyl-5′-[(9H-hypoxanthin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofurans (6g) which were made by the Reformatsky-type reaction of ethyl α-(bromomethyl) acrylate with the corresponding (6-substituted-9H-purin-9-yl)-2-propanone intermediates (5a-g). These ketone intermediates5a-g, 1-(9H-purin-9-yl)-2-propanone (5a), 1-(6-chloro-9H-purin-9-yl)-2-propanone, (5b), 1-(6-iodo-9H-purin-9-yl)-2-propanone (5c), 1-(6-methyl-9H-purin-9-yl)-2-propanone (5d), 1-(9H-adenin-9-yl)-2-propanone (5e), 1-(6-mercapto-9H-purin-9-yl)-2-propanone (5f), and 1-(9H-hypoxanthin-9-yl)-2-propanone (5g) were directly obtained by the alkylation of the 6-substituted purine bases with the chloroacetone in the presence of K2CO3 (or NaH) under DMF (or DMSO). The preliminary in vitro cytotoxcity assay for the synthetic α-methylene-γ-butyro-lactone compounds (6a-g) were determined against three cell lines (PM-3A, P-388, and K-562) and showed the moderate antitumor activity (IC50 ranged from 1.4 to 4.3 μg/ml) with the compound 5′-methyl-5′-[(9H-hypoxanthin-9-yl)methyl]-2′-oxo-3′-methylenetetrahydrofuran (6g) showing the least antitumor activity.

Potential antitumor α-methylene-ψ-butyrolactone-bearing nucleic acid bases. 2. Synthesis of 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl]-2′-oxo-3′-methylenetetrahydrofurans

Ten, heretofore unreported, 5′-methyl-5′-[2-(5-substituted uracil-1-yl)ethyl)]-2′-oxo-3′-methylenetetrahydrofurans (H, F, Cl, Br, I, CH3, CH3, CH2CH3, CH=CH2, SePh) (7a-j) were synthesized and evaluated against four cell lines (K-562, FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone-linked to 5-substituted uracils (7a-j), the convenient Reformasky type reaction was employed which involves the treatment of ethyl α-(bromomethyl)acrylate and zinc with the respective 1-(5-substituted uracil-1-yl)-3-butanone (6a-j). The 5-substituted uracil ketones (6a-j) were directly obtained by the respective Michael type reaction of vinyl methyl ketone with the K2CO3 (or NaH)-treated 5-substituted uracils (5a-j) in the presence of acetic acid in the DMF solvent. The α-methylene-γ-butyrolactone compounds showing the most significant antitumor activity are7e, 7f, 7h and7j (inhibitory concentration (IC50) ranging from 0.69 to 2.9 μg/ml), while7b, 7g and7i have shown moderate to significant activity. The compounds7a, 7c and7d were found to be inactive. The synthetic intermediate compounds6a-j were also screened and found marginal to moderate activity where compounds6b and6g showed significant activity (IC50:0.4∼2.8 μg/ml).

Synthesis and antitumor evaluation of α-methylene-γ-butyrolactone-linked to 5-Substituted uracil nucleic acid bases

Six, heretofore undescribed, 5′-Methyl-5′-(5-Substituted uracil-1-ylmethyl)-2′-oxo-3′-methylenetetrahydrofurans (F, Cl, Br, I, CH3, H) (6a-f) were synthesized and evaluated against three cell lines (FM-3A, P-388 and U-937). For the preparation of α-methylene-γ-butyrolactone bearing 5-substituted uracils (6a-f), the efficient Reformatsky type reaction was employed which involves the treatment of ethyl α-(bromomethyl) acrylate and zinc with the respective 5-substituted uracil-1-ylacetones (5a-f). The acetone derivatives (5a-f) were directly obtained by the respective alkylation reaction of 5-substituted uracils with chloroacetone in the presence of K2CO3 (or NaH). These lactone compounds6a-f exhibited moderate to significant activity in all of the three cell lines, and6b, 6c and6e showed significant antitumor activities (inhibitory concentrations (IC50) ranged from 1.3–3.8 μg/ml).

Synthesis of a series ofcis-diamminedichloro-platinum (II) complexes linked to uracil and uridine as candidate antitumor agents

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichloroplatinum (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-aminoethyl)uracil-6-carboxamide]dichloroplatinum (II) (3b), [5-(2-aminoethyl)carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl) carbamoylu-carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoyluridine]dichloroplatinum (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-carboxamide (2a) and N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-carboxy-2′,3′,5′-tri-0-acetyluridine (4a) and 6-carboxy-2′,3′,5′-tri-0-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH3ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).

Synthesis and antitumor evaluation of acyclic 1-[ω-(N′-2-chloroethyl-N′-nitrosoureido)alkyl]thymidine nucleoside analogues

In the preparation of acyclic thymidine nucleoside analogues, K2CO3 (or NaH) treated thymine in DMSO was alkylated with ω-chloroalkyl nitrite (Cl-(CH2)n-CN; n=1, 2, 3, 4) to provide an isomeric mixture of 1-(ω-cyanoalkyl)thymine (2a-d) and 1,3-bis(ω-cyanoalkyl)thymine in approximately 5∶1 ratios. Reduction of the cyano function2a-d with NaBH4/CoCl2·6H2O gave the corresponding 1-(ω-aminoalkyl)thymine (3a-d). The newly formed primary amino function in3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[ω-(N′2-chloroethy-lureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-(N′-2-chloroethylureido)pentyl] thymine (4d) with glacial acetic acid and dry NaNO2 powder in anhydrous CH2Cl2 gave two types of regioisomeric nitrosoureas, 1-[5-(N′-2-chloroethyl-N′-nitrosoureido)pentyl]thymine (5d) and 1-[5-(N′-2-chloroethyl-N-nitrosoureido)pentyl]thymine in approximately 5∶1 ratios. The in vitro cytotoxicity of the synthesized compounds (2a-d, 3a-d, 4a-d and5a-d) against three cell lines (K-562, P-388 and FM-3A) are measured as IC50 values. Compounds3d and4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.

Synthesis andin vitro cytotoxicity of a homologous series of 5-halosubstituted 1,3-bis(ω-cyanoalkyl)uracil analogues

A homologous series of twenty, hitherto unreported, analogues of 5-halosubstituted 1,3-bis(ω-cyanoalkyl)uracil acyclic nucleosides were synthesized by the series of alkylation reactions of 5-halouracils with the corresponding chloroacetonitrile, chloropropionitrile, chlorobutyronitrile and 5-chlorovaleronitrile (Cl-(CH2)n-CN: n=1, 2, 3, 4) in anhydrous DMSO (or DMF)/K2CO3 (or NaH) under 75°C temperature. Antitumor activities for the synthesized compounds were determined against three cell lines (FM-3A cell, P-388 cell and U-938 cell lines). The compounds that exhibited moderate activity to significant activity, included1a-b, 2a-b, 3a-c, and4a, whose compounds were active against P-388, FM-3A and U-937 cell lines with the compounds1a, 1b, and2a, showing significant antitumor activity (inhibitory concentrations (IC50) ranged from 2.2 to 7.0 μg/ml). Their structure-activity relationship did not show any activity differences in their effective chain length (methyl, ethyl, propyl, butyl) in 1,3-bis(ω-cyanoalkyl) uracils.