Design and Synthesis of 2-Heterocyclyl-3-arylthio-1<i>H</i>-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability

Regina, Giuseppe La; Bai, Ruoli; Rensen, Willeke; Coluccia, Antonio; Piscitelli, Francesco; Gatti, Valerio; Bolognesi, Alessio; Lavecchia, Antonio; Granata, Ilaria; Porta, Amalia; Maresca, Bruno; Soriani, Alessandra; Iannitto, Maria Luisa; Mariani, Marisa; Santoni, Angela; Brancale, Andrea; Ferlini, Cristiano; Dondio, Giulio; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Novellino, Ettore; Silvestri, Romano

doi:10.1021/jm2012886

Cited by 71 publications

(91 citation statements)

References 42 publications

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“…Imipramine-blue possesses a high therapeutic potency in vitro, comparable to that of doxorubicin, for the cell lines SH-SY5Y, MDA-MB231, HeLa, and HEK-293WT (24)(25)(26)(27). The most sensitive cell lines toward imipramine-blue treatment were BL30B95, BL2, BL2B95, and the neuroblastoma cell line KELLY with IC 50 (24 hours) values lower than 0.8 mmol/L (0.79, 0.49, 0.16, and 0.78 mmol/L).…”

Section: Discussionmentioning

confidence: 99%

The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma

Klingenberg¹,

Becker²,

Eberth³

et al. 2014

Molecular Cancer Therapeutics

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Burkitt lymphoma is a rare malignancy arising from B cells. Current chemotherapeutic regimens achieve excellent overall survival rates in children, but less impressive rates in adults. There are cases with poor outcome caused by toxic effects of the therapy, tumor lysis syndrome, or metastatic spread of lymphomas to the central nervous system. Modulators of reactive oxygen species are currently discussed as potential drugs for the treatment of cancer. The NADPH oxidase 4 inhibitor imipramine-blue might satisfy the aforementioned requirements, and was studied here. We used MTT assay, crystal violet assay, and thymidine 3H-incorporation assay to analyze the effects of imipramine-blue on Burkitt lymphoma (BL2, BL2B95, BL30B95, BL41B95), neuroblastoma (KELLY, SH-SY5Y, SMS-KAN), cervix carcinoma (HeLa), breast cancer (MDA-MB231), angiosarcoma (AS-M), human embryonic kidney (HEK293WT), and nonmalignant (FLP1) cell lines. The effects of imipramine-blue on BL2B95 cells in vivo were investigated in xenografts on the chick chorioallantoic membrane (CAM). We report that imipramine-blue is a potent growth inhibitor for several cancer cell lines in vitro with IC 50 values comparable to those of doxorubicin (0.16-7.7 mmol/L). Tumor size of BL2B95 cells inoculated in the CAM was reduced significantly (P < 0.05) after treatment with 10 mmol/L imipramine-blue. Lymphogenic dissemination of BL2B95 and the formation of blood and lymphatic vessels in experimental tumors were not affected. We show that imipramine-blue can be used to decrease the viability of cancer cell lines in vitro and in vivo. Imipramine-blue reduces the size of experimental Burkitt lymphoma significantly but does not affect the dissemination of BL2B95 cells, angiogenesis, and lymphangiogenesis.

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Section: Discussionmentioning

confidence: 99%

The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma

Klingenberg¹,

Becker²,

Eberth³

et al. 2014

Molecular Cancer Therapeutics

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“…3, 4 Accordingly, the search for novel tubulin inhibitors that can overcome multidrug resistance has intensified in recent years; and as a result, a number of active compounds have been identified. 5–13 Our search has focused on the discovery and optimization of novel tubulin inhibitors with high potency and acceptable pharmacologic and pharmacokinetic properties. 9, 10, 12–16 …”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel 2-Aryl-4-benzoyl-imidazole (ABI-III) Analogues Targeting Tubulin Polymerization As Antiproliferative Agents

et al. 2012

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Novel ABI–III compounds were designed and synthesized based on our previously reported ABI-I and ABI–II analogs. ABI–III compounds are highly potent against a panel of melanoma and prostate cancer cell lines, with the best compound having an average IC50 value of 3.8 nM. They are not substrate of Pgp and thus may effectively overcome Pgp mediated multidrug resistance. ABI–III analogs maintain their mechanisms of action by inhibition of tubulin polymerization.

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“…15–19 The ATIs inhibit tubulin polymerization by binding to the colchicine site, inhibiting the binding of [ 3 H]colchicine to tubulin. 15 …”

Section: Introductionmentioning

confidence: 99%

Toward Highly Potent Cancer Agents by Modulating the C-2 Group of the Arylthioindole Class of Tubulin Polymerization Inhibitors

et al. 2012

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New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.

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Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability

Cited by 71 publications

References 42 publications

The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma

The NADPH Oxidase Inhibitor Imipramine-Blue in the Treatment of Burkitt Lymphoma

Discovery of Novel 2-Aryl-4-benzoyl-imidazole (ABI-III) Analogues Targeting Tubulin Polymerization As Antiproliferative Agents

Toward Highly Potent Cancer Agents by Modulating the C-2 Group of the Arylthioindole Class of Tubulin Polymerization Inhibitors

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