The principal goal of this research program is to develop a practical synthetic approach to the spongipyrans, a family of architecturally unique bisspiroketal macrolides, which possess extraordinary antitumor activities. Building upon the progress of the 01-03 years, we achieved the total syntheses of both (+)- spongistatin 1 and 2 in the 04-07 years; the former proved to be the shortest synthesis of a spongistatin reported to date, with a longest linear sequence of 29 steps (other published sequences are ca. greater than or equal too 32 steps). Equally important, we have developed a highly efficient (22 steps, 4% overall yield), second-generation synthesis of the requisite advanced ABCD aldehyde, capable of producing gram quantities (vide infra), which when combined with an equally viable synthesis of the advanced EF Wittig salt, will permit construction of at least one gram of totally synthetic spongistatin 1 for pre-clinical development.
The specific aims (A-E) for the next four years are: (A) to complete a highly efficient third-generation synthesis of spongistatin 1 capable of delivering a minimum of one gram, in order to make this important antitumor agent available for pre-clinical evaluation; (B) to provide advanced intermediates for in depth structure-activity studies; (C) to design and synthesize, guided by the structural activity results, less complex analogs possessing significant antitumor activity; and (D) to prepare photo-affinity, fluorescent and radiolabels to define both the site and molecular mechanism of action of these important antitumor agents. Notwithstanding the enormity of this challenge, we are convinced that the synthetic plan described herein will prove superior to isolation as a practical and environmentally sound source of this exciting and immensely important anticancer agent. In the area of new synthetic methods, the Specific Aims for the next four years will include: (E) the development of new bifunctional reagents based on the Brook rearrangement to construct a variety of structurally complex structures via multicomponent one-flask reactions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA070329-08
Application #
6774167
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
1996-09-01
Project End
2008-02-29
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
8
Fiscal Year
2004
Total Cost
$335,934
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Smith 3rd, Amos B; Risatti, Christina A; Atasoylu, Onur et al. (2011) Design, synthesis, and biological evaluation of diminutive forms of (+)-spongistatin 1: lessons learned. J Am Chem Soc 133:14042-53
Xu, Qunli; Huang, Kuan-Chun; Tendyke, Karen et al. (2011) In vitro and in vivo anticancer activity of (+)-spongistatin 1. Anticancer Res 31:2773-9
Atasoylu, Onur; Furst, George; Risatti, Christina et al. (2010) The solution structure of (+)-spongistatin 1 in DMSO. Org Lett 12:1788-91
Smith 3rd, Amos B; Risatti, Christina A; Atasoylu, Onur et al. (2010) Design, synthesis, and biological evaluation of EF- and ABEF- analogues of (+)-spongistatin 1. Org Lett 12:1792-5
Smith, Amos B; Lin, Qiyan; Doughty, Victoria A et al. (2009) Spongipyran Synthetic Studies. Total Synthesis of (+)-Spongistatin 2. Tetrahedron 65:6470-6488
Smith, Amos B; Sfouggatakis, Chris; Risatti, Christina A et al. (2009) Spongipyran Synthetic Studies. Evolution of a Scalable Total Synthesis of (+)-Spongistatin 1. Tetrahedron 65:6489-6509
Smith 3rd, Amos B; Tomioka, Takashi; Risatti, Christina A et al. (2008) Gram-scale synthesis of (+)-spongistatin 1: development of an improved, scalable synthesis of the F-ring subunit, fragment union, and final elaboration. Org Lett 10:4359-62
Smith 3rd, Amos B; Fox, Richard J; Razler, Thomas M (2008) Evolution of the Petasis-Ferrier union/rearrangement tactic: construction of architecturally complex natural products possessing the ubiquitous cis-2,6-substituted tetrahydropyran structural element. Acc Chem Res 41:675-87
Smith 3rd, Amos B; Sfouggatakis, Chris; Gotchev, Dimitar B et al. (2004) Spongistatin synthetic studies. evolution of a scalable synthesis for the EF fragment of (+)-Spongistatin 1 exploiting a Petasis-Ferrier union/rearrangement tactic. Org Lett 6:3637-40
Smith 3rd, Amos B; Adams, Christopher M (2004) Evolution of dithiane-based strategies for the construction of architecturally complex natural products. Acc Chem Res 37:365-77

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