Literature summary for 3.2.1.166 extracted from

Messore, A.; Madia, V.N.; Pescatori, L.; Saccoliti, F.; Tudino, V.; De Leo, A.; Bortolami, M.; De Vita, D.; Scipione, L.; Pepi, F.; Costi, R.; Rivara, S.; Scalvini, L.; Mor, M.; Ferrara, F.F.; Pavoni, E.; Roscilli, G.; Cassinelli, G.; Milazzo, F.M.; Battistuzzi, G.; Di Santo, R.; Giannini, G.
Novel symmetrical benzazolyl derivatives endowed with potent anti-heparanase activity (2018), J. Med. Chem., 61, 10834-10859 .

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Application

Application	Comment	Organism
drug development	the upregulation of heparanase expression increases tumor size, angiogenesis, and metastasis, represents a validated target in the anti-cancer field. 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives act as anti-heparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Symmetrical 2-aminophenyl benzazolyl-5-acetate derivatives, proving that symmetrical compounds, are more effective than asymmetrical analogues	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis-(methylene))diboronic acid	-	Homo sapiens
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis(3-methylbutane-1,1-diyl))diboronic acid	-	Homo sapiens
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis-(methylene))diboronic acid	-	Homo sapiens
1,3-bis(1-(5,6-dimethylbenzo[d]oxazol-2-yl)piperidin-4-yl)urea	-	Homo sapiens
1,3-bis(4-(5,6-dimethylbenzo[d]oxazol-2-yl)-2-fluorophenyl)urea	-	Homo sapiens
1,3-bis(4-(5,6-dimethylbenzo[d]oxazol-2-yl)phenyl)urea	-	Homo sapiens
1,3-bis[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]urea	-	Homo sapiens
2,2'-((((carbonylbis(azanediyl))bis(4,1-phenylenesulfonyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid	-	Homo sapiens
2,2'-((((Iminomethylene)bis(azanediyl))bis(4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid	-	Homo sapiens
2,2'-(((4,4'-(2-hydroxypropane-1,3-diyl)bis(benzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid	-	Homo sapiens
2,2'-(((4,4'-(2-oxopropane-1,3-diyl)bis(benzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid	-	Homo sapiens
2,2'-(((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-bis(3,1-phenylene))diacetic acid	-	Homo sapiens
2,2'-(((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-bis(4-hydroxy-3,1-phenylene))diacetic acid	-	Homo sapiens
2,2'-(((4,4'-(thiocarbonylbis(azanediyl))bis(3-fluorobenzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid	-	Homo sapiens
2,2'-(((carbonylbis(azanediyl))bis(3,1-phenylene))bis(benzo[d]-oxazole-2,5-diyl))diacetic acid	-	Homo sapiens
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(1H-benzo[d]imidazole-2,5-diyl))diacetic acid	-	Homo sapiens
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(N-isopentylacetamide)	-	Homo sapiens
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid	causes inhibition of the proliferation of human CME-1 synovial sarcoma cells	Homo sapiens
2,2'-(((carbonylbis(azanediyl))bis(4,1-phenylene))bis(benzo[d]-oxazole-2,5-diyl))diacetic acid	-	Homo sapiens
2,2'-(((carbonylbis(azanediyl))bis(piperidine-4,1-diyl))bis(benzo-[d]oxazole-2,5-diyl))diacetic acid	-	Homo sapiens
2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))-bis(1H-benzo[d]imidazole-2,5-diyl))diacetic acid	-	Homo sapiens
2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))-bis(benzo[d]oxazole-2,5-diyl))diacetic acid	-	Homo sapiens
2,2'-(((thiocarbonylbis(azanediyl))bis(4,1-phenylene))bis(benzo-[d]oxazole-2,5-diyl))diacetic acid	-	Homo sapiens
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)	-	Homo sapiens
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)	-	Homo sapiens
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid	-	Homo sapiens
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))dipropionic acid	-	Homo sapiens
2,2'-((2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid	-	Homo sapiens
2-(3-(4-(3-(4-((5-(carboxymethyl)-2-hydroxyphenyl)carbamoyl)-phenyl)-2-hydroxypropyl)-3-hydroxybenzamido)phenyl)acetic acid	-	Homo sapiens
3,3'-((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-dibenzoic acid	-	Homo sapiens
5-[2-[4-([4-[(3-bromo-4-methoxybenzoyl)amino]benzyl]amino)-3-fluorophenyl]-1H-benzimidazol-5-yl]-4-oxopentanoic acid	i.e. SST0871AA1	Homo sapiens
additional information	symmetrical benzazolyl derivatives show potent anti-heparanase activity, synthesis, and molecular docking studies, overview. The anti-metastatic potential of compounds 2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid, 2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid, and 2,2'-((2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid, proves the inhibition of the expression of proangiogenic factors in tumor cells. Molecular modeling of inhibitor binding and mechanism	Homo sapiens
SST0001	N-acetylated, glycol-split heparin	Homo sapiens
[2-(4-[[(2E)-3-(4-bromophenyl)prop-2-enoyl]amino]phenyl)-1,3-benzoxazol-5-yl]acetic acid	-	Homo sapiens
[2-[4-([4-[(3-bromo-4-methoxybenzoyl)amino]benzyl]amino)-3-fluorophenyl]-1H-benzimidazol-5-yl]acetic acid	i.e. SST0867AA1	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
heparan sulfate + H2O	Homo sapiens	-	?	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q9Y251	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
carcinoma cell	upregulation of heparanase expression	Homo sapiens	-
CME-1 cell	-	Homo sapiens	-
fibrosarcoma cell	-	Homo sapiens	-
glioblastoma cell	-	Homo sapiens	-
HT-1080 cell	-	Homo sapiens	-
osteosarcoma cell	-	Homo sapiens	-
synovial sarcoma cell	-	Homo sapiens	-
U-87MG cell	-	Homo sapiens	-
U2-OS cell	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
heparan sulfate + H2O	-	Homo sapiens	?	-	?
additional information	fondaparinux assay method	Homo sapiens	?	-	?

Synonyms

Synonyms	Comment	Organism
endo-beta-D-glucuronidase	-	Homo sapiens
HPSE	-	Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Homo sapiens

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
5	-	assay at	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.000005	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	SST0001
0.00001	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis-(methylene))diboronic acid
0.00008	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-((2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid
0.00018	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid
0.00037	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))dipropionic acid
0.00042	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	[2-(4-[[(2E)-3-(4-bromophenyl)prop-2-enoyl]amino]phenyl)-1,3-benzoxazol-5-yl]acetic acid
0.00045	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid
0.00056	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	1,3-bis[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]urea
0.00064	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	5-[2-[4-([4-[(3-bromo-4-methoxybenzoyl)amino]benzyl]amino)-3-fluorophenyl]-1H-benzimidazol-5-yl]-4-oxopentanoic acid
0.00072	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
0.00082	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
0.00098	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(1H-benzo[d]imidazole-2,5-diyl))diacetic acid
0.00099	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))-bis(1H-benzo[d]imidazole-2,5-diyl))diacetic acid
0.0014	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))-bis(benzo[d]oxazole-2,5-diyl))diacetic acid
0.00176	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-bis(3,1-phenylene))diacetic acid
0.00181	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((thiocarbonylbis(azanediyl))bis(4,1-phenylene))bis(benzo-[d]oxazole-2,5-diyl))diacetic acid
0.00261	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((4,4'-(thiocarbonylbis(azanediyl))bis(3-fluorobenzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
0.00273	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-bis(4-hydroxy-3,1-phenylene))diacetic acid
0.00286	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	[2-[4-([4-[(3-bromo-4-methoxybenzoyl)amino]benzyl]amino)-3-fluorophenyl]-1H-benzimidazol-5-yl]acetic acid
0.0032	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((carbonylbis(azanediyl))bis(4,1-phenylene))bis(benzo[d]-oxazole-2,5-diyl))diacetic acid
0.00487	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis(3-methylbutane-1,1-diyl))diboronic acid
0.00602	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-((((Iminomethylene)bis(azanediyl))bis(4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid
0.00917	-	pH 5.0 37°C, recombinant enzyme	Homo sapiens	3,3'-((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-dibenzoic acid
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis-(methylene))diboronic acid
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis(3-methylbutane-1,1-diyl))diboronic acid
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	1,3-bis(1-(5,6-dimethylbenzo[d]oxazol-2-yl)piperidin-4-yl)urea
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	1,3-bis(4-(5,6-dimethylbenzo[d]oxazol-2-yl)-2-fluorophenyl)urea
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	1,3-bis(4-(5,6-dimethylbenzo[d]oxazol-2-yl)phenyl)urea
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-((((carbonylbis(azanediyl))bis(4,1-phenylenesulfonyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((4,4'-(2-hydroxypropane-1,3-diyl)bis(benzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((4,4'-(2-oxopropane-1,3-diyl)bis(benzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((carbonylbis(azanediyl))bis(3,1-phenylene))bis(benzo[d]-oxazole-2,5-diyl))diacetic acid
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(N-isopentylacetamide)
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-(((carbonylbis(azanediyl))bis(piperidine-4,1-diyl))bis(benzo-[d]oxazole-2,5-diyl))diacetic acid
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
0.01	-	above, pH 5.0 37°C, recombinant enzyme	Homo sapiens	2-(3-(4-(3-(4-((5-(carboxymethyl)-2-hydroxyphenyl)carbamoyl)-phenyl)-2-hydroxypropyl)-3-hydroxybenzamido)phenyl)acetic acid

General Information

General Information	Comment	Organism
physiological function	the upregulation of heparanase expression increases tumor size, angiogenesis, and metastasis, represents a validated target in the anti-cancer field	Homo sapiens