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Novel bivalent twin-drug type hydantoin derivatives were evaluated in vitro using a human brain glioma cell line (U251) and a human carcinoma cell line (KB3-1). Among the 5-substituted hydantoin derivatives (1a-b and 2a-d) examined in this study, bivalent symmetrical 5-substituted hydantoin derivative 1b showed the highest anti-proliferative activity towards both U251 and KB3-1 cells. The values of anti-proliferative activity (IC50) of this hydantoin derivative against the two cell lines (U251 and KB3-1) were 0.46 and 5.21 µM, respectively. The anti-proliferative activity of all of the compounds except for compounds 2a and 2d against U251 cells was higher than that of cisplatin. Bivalent symmetrical compound 1b had a biphenylmethane linker in the molecule. All of the tested bivalent hydantoin derivatives showed higher activity against U251 cells than against KB3-1 cells. For twin-drug type hydantoin derivatives 2a-d, which have a linear methylene linker in the molecules, it was found that methylene linker length in these molecules have an effect on the anti-proliferative activity against U251 and KB3-1 cells.

In connection with our studies on hydantoin derivatives, a conventional regioselective chemical transformation of 5-methylene hydantoins 4a-c to 5-aminomethyl-substituted hydantoins 5-10 or to 5-amino-5-methyl-disubstituted hydantoins 11-14 is described. Synthesis of bivalent twin-drug type hydantoin derivatives 19-24 and the binding property of a bivalent symmetrical hydantoin derivative 24b to sulfated glycosaminoglycans are also described.

An efficient procedure for the preparation of 5-dialkylaminomethylhydantoins 3, which are easily obtained from cyclization of the corresponding urea derivatives 2 starting with beta-aminoalanines 1, is described. Methylenehydantoin and the corresponding 2-thio analogue (4a, 4b) were obtained from hydantoins 3a and 3b, respectively. Some new chemical properties of these hydantoin derivatives are reported.

Novel benzamide derivatives, N-[1-(aminocarbonyl)-2-(1-piperidinyl)ethyl]benzamides (4 and 5), were prepared from the reaction of beta-piperidinoalanine (6) as the starting material.

In connection with our studies on antibacterial compounds in the class of 5-dialkylaminomethylhydantoins against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains, some molecular modifications were attempted. The antibacterial activities of all of the synthesized hydantoin derivatives were evaluated. Among the hydantoin derivatives designed in this study, C₂-symmetrical twin-drug type compound (7) showed the highest level of antibacterial activity against S. aureus strain.

To find new antibacterial leads in the class of hydantoin derivatives, we carried out synthetic investigation and biological evaluation of the title hydantoin derivatives and related compounds. Among the hydantoin derivatives described in this article, compound 3o, in which a 2,6-dichlorophenyl ring was introduced at the N-3 position of the hydantoin nucleus, showed the highest levels of antibacterial activity against both Escherichia coli NBRC14237 (NIHJ) and Staphylococcus aureus ATCC6538P (gram-negative and gram-positive bacteria, respectively) strains.

The reductions of an α, β-unsaturated lactone (5) and lactam (7) with the Ni2+/BH-4 system resulted in the formation of cis-hydrogenated products (8a and 9a) with high stereoselectivity. The cis products (8a and 9a) were easily isomerized to the corresponding trans isomers (8b and 9b, respectively) by refluxing with sodium methoxide in anhydrous methanol. Isotope labeling studies with methyl cinnamate as the substrate indicated that the reduction with this reducing system poceeds stepwise via a carbon-nickel intermediate.

The preparation of amide derivatives (4) by N-acylation of unprotected alpha-amino acids is easily achieved via readily available benzotriazolyl carboxylates (2a-d) or succinimidyl carboxylates (2e-f). These intermediates (2) are prepared from reaction of carboxylic acids (1) with 1-hydroxybenzotriazole (HO-Bt) or N-hydroxysuccinimide (HO-Su) in the presence of equimolar amounts of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSCI). The overall yields of the target compounds (4) were excellent, and this two-stage procedure could be applicable as an alternative procedure for one-pot reaction.

The closure by cyclization with diethyl carbonate (EtO)(2)CO from aminoalcohols 1 as starting material can lead to the oxazolidinones 2a, b and 2c, respectively. In the reaction of trans-isomer (6) and (EtO)(2)CO, isolated products were also only 5-membered oxazolidinone derivative (7), containing its dehydrated derivative 8. The preferential formation of the 5-membered oxazolidinone ring system apparently indicated that this process (5-Exo-Trig ring closure) is more favorable than that of 6- or 7-membered ring derivative (3 or 9) by 6- or 7-Exo-Trig ring closure.

Preparation of β-(sec-amino)alanines (3) by acid hydrolysis of diethyl (sec-aminomethyl)formamidomalonates (2) was studied. Although high reaction temperature resulted in low yield, low reaction temperature (below 30°C) gave good to excellent yields. The hydrolysis of diethyl formamido(piperidinomethyl)malonate (2a) was followed by 1H-NMR, and a plausible mechanism involving the condensation of ethyl hydrogen aminomalonate (7) with 1-piperidinemethanol (5) is proposed.

A conventional new route to the novel oxazolidin-2-one derivatives (3a-f) having two substituents on N-3 and C-4 in the oxazolidin-2-one ring was established with racemic beta-aminoalanine derivatives (1) as the key starting materials.