.ALPHA.-Glucosidase Inhibitors with a 4,5,6,7-Tetrachlorophthalimide Skeleton Pendanted with a Cycloalkyl or Dicarba-closo-dodecaborane Group.

Sou, Sonei; Takahashi, Hiroyasu; Yamasaki, Ryu; Kagechika, Hiroyuki; Endo, Yasuyuki; Hashimoto, Yuichi

doi:10.1248/cpb.49.791

Cited by 51 publications

(20 citation statements)

References 28 publications

(38 reference statements)

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“…[16][17][18] PPS-33 (6) is another competitive a-glucosidase inhibitor, but it also inhibits other enzymes, including maltase and dipeptidylpeptidase type IV.…”

Section: )mentioning

confidence: 99%

“…[11][12][13][14][15][16][17][18] CP0P (4) is a non-competitive inhibitor of a-glucosidase, whereas CP4P (5) is a competitive inhibitor. [16][17][18] PPS-33 (6) is another competitive a-glucosidase inhibitor, but it also inhibits other enzymes, including maltase and dipeptidylpeptidase type IV. 19) The competitive inhibition of a-glucosidase by CP4P (5) and PPS-33 (6) indicated that these compounds might be structural mimics of glucose.…”

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confidence: 99%

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Structural Development of Liver X Receptor (LXR) Antagonists Derived from Thalidomide-Related Glucosidase Inhibitors

Noguchi‐Yachide

Miyachi

Aoyama

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Nuclear receptors (NRs) are ligand-dependent transcription factors which regulate the expression of responsive genes and thereby affect diverse processes, including cell growth, development, differentiation and metabolism. 1)Based on the elucidated human genome sequence, 48 NRs are thought to exist in humans.1) NRs are divided into four subfamilies, including (1) classical steroid hormone receptors, (2) retinoid/vitamin D 3 /thyroid hormone receptors, (3) metabolic receptors, and (4) 1) The LXRs are members of the metabolic receptor subfamily of the NR superfamily, and consist of two subtypes, LXRa and LXRb. The physiological ligands of LXRs are considered to be oxysterols, such as 24(S),25-epoxycholesterol (1, EPC), [1][2][3] and several synthetic agonists, including GW3965 (2) and T0901317 (3), have been reported (Fig. 1). 4,5) LXRs function as heterodimers with other nuclear receptors, the retinoid X receptors (RXRa, RXRb and RXRg), to regulate important aspects of cholesterol homeostasis by controlling expression of their target genes, including ATP binding cassette ABCA1 and CYP7A genes. We have been engaged in structural development studies of thalidomide, a drug first launched as a sedative/hypnotic agent, but withdrawn from the market because of its severe teratogenicity, focusing on its potential for the treatment of a range of diseases, including cancers, diabetes, and rheumatoid arthritis. [11][12][13][14][15] We have developed a series of potent aglucosidase inhibitors, including CP0P (4), CP4P (5) and PPS-33 (6) (Fig. 2).11-18) CP0P (4) is a non-competitive inhibitor of a-glucosidase, whereas CP4P (5) is a competitive inhibitor. [16][17][18] PPS-33 (6) is another competitive a-glucosidase inhibitor, but it also inhibits other enzymes, including maltase and dipeptidylpeptidase type IV.19) The competitive inhibition of a-glucosidase by CP4P (5) and PPS-33 (6) indicated that these compounds might be structural mimics of glucose. On this basis, we found that CP4P (5) and PPS-33 (6) act as antagonists for LXRs. 20) Our former structural development studies based on CP4P (5) suggested that 2Ј-hydrophobic substituents enhance the LXR antagonistic activity of the compounds, and PP2P (7) and PP-60 (8) have been reported to be moderate LXR antagonists. 20) In this paper, we describe the structure-activity relationship of the 2Ј-alkyl group and further structural development of LXR antagonists based on the N-2Ј-alkylphenylphthalimide skeleton. Following our previous discovery of LXR antagonistic activity of 2-substituted phenylphthalimides derived from thalidomide-related glucosidase inhibitors, structure-activity studies and further structural development led to 5-chloro-N-2-n-pentylphenyl-1,3-dithiophthalimide (5CPPSS-50), with IC 50 values of about 10 and 13 m mM for LXRa a and LXRb b, respectively.

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“…[16][17][18] PPS-33 (6) is another competitive a-glucosidase inhibitor, but it also inhibits other enzymes, including maltase and dipeptidylpeptidase type IV.…”

Section: )mentioning

confidence: 99%

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confidence: 99%

Structural Development of Liver X Receptor (LXR) Antagonists Derived from Thalidomide-Related Glucosidase Inhibitors

Noguchi‐Yachide

Miyachi

Aoyama

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…This structural 'similarity,' together with the aforementioned studies on hydroxyflavones and biological efficacy of xanthones enforced many scientists to isolate or synthesize appropriately modified derivatives for the development of prospective new drug candidates. [10][11][12] Isoeuxanthone (Fig. 1b) is one of well-known xanthone derivatives which have diverse biological profiles.…”

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confidence: 99%

Antitumor Activity and DNA-Binding Investigations of the Zn(II) and Cu(II) Complexes with Isoeuxanthone

Wang

Shen

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Recently, more and more attention has been paid to xanthones that are widely present as a class of secondary metabolites in some higher plants and microorganisms. [1][2][3] These naturally occurring compounds and their synthetic analogs have been reported to exhibit multiple important pharmacological properties, such as anti-oxidant, anti-inflammatory, anti-malarial and anti-cancer activity, etc. [4][5][6][7][8][9] As shown in Fig. 1a, xanthones having three linear fused aromatic rings may be viewed as flavone derivatives in which the phenyl group is fused with the two aromatic rings. This structural 'similarity,' together with the aforementioned studies on hydroxyflavones and biological efficacy of xanthones enforced many scientists to isolate or synthesize appropriately modified derivatives for the development of prospective new drug candidates.10-12) Isoeuxanthone (Fig. 1b) is one of well-known xanthone derivatives which have diverse biological profiles.Since DNA is an important cellular receptor, many chemicals exert their antitumor effects to DNA thereby changing the replication of DNA and inhibiting the growth of the tumor cell, which is the basis of designing new and more efficient antitcancer drugs and their effectiveness depends on the mode and affinity of the binding.13) Similarly, interactions of metallic antitumor reagents with DNA are also very important in understanding the mechanisms of their antitumor activities.14,15) We were thus motivated to investigate metallic complexes of isoeuxanthone on their binding modes and affinities to DNA. Therefore, in this context, we report the synthesis and characterization of the mononuclear Zn(II) complex (1) and Cu(II) complex (2) with isoeuxanthone. The interactions of them with calf thymus (ct DNA) have also been studied by absorption spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy and viscosity measurements. In addition, they were evaluated for their cytotoxic activities toward human esophageal cancer (ECA109) and human gastric cancer (SGC7901) cells by microculture tetrazolium (MTT) method. ExperimentalMaterials The ligand HL (isoeuxanthone, namely 1,6-dihydroxyxanthone) was prepared according to the literature 16) with some improvement. All the chemicals were reagent grade and were used without further purification. Calf thymus DNA (ct DNA) and ethidium bromide (EB) were obtained from Sigma Chemical Co. All the measurements involving the interactions of the two complexes with ct DNA were carried out in doubly distilled water buffer containing 5 mM Tris[Tris(hydroxymethyl)-aminomethane] and 50 mM NaCl, and adjusted to pH 7.1 with hydrochloric acid. UV-Vis spectrometer was employed to check a solution of ct DNA purity (A 260 : A 280 Ͼ1.80) and the concentration (eϭ6600 M Ϫ1 cm Ϫ1 at 260 nm) in the buffer. 17,18)Physical Measurements Elemental analyses were conducted using an Elementar Vario EL elemental analyzer. The metal contents of the complexes were determined by titration with EDTA (ethylenediamine tetraacetic acid). Infrared ...

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“…They are responsible for catalyzing the final step in the digestive process of carbohydrate metabolism. α-Glucosidases are the key enzymes that hydrolyze O-and S-glycosyl residues, are involved in the biosynthesis and processing of oligosaccharide chains of Nlinked glycoproteins in the endoplasmic reticulum (ER) [2]. The most extensively studied are α and β-glucosidases that are known to catalyze the hydrolysis of glycosidic bonds involving a terminal glucose at the cleavage site through α-and β-linkages at the anomeric centre [3].…”

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Synthesis, characterization and in vitro evaluation of some new 5-benzylidene-1,3-thiazolidine-2,4-dione analogs as new class of α-glucosidase inhibitors

et al. 2014

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.ALPHA.-Glucosidase Inhibitors with a 4,5,6,7-Tetrachlorophthalimide Skeleton Pendanted with a Cycloalkyl or Dicarba-closo-dodecaborane Group.

Cited by 51 publications

References 28 publications

Structural Development of Liver X Receptor (LXR) Antagonists Derived from Thalidomide-Related Glucosidase Inhibitors

Structural Development of Liver X Receptor (LXR) Antagonists Derived from Thalidomide-Related Glucosidase Inhibitors

Antitumor Activity and DNA-Binding Investigations of the Zn(II) and Cu(II) Complexes with Isoeuxanthone

Synthesis, characterization and in vitro evaluation of some new 5-benzylidene-1,3-thiazolidine-2,4-dione analogs as new class of α-glucosidase inhibitors

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