Heparanase is the sole mammalian enzyme capable of cleaving glycosaminoglycan heparan sulfate side chains of heparan sulfate proteoglycans. Its altered activity is intimately associated with tumor growth, angiogenesis, and metastasis. Thus, its implication in cancer progression makes it an attractive target in anticancer therapy. Herein, we describe the design, synthesis, and biological evaluation of new benzazoles as heparanase inhibitors. Most of the designed derivatives were active at micromolar or submicromolar concentration, and the most promising compounds are fluorinated and/or amino acids derivatives 13a, 14d, and 15 that showed IC 0.16-0.82 μM. Molecular docking studies were performed to rationalize their interaction with the enzyme catalytic site. Importantly, invasion assay confirmed the antimetastatic potential of compounds 14d and 15. Consistently with its ability to inhibit heparanase, compound 15 proved to decrease expression of genes encoding for proangiogenic factors such as MMP-9, VEGF, and FGFs in tumor cells.
Heparanase is the only mammalian endo-β-D-glucuronidase involved in a variety of major diseases. The upregulation of heparanase expression increases tumor size, angiogenesis, and metastasis, representing a validated target in the anti-cancer field. To date, only a few small-molecule inhibitors have been described, but none have gotten through pre-clinical development. Previously, we explored 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives as antiheparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Herein, we report an extended investigation of new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivatives, proving that symmetrical compounds are more effective than asymmetrical analogues, with the most-potent compound, 7g, being active at nanomolar concentration against heparanase. Molecular docking studies were performed on the best-acting compounds 5c and 7g to rationalize their interaction with the enzyme. Moreover, invasion assay confirmed the anti-metastatic potential of compounds 5c, 7a, and 7g, proving the inhibition of the expression of proangiogenic factors in tumor cells.
A new series of pyrimidine
and pyridine diamines was designed as
dual binding site inhibitors of cholinesterases (ChEs), characterized
by two small aromatic moieties separated by a diaminoalkyl flexible
linker. Many compounds are mixed or uncompetitive acetylcholinesterase
(AChE) and/or butyrylcholinesterase (BChE) nanomolar inhibitors, with
compound
9
being the most active on
Electrophorus
electricus
AChE (
Ee
AChE) (
K
i
= 0.312 μM) and compound
22
on equine BChE (
eq
BChE) (
K
i
= 0.099 μM). Molecular docking and molecular dynamic
studies confirmed the interaction mode of our compounds with the enzymatic
active site. UV–vis spectroscopic studies showed that these
compounds can form complexes with Cu
2+
and Fe
3+
and that compounds
18
,
20
, and
30
have antioxidant properties. Interestingly, some compounds were
also able to reduce Aβ
42
and tau aggregation, with
compound
28
being the most potent (22.3 and 17.0% inhibition
at 100 μM on Aβ
42
and tau, respectively). Moreover,
the most active compounds showed low cytotoxicity on a human brain
cell line and they were predicted as BBB-permeable.
We discovered novel and selective sulfonamides/amides acting as inhibitors of the a-carbonic anhydrase\ud
(CA, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae (VchCA). This Gram-negative bacterium is\ud
the causative agent of cholera and colonises the upper small intestine where sodium bicarbonate is present\ud
at a high concentration. The secondary sulfonamides and amides investigated here were potent, low\ud
nanomolar VchCA inhibitors whereas their inhibition of the human cytosolic isoforms CA I and II was in\ud
the micromolar range or higher. The molecules represent an interesting lead for antibacterial agents with\ud
a possibly new mechanism of action, although their CA inhibition mechanism is unknown for the moment
Beer antioxidants
originate mainly from malts, classified as colored,
caramel, and roasted, according to the malting process. This study
aimed to characterize, in terms of phenolic antioxidants, three types
of Pale Ale craft beers brewed using increasing percentage of dark
malt (0, 5, and 15% Caraamber malt, called PA100, PA95, PA85, respectively)
and to evaluate the impact of dealcoholization by osmotic distillation
(OD) on the same antioxidants. All the alcoholic (PA, 6.2–6.8
vol %) and low alcoholic (LA-PA, 1 vol %) beers were analyzed by HPLC-ESI-MS/MS,
total phenolic content (TPC), and antioxidant activity (AA): similar
phenolic profiles were evidenced and 43 compounds identified or tentatively
identified. Some differences were found among PA100, PA95, and PA85:
PA85 was richer in free phenolic compounds (10.55 mg/L) and had a
higher TPC (463.7 GAE mg/L) and AA (852.1 TE mg/L). LA-PA beers showed
the same phenolic profile and similar TPC and AA compared to PA beers;
however, there were some differences regarding LA-PA85 (5.91 mg/L).
Dealcoholization by OD seemed to weakly affect the phenolic fraction.
ESI-MS/MS infusion experiments evidenced oligosaccharides, small organic
acids, and amino acids, whose presence was confirmed and quantitated
by NMR: besides ethanol and other alcohols, weak to strong loss of
low-molecular-weight metabolites was evidenced in LA-PA beers.
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