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.
We have designed and synthesized
a series of new imidazole-based
compounds structurally related to an antiprotozoal agent with nanomolar
activity which we identified recently. The new analogues possess micromolar
activities against Trypanosoma brucei rhodesiense and Leishmania donovani and nanomolar
potency against Plasmodium falciparum. Most of the analogues displayed IC50 within the low
nanomolar range against Trypanosoma cruzi, with very high selectivity toward the parasite. Discussion of structure–activity
relationships and in vitro biological data for the new compounds are
provided against a number of different protozoa. The mechanism of
action for the most potent derivatives (5i, 6a–c, and 8b) was assessed by a target-based assay using
recombinant T. cruzi CYP51. Bioavailability
and efficacy of selected hits were assessed in a T.
cruzi mouse model, where 6a and 6b reduced parasitemia in animals >99% following intraperitoneal
administration of 25 mg/kg/day dose for 4 consecutive days.
Growing attention to environmental protection leads food industries to adopt a model of “circular economy” applying safe and sustainable technologies to recover, recycle and valorize by-products. Therefore, by-products become raw material for other industries. Tomato processing industry produces significant amounts of by-products, consisting of skins and seeds. Tomato skin is very rich in lycopene, and from its seeds, high nutritional oil can be extracted. Alternative use of the two fractions not only could cut disposal costs but also allow one to extract bioactive compounds and an oil with a high nutritional value. This review focused on the recent advance in extraction of lycopene, whose beneficial effects on health are widely recognized.
Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl−pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenylpyrrolyl−pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound 11b being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, showed the key structural features that could confer the ability to establish specific interactions within RNase H. Furthermore, they proved the ability of our compounds to interact with amino acids highly conserved among HIV-1 subspecies isolated among patients carrying drug-resistant variants. In the end, the newly discovered pyrazole carboxylic acid derivatives feature promising serum stability with respect to their corresponding DKAs.
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.
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