The Experts below are selected from a list of 210 Experts worldwide ranked by ideXlab platform
Michele Reni - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms, indications and results of salvage systemic therapy for sporadic and von Hippel–Lindau related hemangioblastomas of the central nervous system
Critical reviews in oncology hematology, 2012Co-Authors: Jody Filippo Capitanio, Elena Mazza, Micaela Motta, Pietro Mortini, Michele ReniAbstract:Hemangioblastomas (HBs) are rare indolent vascular tumors that may occur sporadically or in association with von Hippel-Lindau (VHL) disease. Total neurosurgical resection is the standard upfront approach providing long-term tumor control. At time of tumor recurrence, second surgery, radiosurgery or radiotherapy are the main therapeutic strategies. Limited information is available on the role of pharmacological strategies. Anti-angiogenic agents, particularly multitarget tyrosine kinase inhibitors (Semaxanib, sunitinib, vatalanib), thalidomide and interferon alfa-2a are currently the most widely studied strategies to prolonge disease stability. Salvage therapy with anti-angiogenetic drugs may be of benefit in some patients who are not suitable for surgery, radiosurgery or radiotherapy, with progressive or recurrent hemangioblastoma especially those located in retina, since anti-angiogenetic therapy may delay tumor progression. This strategy warrants prospective evaluation in a clinical trial.
Richard J. K. Taylor - One of the best experts on this subject based on the ideXlab platform.
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tandem horner wadsworth emmons heck procedures for the preparation of 3 alkenyl oxindoles the synthesis of Semaxanib and gw441756
Tetrahedron, 2010Co-Authors: Jana Lubkoll, Alessia Millemaggi, Alexis Perry, Richard J. K. TaylorAbstract:Abstract A tandem sequence involving Horner–Wadsworth–Emmons (HWE) olefination followed by a palladium-catalysed intramolecular Heck reaction has been developed to provide rapid access to 3-alkenyl-oxindoles from α-halo-anilides. This one-pot microwave accelerated process proceeds with catalytic palladium(II) acetate or tetrakis(triphenylphosphine)palladium, and has been used to prepare a range of adducts derived from aromatic, heteroaromatic and aliphatic aldehydes. The procedures can be used to prepare N -unprotected oxindoles directly and the applicability of the process has been established by carrying out one-pot syntheses of Semaxanib, an angiogenesis signalling inhibitor, and GW441756, an aza-oxindole Trk A inhibitor.
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Tandem Horner-Wadsworth-Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: the synthesis of Semaxanib and GW441756
Tetrahedron, 2010Co-Authors: Jana Lubkoll, Alessia Millemaggi, Alexis Perry, Richard J. K. TaylorAbstract:Abstract A tandem sequence involving Horner–Wadsworth–Emmons (HWE) olefination followed by a palladium-catalysed intramolecular Heck reaction has been developed to provide rapid access to 3-alkenyl-oxindoles from α-halo-anilides. This one-pot microwave accelerated process proceeds with catalytic palladium(II) acetate or tetrakis(triphenylphosphine)palladium, and has been used to prepare a range of adducts derived from aromatic, heteroaromatic and aliphatic aldehydes. The procedures can be used to prepare N -unprotected oxindoles directly and the applicability of the process has been established by carrying out one-pot syntheses of Semaxanib, an angiogenesis signalling inhibitor, and GW441756, an aza-oxindole Trk A inhibitor.
Nicholas S Kirk - One of the best experts on this subject based on the ideXlab platform.
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Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study
Bioorganic & medicinal chemistry letters, 2019Co-Authors: Geraud N. Sansom, Nicholas S Kirk, Christopher P. Guise, Robert F. Anderson, Jeff B. Smaill, Adam V. Patterson, Michael J. KelsoAbstract:Abstract Amide- and ester-linked kinase inhibitor-cytotoxin conjugates were rationally designed and synthesised as prototype hypoxia-activated anticancer mutual prodrugs. Chemical reduction of an aryl nitro trigger moiety was shown to initiate a spontaneous cyclisation/fragmentation reaction that simultaneously released the kinase inhibitor Semaxanib (SU5416) and the amine- or alcohol-linked cytotoxin from the prodrugs. Preliminary cell testing and reduction potential measurements support optimisation of the compounds towards tumour-selective mutual prodrugs.
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Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors
Bioorganic & medicinal chemistry letters, 2016Co-Authors: Nicholas S Kirk, Pichit Sudta, Anna Bezos, Anthony C Willis, Christopher R Parish, Sunit Suksamrarn, Marie Ranson, Michael J. KelsoAbstract:Sunitinib (Sutent®) is a receptor tyrosine kinase (RTK) and angiogenesis inhibitor approved for the treatment of renal cell carcinomas, gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. A key structural motif retained throughout medicinal chemistry efforts during sunitinib's development was the indoline-2-one group. In the search for new anti-angiogenic scaffolds, we previously reported that non-indoline-2-one-based derivatives of Semaxanib (SU5416, a structurally simpler sunitinib predecessor that underwent Phase III trials) are active as angiogenesis inhibitors, indicating that the group is not essential for activity. This Letter describes the synthesis and structure-activity relationships of another class of non-indoline-2-one angiogenesis inhibitors related to sunitinib/Semaxanib; the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones. A focussed library of 19 analogues was prepared using a simple novel process, wherein commercially available substituted arylacetic acids activated with an amide coupling reagent (HBTU) were reacted with the potassium salt of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde in one-pot. Screening of the library using a cell-based endothelial tube formation assay identified 6 compounds with anti-angiogenesis activity. Two of the compounds were advanced to the more physiologically relevant rat aortic ring assay, where they showed similar inhibitory effects to Semaxanib at 10μg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors.
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synthesis structural characterisation and preliminary evaluation of non indolin 2 one based angiogenesis inhibitors related to sunitinib sutent
Australian Journal of Chemistry, 2013Co-Authors: Pichit Sudta, Nicholas S Kirk, Anna Bezos, Anthony Gurlica, Rhys Mitchell, Thomas G Weber, Anthony C Willis, Samran Prabpai, Palangpon Kongsaeree, Christopher R ParishAbstract:The indolin-2-one fused-ring system and the 2,4-dimethylpyrrole unit represent key structural motifs in the anticancer drug sunitinib (Sutent®) and predecessor angiogenesis inhibitors that have undergone anticancer clinical trials (e.g. Semaxanib, SU5416). In pursuit of novel anti-angiogenic scaffolds, we were interested in identifying whether the indolin-2-one group in these structures could be modified without losing activity. This paper describes novel condensation chemistry used to prepare a test series of (E)- and (Z)-alkenes related to SU5416 that retain the 2,4-dimethylpyrrole unit while incorporating ring-opened indolin-2-ones. Unique structural characteristics were identified in the compounds, such as intramolecular hydrogen bonds in the (Z)-alkenes, and several examples were shown to possess significant anti-angiogenic activity in a rat aorta in vitro model of angiogenesis. The work demonstrates that the indolin-2-one moiety is not an absolute requirement for angiogenesis inhibition in the sunitinib/SU5416 class.
James L. Abbruzzese - One of the best experts on this subject based on the ideXlab platform.
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A phase I study of escalating doses of the tyrosine kinase inhibitor Semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma
Japanese journal of clinical oncology, 2006Co-Authors: Paulo M. Hoff, Robert A. Wolff, Karla Bogaard, Sherry Waldrum, James L. AbbruzzeseAbstract:Background: One of the most studied pro-angiogenic factors involved in the development of colorectal cancer is the vascular endothelial growth factor (VEGF). The small molecule tyrosine kinase inhibitor Semaxanib (SU5416) is one of the several agents targeting the VEGF signaling pathway, and its development centered mostly in the treatment of colorectal cancer. Methods: We designed and conducted an NCI-sponsored trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Semaxanib given twice weekly in combination with weekly irinotecan in patients with advanced colorectal cancer who had failed at least one prior treatment. The irinotecan dose was fixed at 125 mg/m 2 given weekly for 4 weeks followed by 2 weeks of rest. Patients with prior pelvic irradiation received a reduced doseof100mg/m 2 .TheSemaxanibdosewasescalated,goingfrom85to110mg/m 2 andfinallyto 145 mg/m 2 . Results: Ten patients were treated in our study and all were evaluable for toxicity. There were no drug-related Grade 4 toxicities. There was one episode of Grade 3 headache and one episode of Grade 3 vomiting. The most common Grades 1 and 2 toxicities included diarrhea, abdominal cramping, anemia and nausea. Nine patients completed at least one 6 week cycle of treatment and were considered evaluable for response. Among those nine, two had a partial response, three had stable disease and four had progressive disease after the first cycle. Conclusions: Both irinotecan and Semaxanib could be given at their full single-agent recommended doses without significant toxicity, and the combination showed signs of clinical activity. However, owing to discouraging results from Phase III trials, it is unlikely that this combination will be further explored.
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APhase I Study of Escalating Doses of the Tyrosine Kinase Inhibitor Semaxanib (SU5416) in Combination with Irinotecan in Patients with Advanced Colorectal Carcinoma
2005Co-Authors: Paulo M. Hoff, Robert A. Wolff, Karla Bogaard, Sherry Waldrum, James L. AbbruzzeseAbstract:Background: One of the most studied pro-angiogenic factors involved in the development of colorectal cancer is the vascular endothelial growth factor (VEGF). The small molecule tyrosine kinase inhibitor Semaxanib (SU5416) is one of the several agents targeting the VEGF signaling pathway, and its development centered mostly in the treatment of colorectal cancer. Methods: We designed and conducted an NCI-sponsored trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Semaxanib given twice weekly in combination with weekly irinotecan in patients with advanced colorectal cancer who had failed at least one prior treatment. The irinotecan dose was fixed at 125 mg/m2 given weekly for 4 weeks followed by 2 weeks of rest. Patients with prior pelvic irradiation received a reduced dose of 100mg/m2. The Semaxanib dosewas escalated, going from85 to 110mg/m2 and finally to 145 mg/m2. Results: Ten patients were treated in our study and all were evaluable for toxicity. There were no drug-related Grade 4 toxicities. There was one episode of Grade 3 headache and one episode of Grade 3 vomiting. The most common Grades 1 and 2 toxicities included diarrhea, abdominal cramping, anemia and nausea. Nine patients completed at least one 6 week cycle of treatment and were considered evaluable for response. Among those nine, two had a partial response, three had stable disease and four had progressive disease after the first cycle. Conclusions: Both irinotecan and Semaxanib could be given at their full single-agent recom-mended doses without significant toxicity, and the combination showed signs of clinical activity. However, owing to discouraging results from Phase III trials, it is unlikely that this combination will be further explored. Key words: Semaxanib – irinotecan – colon cancer – phase II – angiogenesi
Jody Filippo Capitanio - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms, indications and results of salvage systemic therapy for sporadic and von Hippel–Lindau related hemangioblastomas of the central nervous system
Critical reviews in oncology hematology, 2012Co-Authors: Jody Filippo Capitanio, Elena Mazza, Micaela Motta, Pietro Mortini, Michele ReniAbstract:Hemangioblastomas (HBs) are rare indolent vascular tumors that may occur sporadically or in association with von Hippel-Lindau (VHL) disease. Total neurosurgical resection is the standard upfront approach providing long-term tumor control. At time of tumor recurrence, second surgery, radiosurgery or radiotherapy are the main therapeutic strategies. Limited information is available on the role of pharmacological strategies. Anti-angiogenic agents, particularly multitarget tyrosine kinase inhibitors (Semaxanib, sunitinib, vatalanib), thalidomide and interferon alfa-2a are currently the most widely studied strategies to prolonge disease stability. Salvage therapy with anti-angiogenetic drugs may be of benefit in some patients who are not suitable for surgery, radiosurgery or radiotherapy, with progressive or recurrent hemangioblastoma especially those located in retina, since anti-angiogenetic therapy may delay tumor progression. This strategy warrants prospective evaluation in a clinical trial.
