Synthesis of 1-naphtylpiperazine derivatives as serotoninergic ligands and their evaluation as antiproliferative agents

Fiorino, Ferdinando; Magli, Elisa; Perissutti, Elisa; Severino, Beatrice; Frecentese, Francesco; Esposito, Antonella; Angelis, Francesca De; Incisivo, Giuseppina Maria; Massarelli, Paola; Nencini, Cristina; Gennaro, Elena Di; Budillon, Alfredo; Cintio, Alessandra Di; Santagada, Vincenzo; Caliendo, Giuseppe

doi:10.1016/j.ejmech.2011.03.001

Cited by 12 publications

(14 citation statements)

References 29 publications

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“…Serotoninergic receptor ligands SER137, SER142, SER167, SER195, SER196, SER198, SER79, SER177, SER31, SER68, endowed with different binding affinity for 5-HT2A and 5-HT2C receptors, were examined for their ability to affect BC cell viability. MCF7 (ER + , PR + , HER2 -) cells were treated with raising concentration (1μM, 5μM, 15μM, 50μM, 100μM) of SER, in agreement with previous report [31]. We found that all compounds determined a dose-dependent growth inhibition upon both 48-and 72-hours treatment.…”

Section: Antiproliferative Effect Of Serotoninergic Receptor Ligands supporting

confidence: 91%

“…Of note, transcriptomic and metabolomic data from breast tumor specimens highlighted the correspondence between poor prognosis and increased tumor-specific serotonin production [36]. Seven distinct families of 5-HT receptors are expressed in a tissue-specific manner across a variety of normal and tumor cells [31]. In BC, serotonin confers proliferative advantage to tumor cells by increasing proliferation rate and decreasing programmed cell death, mainly through 5-HT2A and 5-HT2C receptors [18,26].…”

Section: Discussionmentioning

confidence: 99%

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Serotoninergic Receptor Ligands Improve Tamoxifen Effectiveness on Breast Cancer Cells

Ambrosio¹,

Magli²,

Caliendo³

et al. 2021

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Background: The tightly regulated pattern of serotonin (or 5-Hydroxytryptamine, 5-HT) in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis and angiogenesis. Antagonists of serotonin receptors or inhibitors of serotonin reuptake/synthesis may be co-prescribed with Tamoxifen in estrogen receptor-positive (ER+) tumors, and may modulate its efficacy. Thus, the discovery of novel compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT2A and 5-HT2C receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER+ cells. Methods: Cell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; CTGF mRNA levels have been measured by qPCR. All data were statistically analyzed using GraphPad Prism 7. Results: We found that SER were more effective on MCF7 ER+ cells (IC50 range 10.2µM - 99.2µM) compared to SKBR3 (IC50 range 43.3µM - 260µM) and MDA-MB231 BC cells (IC50 range 91.3µM - 306µM). Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 BC cells and modulated the expression of CTGF. Moreover, in a cell model of Tamoxifen-resistance, SER79 and SER68 restored drug responsiveness and reduced CTGF levels. Conclusions: These results identified new compounds potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients.

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Section: Antiproliferative Effect Of Serotoninergic Receptor Ligands supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Serotoninergic Receptor Ligands Improve Tamoxifen Effectiveness on Breast Cancer Cells

Ambrosio¹,

Magli²,

Caliendo³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Of note, transcriptomic and metabolomic data from breast tumor specimens highlighted the correspondence between poor prognosis and increased tumor-specific serotonin production [ 36 ]. Seven distinct families of 5-HT receptors are expressed in a tissue-specific manner across a variety of normal and tumor cells [ 37 ]. In BC, serotonin confers proliferative advantage to tumor cells by increasing proliferation rate and decreasing programmed cell death, mainly through 5-HT 2A and 5-HT 2C receptors [ 18 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells

et al. 2022

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Background Serotonin (or 5-Hydroxytryptamine, 5-HT) signals in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis, and angiogenesis. Thus, the discovery of novel compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT2A and 5-HT2C receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER+ cells. Methods Cell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; mRNA levels of CTGF and ABC transporters have been further measured by qPCR. Protein levels of 5-HT2C receptors have been analyzed by Western blot. All data were statistically analyzed using GraphPad Prism 7. Results We found that treatment with SER for 72 h reduced viability of BC cells. SER were more effective on MCF7 ER+ cells (IC50 range 10.2 μM - 99.2 μM) compared to SKBR3 (IC50 range 43.3 μM - 260 μM) and MDA-MB231 BC cells (IC50 range 91.3 μM - 306 μM). This was paralleled by accumulation of cells in G0/G1 phase of cell cycle. Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 cells and modulated the expression of CTGF, without affecting viability of MCF10A non-cancer breast epithelial cells. In a cell model of Tamoxifen resistance, SER68 also restored drug effect independently of CTGF. Conclusions These results identified serotoninergic receptor ligands potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients.

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“…On the other hand, 1,2,3-benzotriazin-4(3H)-one compounds have been reported as active antiproliferative agent [9], anti-in ammatory [10,11], anti-depressant [12], anticancer [13], antidiarrhoeal [14] and as anesthetics [15] (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 1,2,3-Benzotriazin-4(3H)-one derivatives as α-glucosidase inhibitor and their in-silico study

Khalid

Shafqat

Ahmad

et al. 2022

Preprint

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α-Glucosidase inhibition is considered as an effective strategy for the treatment of diabetes mellitus. Currently, three α-glucosidase inhibitors are being used as drugs; Acarbose, Voglibose and Miglitol. The side effects of these drugs are forcing researchers to search for new and effective molecules. In this research work, novel 1,2,3-benzotriazin-4(3H)-one sulfonamides were synthesized and investigated for their α-glucosidase inhibition activity. TCT: DMF adduct have been utilized for the direct synthesis of targeted sulfonamides. All reactions were performed at room temperature under mild conditions. In-vitro enzyme inhibition studies led us to discover many potent inhibitors demonstrating good to excellent activity. The compound 5c with dimethyl substituent was found to be more potent inhibitor than acarbose with the IC50 value of 29.75±0.14 μM. Compounds 5a, 5b, 5d, 5e, 5f and 5m showed good inhibition results with IC50 value 31.97±0.03, 33.24±0.01, 33.76±1.05, 35.98±0.03, 30.87±0.51 and 37.24±0.04 µM respectively. Further structure activity relationship was analyzed by molecular docking studies.

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Synthesis of 1-naphtylpiperazine derivatives as serotoninergic ligands and their evaluation as antiproliferative agents

Cited by 12 publications

References 29 publications

Serotoninergic Receptor Ligands Improve Tamoxifen Effectiveness on Breast Cancer Cells

Serotoninergic Receptor Ligands Improve Tamoxifen Effectiveness on Breast Cancer Cells

Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells

Synthesis of 1,2,3-Benzotriazin-4(3H)-one derivatives as α-glucosidase inhibitor and their in-silico study

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