7 research outputs found
ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors
A systematic study of medicinal chemistry
aimed at identifying
a new generation of HDAC inhibitors, through the introduction of a
thiol zinc-binding group (ZBG) and of an amide-lactam in the ω-position
of the polyethylene chain of the vorinostat scaffold, allowed the
selection of a new class of potent pan-HDAC inhibitors (pan-HDACis).
Simple, highly versatile, and efficient synthetic approaches were
used to synthesize a library of these new derivatives, which were
then submitted to a screening for HDAC inhibition as well as to a
preliminary in vitro assessment of their antiproliferative activity.
Molecular docking into HDAC crystal structures suggested a binding
mode for these thiol derivatives consistent with the stereoselectivity
observed upon insertion of amide-lactam substituents in the ω-position.
ST7612AA1 (<b>117</b>), selected as a drug candidate for further
development, showed an in vitro activity in the nanomolar range associated
with a remarkable in vivo antitumor activity, highly competitive with
the most potent HDAC inhibitors, currently under clinical trials.
A preliminary study of PK and metabolism is also illustrated
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
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 <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 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 <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
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 <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 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 <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
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 <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 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 <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
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 <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 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 <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
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 <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 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 <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
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 <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 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 <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells