Non-aromatic polyketide natural products of marine origin are often characterized by both significant structural complexity and extraordinary biological activities. Because these exciting compounds are not typically available in any meaningful quantities from natural sources, total chemical synthesis is the only means by which sufficient amounts of material may be accessed for the full biological/preclinical evaluation of these compounds. No natural product better exemplifies this class of compound than spongistatin 1. This extraordinarily complex and precious marine natural product has an average IC50 value against the NCI panel of 60 human cancer cell lines of 0.12 pM. The ultimate goal of this proposal is to adapt spongistatin 1 for use in an antibody-drug conjugate (ADC) construct, by way of the design, synthesis and evaluation of a series of analogs of spongistatin 1 to identify appropriate linker sites for bioconjugation and to identify a significanly structurally simplified analog that retains the sub-nanomolar potency of the natural product. Our focus on an ADC approach derives mainly from two considerations: 1) this approach requires far less drug material than conventional approaches, rendering the synthesis of the kinds of amounts required for full clinical evaluation a significantly more realistic proposition, and 2) th low pM potency of spongistatin 1 renders it an ideal candidate for use in an ADC, as so little drug material makes it to the target that extraordinary potency is required for any meaningful clinical efficacy. In order to achieve these goals, we will continue to develop synthetic methods for the synthesis of polyketide natural products that are characterized by unprecedented levels of step-economy, efficiency, and scalability to continue to push the frontiers of efficiency in the chemical synthesis. We will then apply these methods to the development of a synthesis of spongistatin 1 that may easily be adapted for use in the preparation of the designed analogs. Finally, we will identify and synthesize significant quantities of the most significantly structuraly simplified compound equipped with a linker that retains the low pM potency of spongistatin 1.

Public Health Relevance

Spongistatin 1 is a structurally complex macrolide natural product of marine origin that has been shown to be an extraordinarily potent cytotoxic agent with a ?-tubulin- binding/microtubule-destabilizing mechanism of action. The synthesis and evaluation of analogs of the natural product, with the ultimate aim of advancing a compound into the clinic, will require new synthetic chemistry that is characterized by unprecedented levels of step-economy, efficiency, and scalability. This proposal describes our plans to develop such synthetic chemistry and apply it to the synthesis of a series of analogs of spongistatin 1 to identify and prepare multi-gram quantities of a suitable candidate for use in an antibody-drug conjugate (ADC) approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM058133-13
Application #
8632159
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
1998-08-01
Project End
2018-04-30
Budget Start
2014-09-01
Budget End
2015-04-30
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Chemistry
Type
Graduate Schools
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10027
Foley, Corinne N; Leighton, James L (2015) A Highly Stereoselective, Efficient, and Scalable Synthesis of the C(1)-C(9) Fragment of the Epothilones. Org Lett 17:5858-61
Ho, Stephen; Sackett, Dan L; Leighton, James L (2015) A ""methyl extension"" strategy for polyketide natural product linker site validation and its application to dictyostatin. J Am Chem Soc 137:14047-50
Foley, Corinne N; Leighton, James L (2014) Beyond the Roche ester: a new approach to polypropionate stereotriad synthesis. Org Lett 16:1180-3
Tanis, Paul S; Infantine, Joshua R; Leighton, James L (2013) Exploiting pseudo C2-symmetry for an efficient synthesis of the F-ring of the spongistatins. Org Lett 15:5464-7
Suen, Linda M; Steigerwald, Michael L; Leighton, James L (2013) A new and more powerfully activating diamine for practical and scalable enantioselective aldehyde crotylsilylation reactions. Chem Sci 4:2413-2417
Ho, Stephen; Bucher, Cyril; Leighton, James L (2013) A highly step-economical synthesis of dictyostatin. Angew Chem Int Ed Engl 52:6757-61
Reznik, Samuel K; Leighton, James L (2013) Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts. Chem Sci 4:1497-1501
Harrison, Tyler J; Rabbat, Philippe M A; Leighton, James L (2012) An ""aprotic"" Tamao oxidation/syn-selective tautomerization reaction for the efficient synthesis of the C1-C9 fragment of fludelone. Org Lett 14:4890-3
Chalifoux, Wesley A; Reznik, Samuel K; Leighton, James L (2012) Direct and highly regioselective and enantioselective allylation of β-diketones. Nature 487:86-9
Reznik, Samuel K; Marcus, Brian S; Leighton, James L (2012) Complex fragment coupling by crotylation: A powerful tool for polyketide natural product synthesis. Chem Sci 3:3326-3330

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