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 IC₅₀ 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 IC₅₀ 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

MOESM1 of Human lung adenocarcinoma cell cultures derived from malignant pleural effusions as model system to predict patients chemosensitivity

Additional file 1: Table S1. Whole genome exome sequencing. Analysis of sequence reads. Table S2. Doubling time and latency of MPE primary cultures in Rag2/Il2rgamma double knock-out mice

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 IC₅₀ 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 IC₅₀ 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

MOESM2 of Human lung adenocarcinoma cell cultures derived from malignant pleural effusions as model system to predict patients chemosensitivity

Additional file 2. Distribution in the chromosomes of the common non-synonymous variants

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 IC₅₀ 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 IC₅₀ 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