Jung-Hyuck Cho

Low convulsive activity of a new carbapenem antibiotic, DK-35C, as compared with existing congeners

Since carbapenems and cephalosporins have been suggested to induce convulsive side effects through an inhibitory action on the central gamma-aminobutyric acid (GABA)-mediated inhibitory transmission, the present study evaluated the convulsive activity of a new carbapenem antibiotic (1R,5S,6S)-6[(R)-1-hydroxyethyl]-2-[(3S,5S)-5(S-methyl-4thiomorpholin ylcarbonyl)pyrrolidin-3-thio]-l-methylcarbapen-2-em-3- carboxylic acid (DK-35C) in in vitro and in vivo experiments, in comparison with cefazolin, imipenem and meropenem. In in vitro experiments, their abilities to inhibit [3H]muscimol (5 nM) binding to GABA(A) receptors were measured using crude synaptic membranes prepared from the rat cerebral cortex. The concentrations (mM) of the antibiotics which inhibit 50% of the specific binding, were 0.6 for imipenem, 1.8 for cefazolin, 15.4 for DK-35C and 27.6 for meropenem. In in vivo experiments, intracerebroventricular (i.c.v.) injections of cefazolin, imipenem and DK-35C induced convulsions in a dose-dependent manner in rats. The doses (nmol/rat) of the antibiotics which induce convulsions in 50% of rats, were 57 for imipenem, 96 for cefazolin, 377 for DK-35C and >3000 for meropenem. In the mouse pentylenetetrazole (PTZ) convulsive model, intravenous pretreatment with cefazolin (800 mg/kg) or imipenem (200 mg/kg) shifted the dose-response curve of PTZ (i.p.) to the left, indicating enhancement of the convulsive activity of PTZ. However, pretreatment with cefazolin, meropenem or DK-35C at a dose of 400 mg/kg did not produce any marked effects on the convulsive activity of PTZ compared with the saline vehicle-pretreated control. The results clearly demonstrate a good correlation between in vitro GABA(A) receptor binding assay and in vivo i.c.v. convulsive model using rats, and suggest that DK-35C may possess a relatively weak convulsive activity mediated through an interaction with GABA(A) receptors.

Synthesis and antibacterial activities of novel oxazolidinones having cyclic sulfonamide moieties

The synthesis of a new series of oxazolidinones having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the oxazolidinone ring was investigated. A particular compound 15g having [1,2,5]thiadiazolidin-1,1-dioxide moiety showed the most potent antibacterial activity.

Synthesis and antibacterial activities of novel oxazolidinones having spiro[2,4]heptane moieties.

The synthesis of a new series of oxazolidinones having spiro[2,4]heptane moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the oxazolidinone ring was investigated. A particular compound Ih having fluoro group showed the most potent antibacterial activity.

Stereocontrolled synthesis of novel 6′(α)-hydroxy carbovir analogues

Abstract This paper describes the racemic and stereoselective synthetic route for a novel 6′(α)-hydroxy-carbovir from a simple acyclic precursor, Solketal. The relative stereochemistry of the target nucleosides was successfully controlled by a sequential stereoselective glycolate Claisen rearrangement followed by a ring-closing metathesis (RCM). Adenine and cytosine were coupled using a Pd(0) catalyzed allylic alkylation strategy in a high regio- and stereoselective manner.

Synthesis and biological activities of C-2, N-9 substituted 6-benzylaminopurine derivatives as cyclin-dependent kinase inhibitor.

In this study, C‐2, N‐9 substituted 6‐benzylaminopurine derivatives were synthesized and their inhibitory effects on cyclin‐dependent kinase (CDK2) were evaluated. The effect of substituents at the C‐2 and N‐9 positions of substituted purine was investigated. Among the compounds tested, compound 7b‐iii (6‐benzylamino‐2‐thiomorpholinyl‐9‐isopropylpurine) was the most active inhibitor (IC50 = 0.9 mM). Compound 7b‐iii showed 10‐fold higher activity compared to olomoucine and almost the same activity as roscovitine. Results from structure‐activity relationship studies should allow the design of more potent and selective CDK inhibitors, which may provide an effective therapy for cancer or other CDK dependent diseases.

Synthesis and Antibacterial Activity of 1β-Methylcarbapenems Having a 2, 2-disubstituted-1, 3-Diazabicyclo[3.3.0]octan-4-one Moiety and Related Compounds. Part III

The synthesis of new series of 1β‐methylcarbapenems having a 2, 2‐disubstituted‐1, 3‐diazabicyclo[3.3.0]octan‐ and ‐[4.3.0]nonan‐4‐one moiety is described.Their in vitro antibacterial activities against both Gram‐positive and Gram‐negative bacteria were tested and the effect of the substituent of the bicyclic ring was investigated. A particular compound (16 f) bearing a hydroxymethyl group showed the most potent antibacterial activity and the compound (17 a) with a 1, 3‐diazabicyclo[4.3.0]nonane moiety exhibited excellent stability against renal dehydropeptidase‐I (DHP‐I) to Meropenem.

Synthesis and antibacterial activity of 1β-methyl-2-(5-substituted thiazolidinopyrrolidin-3-ylthio)carbapenems and related compounds

The synthesis of a new series of 1β‐methylcarbapenems containing the substituted thiazolidinopyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram‐positive and Gram‐negative bacteria were tested and the effect of substituent on the thiazolidine ring was investigated.A particular compound (18 c) having a 2‐amide substituted thiazolidine moiety showed the most potent antibacterial activity.

Synthesis and biological properties of C‐2, C‐8, N‐9 substituted 6‐(3‐chloroanilino)‐purine derivatives as cyclin‐dependent kinase inhibitors. Part II

In this study, C‐2, C‐8, N‐9 substituted 6‐(3‐chloroanilino)purine derivatives were synthesized and their inhibitory effects on cyclin‐dependent kinases (CDK2, 4) as well as their cytotoxicities were evaluated. The effects of substituents at the C‐2, C‐8, and N‐9 positions of the substituted purine were investigated. Among the compounds tested, [6‐(3‐chloroanilino)‐2‐(2‐hydroxymethyl‐4‐hydroxypyrrolidyl)‐9‐isopropylpurine] (4h) was the most active inhibitor of CDK2 with IC50 of 0.3μM, i.e. a two‐fold increased inhibitory activity as compared to roscovitine. Results from structure‐activity relationship studies should allow the design of more potent and selective CDK2 inhibitors, which may provide an effective therapy for cancer or other CDK‐dependent diseases.

Synthesis and biological activity of 1β-methyl-2-[5-(2-N-substituted aminoethylcarbamoyl)pyrrolidin-3-ylthio]carbapenem derivatives

The synthesis of a new series of 1beta-methylcarbapenems having the substituted aminoethylcarbamoylpyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. In particular, the compound 11g having piperazinyl urea moiety showed the most potent antibacterial activity and 11k exhibited excellent anti-MRSA.

Synthesis of 1H‐Pyrazole‐1‐carboxamide Derivatives and Their Antiproliferative Activity against Melanoma Cell Line

Synthesis of a new series of 1H‐pyrazole‐1‐carboxamide derivatives is described. Their antiproliferative activity against A375 human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The pharmacological results indicated that most of the newly synthesized compounds showed moderate activity against A375, compared with sorafenib. Among all of these derivatives, compound IIe which has N‐methylpiperazinyl and phenolic moieties showed the most potent antiproliferative activity against A375 human melanoma cell line.