• Archives of Pharmacal Research
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• v.21 no.4
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• pp.452-457
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• 1998

Three compounds, 5-(acetoxymethyl)-5-(hydroxymethyl)-3-tetradecyl-2,5-dihydro-2-furanone (3), 5-(acetoxymethyl)-5-(hydroxymethyl)-3,3-dihexyltetrahydro-2-furanone (4) and 5-(acetoxymethyl)-5-(hydroxymethyl)-3,3-dioctyltetrahydro-2-furanone (5), were designed and synthesized as surrogates of the ultrapotent DAG analogue, 5-(acetoxymethyl)-5-(hydroxymethyl) 3-[(Z)-tetradecylideneltetrahydro-2-furanone (1), a compound that showed high affinity for PKC-$\alpha$ ($K_1$=35 nM) in a competition binding assay with [$^3H$-20]phorbol-12,13-dibutyrate (PDBU). In an attempt to overcome the problem of generating geometrical E- and Z- isomers, as encountered with 1, the double bond was moved to an endocyclic location as in 3, or an additional alkyl chain was appended to C3 to give the corresponding 3,3-dialkyl saturated lactones (4 and 5). The lactone was constructed from glycidyl-4-methoxyphenyl ether in 5 steps. The target compounds showed reduced binding affinities for PKC-.alpha. with $K_{i}$ values of 192 nM (3), 4,829 nM (4), and 2,812 nM (5), respectively. These results indicate that constrained DAG analogues having a tetrahydro-2-furanone template are effectively discriminated by PKC-(X in terms of the direction of the long alkyl chain connected to the 3-position.n.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.175.4-176
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• 2003

Our long-term research goals involve the SARs study and the synthetic procedure development of wogonin and its analogs. We investigated efficient synthetic pathways of wogonin and its bioisosteres in a large quantity to decipher the structural requirements for anti-inflammatory activities. We plan to serially delete or modify the 5,7-dihydroxyl groups of wogonin to observe the effects of the hydroxyl groups on anti-inflammatory activity. Also we modofied the 8- methoxy group on a ring since it is known to be necessary for biological activity. (omitted)

• Bulletin of the Korean Chemical Society
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• v.25 no.2
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• pp.207-212
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• 2004

In this study, we attempted to prepare compounds with heterocyclic replacements for metabolically unstable esters of benzopyranyl indole-2-carboxylic esters, which showed good in vitro and in vivo cardioprotective efficacies possibly through the opening of mitochondrial ATP-sensitive potassium channel ($K_{ATP}$). Initially, we tried to construct indolin-2-yl-heterocycles using unprotected indoline-2-carboxylic acid, but the cyclization was proceeded with oxidation of the indoline ring to the indole, which didn't react with benzopyranyl epoxide. Thus we introduced N-Boc group to deplete the electron density of the indoline ring. We successfully prepared various indolin-2-yl-heterocycles by the cyclization of the building blocks including carboxamide, ${\beta}$-hydroxy amide, hydrazide, nitrile starting from N-Boc-indoline-2-carboxylic acid.

• Archives of Pharmacal Research
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• v.21 no.2
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• pp.193-197
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• 1998

A number of substituted isoquinolin-1-ones, possible bioisosteres of the 5-aryl substituted 2,3-dihydroimidazo[2,$1-a$]isoquinolines, were synthesized and tested for their antitumor activity against five different human tumor cell lines. O-(3-hydroxyporpyl) substituted compound (15) exhibited the best antitumor activity which is 3-5 times better than 5-[$4^1$-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,$1-a$]isoquinoline (1).

• Archives of Pharmacal Research
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• v.23 no.4
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• pp.283-287
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• 2000

A series of 2-(1-hydroxyiminoalkyl)-1,4-dimethoxy-9,10-anthraquinones (oximes) was synthesized and evaluated for cytotoxicity against L1210 cells and A549 cells. These oximes showed a greater cytotoxic activity compared to those of 2-(1-hyd roxyalkyl)-1,4-dimethoxy-9,10-anthraquinones as the hydroxyalkyl bioisosteres. The enhanced cytotoxiciy assumed to be due to the improved water solubility of the hydroxyimino group. Moreover, it was found that the cytotoxicity of the oximes decreased with elongation of alkyl groups at the side chain. All of the synthesized compounds showed higher cytotoxicity against L1210 cells than A549 cells.

• Archives of Pharmacal Research
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• v.24 no.4
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• pp.270-275
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• 2001

Bioisostere approach has been shown to be useful to augment potency or to modify certain physiological properties of a lead compound. Based upon well documented bioisosterism, an isosteric replacement of benzene ring of 4-hydroxy-2-quinolone compound (L-695902) with a thiophene moiety was carried out to prepare the title compounds, 4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b] pyrimidines 15. The resulting bioisosteric compounds 15 were evaluated for their antagonistic activity (birding assay) for NMDA receptor glycine site.

• Bulletin of the Korean Chemical Society
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• v.18 no.9
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• pp.939-945
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• 1997

Several types of 4-substituted-quinoline-2-carboxylic acid derivatives possessing different substituents at C4-position such as sulfonyl, phosphonyl, carbonyl groups, or a flexible alkyl chain have been synthesized and evaluated for their in vitro antagonistic activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Of them, 5,7-dichloro-4-(tolylsulfonylamino)-quinoline-2-carboxylic acid 9 was found to have the best in vitro binding affinity with IC50 of 0.57 μM. On the other hand, in compounds 21 and 22 the introduction of flexible alkyl chains on C4 of the quinoline mother nuclei caused a significant decrease of the in vitro binding affinity. In addition, replacement of polar carboxylic acid group on C2 by neutral bioisosteres in compounds 23a-d also seems to be disadvantageous to in vitro activity. In the structure-activity relationship (SAR) study of the 4-substituted quinoline-2-carboxylic acid acid derivatives, it was realized that the substitution pattern on C4 significantly influences on the binding affinity for the glycine site of NMDA receptor and the binding affinity might be increased by the introduction of a suitable electron rich substituent at C4 which has the ability of H-bonding donor.

• Archives of Pharmacal Research
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• v.22 no.2
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• pp.179-183
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• 1999

3-Arylisoquinolin-1(2H)-ones (2) are possible bioisosteres of the $5-[4^{l}-(piperidinomethyl)phenyl]-2<$,3-dihydroimidazo[2,1-$\alpha$]isoquinoline (1) which is in clinical evaluation for the treatment of cancer. Structure-activity relationship studies of 3-arylisoquinolin-1(2H)-ones. (2) led to the synthesis of 3-arylquinolin-2(1H)-ones (3). A number of 3-phenyl substituted quinolin-2(1H)-ones were synthesized and tested for their in vitro antitumor activity against four different human tumor cell lines and 3-phenyl-N-benzyl-3,4-dihydroquinolin-2(1H)-one (12) showed the most potent activity.