Specific Nonpeptide Inhibitors of Puromycin-Sensitive Aminopeptidase with a 2,4(1H,3H)-Quinazolinedione Skeleton

Kakuta, Hiroki; Tanatani, Aya; Nagasawa, Kazuo; Hashimoto, Yuichi

doi:10.1248/cpb.51.1273

Cited by 51 publications

(55 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…19 In addition, the present study highlights all the side products deriving from Garin et al's procedure thus giving some hints for its mechanistic aspects and the inconveniences that might result from its use. In view of the biological relevance of benzo[d]oxazin-4-ones (see for example references [20][21][22][23][24] and of the activity of Hg(SCH 3 ) 2 , the presence of this impurity should be monitored with great care.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

et al. 2007

View full text Add to dashboard Cite

The compound URB754 was recently identified as a potent inhibitor of the endocannabinoid‐deactivating enzyme monoacylglycerol lipase (MGL) by screening of a commercial chemical library. Based on HPLC/MS, NMR and EI/MS analyses, the present paper shows that the MGL‐inhibitory activity attributed to URB754 is in fact due to a chemical impurity present in the commercial sample, identified as bis(methylthio)mercurane. Although this organomercurial compound is highly potent at inhibiting MGL (IC50 = 11.9±1.1 nM), its biological use is prohibited by its toxicity and target promiscuity.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Although the most effective alkyl substituent could not be deduced from the investigated alkyl groups, the preferred site of substitution seems to be ortho. Quinazolinedione derivatives (12-14), which are bioisosters of the corresponding homophthalimide derivatives (5-9) in peptidase-inhibitory activity assays, 15) were unexpectedly inactive. Interestingly, reduction of the 3-carbonyl group (substituent Y in Table 1) tivity, while reduction of another carbonyl group at position 1, i.e., compound 18, did not affect the activity.…”

Section: 25)mentioning

confidence: 99%

“…Our studies resulted in the creation of TNF-a production regulators (including bi-directional ones, as well as pure inhibitors and enhancers), 3,4,[6][7][8] androgen antagonists, 3,4,9,10) peptidase inhibitors, 4,[11][12][13][14][15] glucosidase inhibitors, 16,17) thymidine phosphorylase inhibitors 18) and cyclooxygenase inhibitors. 19,20) Nevertheless, not all of the beneficial pharmacological effects elicited by thalidomide can be fully interpreted in terms of the above activities, indicating the existence of other target molecules/phenomena.…”

mentioning

confidence: 99%

“…So we chose N-phenyl(homo)phthalimide or N-phenylquinazolinedione derivatives as lead compounds, based on our previous studies on peptidase inhibitors and COX inhibitors derived from thalidomide. 4,[12][13][14][15][16]19,20) Substituted phthalimide and homophthalimide compounds were prepared by routine organic synthetic methods, i.e., condensation of appropriate amines with phthalic (3) or homophthalic anhydride (4)(5)(6)(7)(8)(9)(10)(11). Quinazolinedione derivatives (12)(13)(14) were prepared by the condensation of 2,6-dialkylanilines and methyl anthranilate in the presence of triphosgene.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Thalidomide as a Nitric Oxide Synthase Inhibitor and Its Structural Development

Shimazawa

Sano

Tanatani

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

Thalidomide has been found to exhibit weak nitric oxide synthase (NOS)-inhibitory activity. Structural development studies of thalidomide showed that some N-2,6-dimethylphenylhomophthalimide analogs possess NOS-inhibiting activity.Key words thalidomide; nitric oxide synthase (NOS); inhibitor; structural development Thalidomide (1) is a hypnotic/sedative drug that was withdrawn from the market because of its severe teratogenicity. [2][3][4] In spite of this, research into thalidomide was not halted, and the drug has since been established to be effective for the treatment of various diseases, including leprosy, myeloma and AIDS. [3][4][5] Although thalidomide affects production of various cytokines, the prevailing hypothesis was that the effectiveness of thalidomide in these diseases is elicited entirely through regulation of tumor necrosis factor (TNF)-a production.We have been engaged in structural development studies of thalidomide, and have demonstrated that thalidomide is in fact a multi-target drug. Our studies resulted in the creation of TNF-a production regulators (including bi-directional ones, as well as pure inhibitors and enhancers), 3,4,[6][7][8] androgen antagonists, 3,4,9,10) peptidase inhibitors, 4,[11][12][13][14][15] glucosidase inhibitors, 16,17) thymidine phosphorylase inhibitors 18) and cyclooxygenase inhibitors. 19,20) Nevertheless, not all of the beneficial pharmacological effects elicited by thalidomide can be fully interpreted in terms of the above activities, indicating the existence of other target molecules/phenomena. We suspected that nitric oxide synthase (NOS) might be another target molecule of thalidomide, because the drug is effective against diabetes and has hypoglycemic effect, whereas NO acts as disease-progressing factor.The family of nitric oxide synthases (NOS), which includes neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS), 21) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO), an important cellular messenger molecule which has been implicated in both physiological and pathophysiological functions. In this paper, we describe evaluation of the NOS-inhibitory activity of thalidomide and its analogs.First we investigated NOS-inhibitory activity of thalidomide (1). Inhibitory activity was assayed by monitoring nitrite/nitrate production using Ichimori's protocol with a little modifications. 22,23) Although the quantitative values differed from experiment to experiment, the results were basically reproducible, and average inhibition rate are presented in Table 1. In the assay system, the IC 50 value of N G -nitro-L-arginine methyl ester (NNA, 2), which is a well-known analog of the endogenous NOS substrate, L-arginine, was determined to be 10 mM. The assay was performed in triplicate, and repeated at least three times. The result showed that thalidomide at 1 mM inhibits NOS by about 23% (Table 1). Although the NOS-inhibitory activity of thalidomide was weak, one or more of the thalidomide metabolites or decomposition products mig...

show abstract

“…In recent decades, quinazoline-2,4(1H, 3H)-diones have drawn the attention of chemists and medicinal chemists because of their various biological activities for use as anticonvulsants [14], antibacterial [15], psychosedative [16] and antihypertensive or hypotensive compounds [17]. As such, quinazoline-2,4(1H, 3H)-dione derivatives have been widely used as key structures in the production of medicinal drugs [18,19].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, anticonvulsant, antioxidant and binding interaction of novel N-substituted methylquinazoline-2,4(1H,3H)-dione derivatives to bovine serum albumin: A structure–activity relationship study

Prashanth

Madaiah

Revanasiddappa

et al. 2013

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

View full text Add to dashboard Cite

Specific Nonpeptide Inhibitors of Puromycin-Sensitive Aminopeptidase with a 2,4(1H,3H)-Quinazolinedione Skeleton

Cited by 51 publications

References 42 publications

Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

Thalidomide as a Nitric Oxide Synthase Inhibitor and Its Structural Development

Synthesis, anticonvulsant, antioxidant and binding interaction of novel N-substituted methylquinazoline-2,4(1H,3H)-dione derivatives to bovine serum albumin: A structure–activity relationship study

Contact Info

Product

Resources

About