Daniela Curti - Academia.edu (original) (raw)
Papers by Daniela Curti
European journal of medicinal chemistry, Nov 1, 2016
In the early 2000s, the Sigma Receptor (SR) family was identified as potential "druggable" target... more In the early 2000s, the Sigma Receptor (SR) family was identified as potential "druggable" target in cancer treatment. Indeed, high density of SRs was found in breast, lung, and prostate cancer cells, supporting the idea that SRs could play a role in tumor growth and progression. Moreover, a link between the degree of SR expression and tumor aggressiveness has been postulated, justified by the presence of SRs in high metastatic-potential cancer cells. As a consequence, considerable efforts have been devoted to the development of small molecules endowed with good affinity towards the two SR subtypes (S1R and S2R) with potential anticancer activity. Herein we report the synthesis and biological profile of aryl-alkyl(alkenyl)-4-benzylpiperidine derivatives-as novel potential anticancer drugs targeting SR. Among them, 3 (RC-106) exhibited a preclinical profile of antitumor efficacy on a panel of cell lines representative of different cancer types (i.e. Paca3, MDA-MB 231) expressing both SRs, and emerged as a hit compound of a new class of SRs modulators potentially useful for the treatment of cancer disease. Keywords Sigma Receptor (SR); pan-SR modulators; compound 3 (RC-106); S1R agonist/antagonist profile; potential anticancer property; apoptotic pathway. Recent studies describe how S2R ligands trigger a cell response which inhibit the activity of the P-glycoprotein, responsible for the active extrusion of anticancer drugs, leading to cell death. [17,18]. Moreover, the hypothesis of a correlation between S2R and Progesterone Receptor Membrane Component 1 (PGRMC1) [19,20] supports the idea that S2R may exert a critical role in tumorigenesis [18]. Indeed, the over-expression of PGRMC1 has been associated to tumor stage and to actively proliferating and invasive cancer cells [21]. It is also relevant that proliferating breast carcinoma cells express S2R up to ten times more than quiescent cells, and the degree of S2R expression has been correlated with tumor staging and grading [22-24]. The highest level of S2R has been detected in pancreatic cancer cell lines (Panc-02, Panc-01, CFPAC-1, AsPC-1) [25]. A recent study, carried out on mouse breast cancer (EMT-6) and human melanoma (MDA-MB-435) cell lines, demonstrate that siramesine (Fig. 1), a S2R selective ligand commonly used as reference compound, can induce cell death (with an EC 50 in both cell lines lower than 10 µM) by three different mechanisms: caspase activation, autophagy, and impaired cell-cycle progression [26]. In the same work, it has been also demonstrated that other S2R ligands, i.e. SV119, WC-26 and RHM-138 (Fig. 1), possess a cytotoxic
Pharmacological Research, Apr 1, 2010
The proliferative and antiapoptotic actions of endothelin (ET)-1 in cancer cells have been docume... more The proliferative and antiapoptotic actions of endothelin (ET)-1 in cancer cells have been documented and ET receptor antagonists have been exploited as potential anticancer drugs. Glioblastoma cell lines express both ETA and ETB receptors and previous works have shown that ETB receptors are involved in the proliferation of different cancer cell types. In this study we have investigated the effects of two structurally unrelated ETB receptor antagonists, BQ788 and A192621, on cell survival, proliferation and apoptosis in 1321-N1, U87 and IPDDCA2 glioma cell lines. BQ788 and A192621 reduced glioma cells viability and proliferation assessed by BrdU incorporation and cell cycle analysis by flow cytometry, while in contrast the ETA receptor antagonist BQ123 had no effect on cell survival. TUNEL assay and immunocytochemical experiments showed that BQ788 and A192621 trigger apoptotic processes mainly via activation of the intrinsic mitochondrial pathway involving caspase-9 activation, AIF release and cytochrome c translocation. Furthermore, treatment with ETB antagonists downregulates ERK-and p38MAPK-dependent pathways but does not affect VEGF mRNA levels. Our findings support the hypothesis that ETB antagonists represent a new promising therapeutic strategy for the treatment of high grade gliomas.
Pharmaceuticals
Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It i... more Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world’s population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs. One potential alternative is represented by sigma-1 receptor (S1R) antagonists due to their promising analgesic effects. Here, we report the synthesis and biological evaluation of a series of S1R antagonists based on a 2-aryl-4-aminobutanol scaffold. After assessing affinity toward the S1R and selectivity over the sigma-2 receptor (S2R), we evaluated the agonist/antagonist profile of the compounds by investigating their effects on nerve growth factor-induced neurite outgrowth and aquaporin-mediated water permeability in the presence and absence of oxidative stress. (R/S)-RC-752 emerged as the most interesting compound for S1R affinity (Ki S1R = 6.2 ± 0.9) and func...
Italian Journal of Neurological Sciences, 1997
Journal of the Neurological Sciences, 1997
Experimental Neurology, 2010
In the present study, we investigated whether cultured astrocytes derived from adult neural precu... more In the present study, we investigated whether cultured astrocytes derived from adult neural precursor cells (NPCs) obtained from the subventricular zone (SVZ) of wobbler mice display metabolic traits of the wobbler astrocytes in situ and in primary culture. We also utilized NPC-derived astrocytes as a tool to investigate the involvement of astrocytes in the molecular mechanism of MND focusing on the possible alteration of glutamate reuptake since excitotoxicity glutamate-mediated may be a contributory pathway. NPC-derived wobbler astrocytes are characterized by high immunoreactivity for GFAP, significant decrease of glutamate uptake and reduced immunoreactivity for glutamate transporters GLT1 and GLAST. Spinal cord motor neurons obtained from healthy mouse embryos, when co-cultured with wobbler NPC-derived astrocytes, show reduced viability and morphologic alterations. These suffering motor neurons are caspase-7 positive, and treatment with anti-apoptotic drug V5 increases cell survival. Physical contact with wobbler astrocytes is not essential because purified motor neurons display reduced survival also when treated with the medium conditioned by wobbler NPC-derived astrocytes. Toxic levels of glutamate were revealed by HPLC assay in the extracellular medium of wobbler NPC-derived astrocytes, whereas the level of intracellular glutamate is reduced if compared with controls. Moreover, glutamate receptor antagonists are able to enhance motor neuron survival. Therefore, our results demonstrate that astrocytes derived from wobbler neural precursor cells display impaired glutamate homeostasis that may play a crucial role in motor neuron degeneration. Finally, the cultured astrocytes derived from NPCs of adult mice may offer a useful alternative in vitro model to study the molecular mechanisms involved in neurodegeneration.
Chirality, 2013
In this study we addressed the role of chirality in the biological activity of RC-33, recently st... more In this study we addressed the role of chirality in the biological activity of RC-33, recently studied by us in its racemic form. An asymmetric synthesis procedure was the first experiment, leading to the desired enantioenriched RC-33 but with an enantiomeric excess (ee) not good enough for supporting the in vitro investigation. An enantioselective high-performance liquid chromatography (HPLC) procedure was then successfully carried out, yielding both RC-33 enantiomers in amounts and optical purity suitable for the pharmacological study. The absolute configuration of pure enantiomers was easily assigned exploiting the asymmetric synthesis previously devised. As emerged in the preliminary in vitro biological investigation, (S)-and (R)-RC-33 possess a comparable affinity towards the σ 1 receptor and a very a similar behavior in the calcium influx assay, resulting in an equally effective σ 1 receptor agonist. Overall, the results obtained so far suggest that the interaction with the biological target is nonstereoselective and leads us to hypothesize that there is a lack of stereoselectivity in the biological activity of RC-33. Chirality 25:814-822, 2013.
Bioorganic & Medicinal Chemistry, 2011
Bioorganic & Medicinal Chemistry, 2013
Strong pharmacological evidences indicate that r1 receptors are implicated in the pathophysiology... more Strong pharmacological evidences indicate that r1 receptors are implicated in the pathophysiology of all major CNS disorders. In the last years our research group has conducted extensive studies aimed at discovering novel r1 ligands and we recently selected (R/S)-RC-33 as a novel potent and selective r1 receptor agonist. As continuation of our work in this field, here we report our efforts in the development of this new r1 receptor agonist. Initially, we investigated the binding of (R) and (S) enantiomers of RC-33 to the r1 receptor by in silico experiments. The close values of the predicted affinity of (R)-RC-33 and (S)-RC-33 for the protein evidenced the non-stereoselective binding of RC-33 to the r1 receptor; this, in turn, supported further development and characterization of RC-33 in its racemic form. Subsequently, we setup a scaled-up, optimized synthesis of (R/S)-RC-33 along with some compound characterization data (e.g., solubility in different media and solid state characterization by thermal analysis techniques). Finally, metabolic studies of RC-33 in different biological matrices (e.g., plasma, blood, and hepatic S9 fraction) of different species (e.g., rat, mouse, dog, and human) were performed. (R/S)-RC-33 is generally stable in all examined biological matrices, with the only exception of rat and human liver S9 fractions in the presence of NADPH. In such conditions, the compound is subjected to a relevant oxidative metabolism, with a degradation of approximately 65% in rat and 69% in human. Taken together, our results demonstrated that (R/S)-RC-33 is a highly potent, selective, metabolically stable r1 agonist, a promising novel neuroprotective drug candidate.
European journal of medicinal chemistry, Nov 1, 2016
In the early 2000s, the Sigma Receptor (SR) family was identified as potential "druggable" target... more In the early 2000s, the Sigma Receptor (SR) family was identified as potential "druggable" target in cancer treatment. Indeed, high density of SRs was found in breast, lung, and prostate cancer cells, supporting the idea that SRs could play a role in tumor growth and progression. Moreover, a link between the degree of SR expression and tumor aggressiveness has been postulated, justified by the presence of SRs in high metastatic-potential cancer cells. As a consequence, considerable efforts have been devoted to the development of small molecules endowed with good affinity towards the two SR subtypes (S1R and S2R) with potential anticancer activity. Herein we report the synthesis and biological profile of aryl-alkyl(alkenyl)-4-benzylpiperidine derivatives-as novel potential anticancer drugs targeting SR. Among them, 3 (RC-106) exhibited a preclinical profile of antitumor efficacy on a panel of cell lines representative of different cancer types (i.e. Paca3, MDA-MB 231) expressing both SRs, and emerged as a hit compound of a new class of SRs modulators potentially useful for the treatment of cancer disease. Keywords Sigma Receptor (SR); pan-SR modulators; compound 3 (RC-106); S1R agonist/antagonist profile; potential anticancer property; apoptotic pathway. Recent studies describe how S2R ligands trigger a cell response which inhibit the activity of the P-glycoprotein, responsible for the active extrusion of anticancer drugs, leading to cell death. [17,18]. Moreover, the hypothesis of a correlation between S2R and Progesterone Receptor Membrane Component 1 (PGRMC1) [19,20] supports the idea that S2R may exert a critical role in tumorigenesis [18]. Indeed, the over-expression of PGRMC1 has been associated to tumor stage and to actively proliferating and invasive cancer cells [21]. It is also relevant that proliferating breast carcinoma cells express S2R up to ten times more than quiescent cells, and the degree of S2R expression has been correlated with tumor staging and grading [22-24]. The highest level of S2R has been detected in pancreatic cancer cell lines (Panc-02, Panc-01, CFPAC-1, AsPC-1) [25]. A recent study, carried out on mouse breast cancer (EMT-6) and human melanoma (MDA-MB-435) cell lines, demonstrate that siramesine (Fig. 1), a S2R selective ligand commonly used as reference compound, can induce cell death (with an EC 50 in both cell lines lower than 10 µM) by three different mechanisms: caspase activation, autophagy, and impaired cell-cycle progression [26]. In the same work, it has been also demonstrated that other S2R ligands, i.e. SV119, WC-26 and RHM-138 (Fig. 1), possess a cytotoxic
Pharmacological Research, Apr 1, 2010
The proliferative and antiapoptotic actions of endothelin (ET)-1 in cancer cells have been docume... more The proliferative and antiapoptotic actions of endothelin (ET)-1 in cancer cells have been documented and ET receptor antagonists have been exploited as potential anticancer drugs. Glioblastoma cell lines express both ETA and ETB receptors and previous works have shown that ETB receptors are involved in the proliferation of different cancer cell types. In this study we have investigated the effects of two structurally unrelated ETB receptor antagonists, BQ788 and A192621, on cell survival, proliferation and apoptosis in 1321-N1, U87 and IPDDCA2 glioma cell lines. BQ788 and A192621 reduced glioma cells viability and proliferation assessed by BrdU incorporation and cell cycle analysis by flow cytometry, while in contrast the ETA receptor antagonist BQ123 had no effect on cell survival. TUNEL assay and immunocytochemical experiments showed that BQ788 and A192621 trigger apoptotic processes mainly via activation of the intrinsic mitochondrial pathway involving caspase-9 activation, AIF release and cytochrome c translocation. Furthermore, treatment with ETB antagonists downregulates ERK-and p38MAPK-dependent pathways but does not affect VEGF mRNA levels. Our findings support the hypothesis that ETB antagonists represent a new promising therapeutic strategy for the treatment of high grade gliomas.
Pharmaceuticals
Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It i... more Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world’s population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs. One potential alternative is represented by sigma-1 receptor (S1R) antagonists due to their promising analgesic effects. Here, we report the synthesis and biological evaluation of a series of S1R antagonists based on a 2-aryl-4-aminobutanol scaffold. After assessing affinity toward the S1R and selectivity over the sigma-2 receptor (S2R), we evaluated the agonist/antagonist profile of the compounds by investigating their effects on nerve growth factor-induced neurite outgrowth and aquaporin-mediated water permeability in the presence and absence of oxidative stress. (R/S)-RC-752 emerged as the most interesting compound for S1R affinity (Ki S1R = 6.2 ± 0.9) and func...
Italian Journal of Neurological Sciences, 1997
Journal of the Neurological Sciences, 1997
Experimental Neurology, 2010
In the present study, we investigated whether cultured astrocytes derived from adult neural precu... more In the present study, we investigated whether cultured astrocytes derived from adult neural precursor cells (NPCs) obtained from the subventricular zone (SVZ) of wobbler mice display metabolic traits of the wobbler astrocytes in situ and in primary culture. We also utilized NPC-derived astrocytes as a tool to investigate the involvement of astrocytes in the molecular mechanism of MND focusing on the possible alteration of glutamate reuptake since excitotoxicity glutamate-mediated may be a contributory pathway. NPC-derived wobbler astrocytes are characterized by high immunoreactivity for GFAP, significant decrease of glutamate uptake and reduced immunoreactivity for glutamate transporters GLT1 and GLAST. Spinal cord motor neurons obtained from healthy mouse embryos, when co-cultured with wobbler NPC-derived astrocytes, show reduced viability and morphologic alterations. These suffering motor neurons are caspase-7 positive, and treatment with anti-apoptotic drug V5 increases cell survival. Physical contact with wobbler astrocytes is not essential because purified motor neurons display reduced survival also when treated with the medium conditioned by wobbler NPC-derived astrocytes. Toxic levels of glutamate were revealed by HPLC assay in the extracellular medium of wobbler NPC-derived astrocytes, whereas the level of intracellular glutamate is reduced if compared with controls. Moreover, glutamate receptor antagonists are able to enhance motor neuron survival. Therefore, our results demonstrate that astrocytes derived from wobbler neural precursor cells display impaired glutamate homeostasis that may play a crucial role in motor neuron degeneration. Finally, the cultured astrocytes derived from NPCs of adult mice may offer a useful alternative in vitro model to study the molecular mechanisms involved in neurodegeneration.
Chirality, 2013
In this study we addressed the role of chirality in the biological activity of RC-33, recently st... more In this study we addressed the role of chirality in the biological activity of RC-33, recently studied by us in its racemic form. An asymmetric synthesis procedure was the first experiment, leading to the desired enantioenriched RC-33 but with an enantiomeric excess (ee) not good enough for supporting the in vitro investigation. An enantioselective high-performance liquid chromatography (HPLC) procedure was then successfully carried out, yielding both RC-33 enantiomers in amounts and optical purity suitable for the pharmacological study. The absolute configuration of pure enantiomers was easily assigned exploiting the asymmetric synthesis previously devised. As emerged in the preliminary in vitro biological investigation, (S)-and (R)-RC-33 possess a comparable affinity towards the σ 1 receptor and a very a similar behavior in the calcium influx assay, resulting in an equally effective σ 1 receptor agonist. Overall, the results obtained so far suggest that the interaction with the biological target is nonstereoselective and leads us to hypothesize that there is a lack of stereoselectivity in the biological activity of RC-33. Chirality 25:814-822, 2013.
Bioorganic & Medicinal Chemistry, 2011
Bioorganic & Medicinal Chemistry, 2013
Strong pharmacological evidences indicate that r1 receptors are implicated in the pathophysiology... more Strong pharmacological evidences indicate that r1 receptors are implicated in the pathophysiology of all major CNS disorders. In the last years our research group has conducted extensive studies aimed at discovering novel r1 ligands and we recently selected (R/S)-RC-33 as a novel potent and selective r1 receptor agonist. As continuation of our work in this field, here we report our efforts in the development of this new r1 receptor agonist. Initially, we investigated the binding of (R) and (S) enantiomers of RC-33 to the r1 receptor by in silico experiments. The close values of the predicted affinity of (R)-RC-33 and (S)-RC-33 for the protein evidenced the non-stereoselective binding of RC-33 to the r1 receptor; this, in turn, supported further development and characterization of RC-33 in its racemic form. Subsequently, we setup a scaled-up, optimized synthesis of (R/S)-RC-33 along with some compound characterization data (e.g., solubility in different media and solid state characterization by thermal analysis techniques). Finally, metabolic studies of RC-33 in different biological matrices (e.g., plasma, blood, and hepatic S9 fraction) of different species (e.g., rat, mouse, dog, and human) were performed. (R/S)-RC-33 is generally stable in all examined biological matrices, with the only exception of rat and human liver S9 fractions in the presence of NADPH. In such conditions, the compound is subjected to a relevant oxidative metabolism, with a degradation of approximately 65% in rat and 69% in human. Taken together, our results demonstrated that (R/S)-RC-33 is a highly potent, selective, metabolically stable r1 agonist, a promising novel neuroprotective drug candidate.