Straightforward access to anhydrovinblastine starting from the parent alkaloid leurosine is reported. The key deoxygenation step was first optimized on a model substrate. However, applied to leurosine, only the low-valent Cp2TiCl gave satisfactory results.
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Potent Vinblastine C20' Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line.
ACS Med Chem Lett
September 2013
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
A series of disubstituted C20'-urea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH- mediated alkene functionalization reaction of anhydrovinblastine. Three analogs were examined across a panel of 15 human tumor cell lines, displaying remarkably potent cell growth inhibition activity (avg. IC = 200-300 pM), being 10-200-fold more potent than vinblastine (avg.
View Article and Find Full Text PDFSynthesis and biological evaluation of a new series of highly functionalized 7'-homo-anhydrovinblastine derivatives.
J Med Chem
August 2013
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, UPR 2301 du CNRS, LabEx Lermit, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
Sixteen new 7'-homo-anhydrovinblastine derivatives were prepared in one or two steps from vinorelbine by means of an original and regiospecific rearrangement and subsequent diastereoselective reduction. This strategy has allowed fast access to a family of vinca alkaloid derivatives with an enlarged and functionalized ring C'. Their synthesis and biological evaluation are reported.
View Article and Find Full Text PDFA remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives.
J Med Chem
February 2013
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH(4)-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an X-ray cocrystal structure, remarkably large C20' urea derivatives are accommodated.
View Article and Find Full Text PDFSelective deoxygenation of leurosine: concise access to anhydrovinblastine.
J Org Chem
September 2002
CEA/Saclay, Service de Marquage Moléculaire et de Chimie Bioorganique, Bât. 547, Département de Biologie Joliot-Curie, 91191 Gif sur Yvette Cedex, France.
Straightforward access to anhydrovinblastine starting from the parent alkaloid leurosine is reported. The key deoxygenation step was first optimized on a model substrate. However, applied to leurosine, only the low-valent Cp2TiCl gave satisfactory results.
View Article and Find Full Text PDFVinorelbine: an active drug for the management of patients with heavily pretreated Hodgkin's disease.
Ann Oncol
November 1994
Division of Medical Oncology, Istituto Nazionale Tumori, Milan, Italy.
Background: This study evaluated the therapeutic effect of the weekly administration of vinorelbine (5'-nor-anhydrovinblastine), a semisynthetic vinca alkaloid, in heavily pretreated patients with Hodgkin's disease.
Patients And Methods: Twenty-four patients with Hodgkin's disease refractory or resistant to at least two chemotherapy regimens were enrolled in this study. Vinorelbine was administered in a weekly dose of 30 mg/m2 i.
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