As an especially unique target for chemical synthesis, diazonamide A has the potential to be constructed through a plethora of synthetic routes, each attended by different challenges and opportunities for discovery. In this article, we detail our second total synthesis of diazonamide A through a sequence entirely distinct from that employed in our first campaign, one whose success required the development of several special strategies and tactics. We also disclose our complete studies regarding the chemical biology of diazonamide A and its structural congeners, and more fully delineate the scope of our protocol for Robinson-Gabriel cyclodehydration using pyridine-buffered POCl(3).
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Sci Transl Med
November 2016
Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types.
View Article and Find Full Text PDFAnticancer Agents Med Chem
August 2008
Department of Chemistry, University of Delhi, Delhi-110007, India.
The chemical, biological and ecological diversity of the marine ecosystem has contributed immensely in the discovery of extremely potent compounds that have shown potent activities in antitumor, analgesia, antiinflammatory, immunomodulation, allergy, anti-viral etc. The compounds of marine origin are diverse in structural class from simple linear peptides to complex macrocyclic polyethers. The recent advances in the sophisticated instruments for the isolation and characterization of marine natural products and development of high-throughput screening, have substantially increased the rate of discovery of various compounds of biomedical application.
View Article and Find Full Text PDFNat Prod Rep
April 2008
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
The complex structure of the marine metabolic diazonamide A comprises a dichlorinated indole bis-oxazole heteroaromatic fragment, and a [b]-fused dihydrobenzofuran-dihydroindole unit containing an animal carbon, all incorporated within a strained double macrocyclic array. This review details the synthetic studies on this fascinating natural product starting from early studies on the original structure (1991-2001), through the synthesis of the originally proposed structure and the subsequent structural revision, to the eventual successful syntheses of the natural product itself. Throughout we focus on the innovative ways in which synthetic chemists have approached the challenges posed by this natural product.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
February 2005
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Fax: (+1) 858-784-2469.
Over the course of the past half century, the structural elucidation of unknown natural products has undergone a tremendous revolution. Before World War II, a chemist would have relied almost exclusively on the art of chemical synthesis, primarily in the form of degradation and derivatization reactions, to develop and test structural hypotheses in a process that often took years to complete when grams of material were available. Today, a battery of advanced spectroscopic methods, such as multidimensional NMR spectroscopy and high-resolution mass spectrometry, not to mention X-ray crystallography, exist for the expeditious assignment of structures to highly complex molecules isolated from nature in milligram or sub-milligram quantities.
View Article and Find Full Text PDFJ Am Chem Soc
October 2004
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
As an especially unique target for chemical synthesis, diazonamide A has the potential to be constructed through a plethora of synthetic routes, each attended by different challenges and opportunities for discovery. In this article, we detail our second total synthesis of diazonamide A through a sequence entirely distinct from that employed in our first campaign, one whose success required the development of several special strategies and tactics. We also disclose our complete studies regarding the chemical biology of diazonamide A and its structural congeners, and more fully delineate the scope of our protocol for Robinson-Gabriel cyclodehydration using pyridine-buffered POCl(3).
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