The principle objectives of this science described in this proposal are to develop the chemistry and biology of two complex marine-derived natural products that possess potent pharmacological activity, and that are either unavailable, or available only in minute amounts from their natural sources. The first target is spirastrellolide B, a very complex macrolide that displays nanomolar IC50 values against protein phosphatases of relevance to cancer therapy. A concise, potentially gram-scale, synthesis of this compound is proposed that will provide material for further biological study. Structural biology information, along with analysis of the chemical features of a number of compounds related to spirastrellolide will also be used to try and identify molecules that modulate protein phosphatases in an selective fashion. The second target is adriatoxin, a decacyclic 'ladder'polyether that has been implicated in diarrhetic shellfish poisoning and is a close analog of compounds that have remarkable anti-cancer activity. A concise, 30 step synthesis, that employs new chemistry is described for adriatoxin, and material obtained by the synthesis will be used to identify adriatoxin's molecular target. The marine environment is a prolific source of pharmacologically interesting molecules that have potential both as drugs and as probes for biological systems. However there are a number of obstacles that prevent this potential from becoming routine reality, the two most significant being the often high level of complexity among molecules produced by marine organisms and the fact that they are usually only produced in miniscule amounts. The primary goals of the research in this proposal are to develop new synthetic chemistry routes to two important classes of complex marine natural products that have potent biological activity and to use material produced by this endeavor to study their biology.

Public Health Relevance

Complex natural products have long been a rich source of pharmacologically interesting molecules that have both potential and proven utility as drugs. This is particularly true in the realm of anti-bacterial and anti-cancer agents. One key factor that prevents further success in this arena is the lack of robust and general chemistry routes that can be adopted for thorough structure-activity investigations, particularly if there is limited material available from the natural source. In many cases this is a serious impediment to the further study of the biological potential of naturally occurring compounds. The goals of the research described in this proposal are to develop the chemistry and biology of two complex molecules: spirastrellolide B, a molecule with potent anti-cancer activity;and adriatoxin, a member of a class of molecules that possess a variety of biological activities ranging from ion-channel inhibition to anti-cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA110246-08
Application #
8265671
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Misra, Raj N
Project Start
2004-03-24
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$229,247
Indirect Cost
$72,583
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Jackson, Katrina L; Henderson, James A; Motoyoshi, Hajime et al. (2009) A total synthesis of norhalichondrin B. Angew Chem Int Ed Engl 48:2346-50
Griggs, Nolan D; Phillips, Andrew J (2008) A concise and modular synthesis of pyranicin. Org Lett 10:4955-7
Jackson, Katrina L; Henderson, James A; Morris, Jonathan C et al. (2008) A synthesis of the C1-C15 domain of the halichondrins. Tetrahedron Lett 49:2939-2941
Nasveschuk, Christopher G; Ungermannova, Dana; Liu, Xuedong et al. (2008) A concise total synthesis of largazole, solution structure, and some preliminary structure activity relationships. Org Lett 10:3595-8
Keaton, Katie A; Phillips, Andrew J (2008) Toward the synthesis of spirastrellolide B: a synthesis of the C1-C23 subunit. Org Lett 10:1083-6
Um, Joann M; Houk, K N; Phillips, Andrew J (2008) Origin of stereoselectivity in the reduction of a planar oxacarbenium. Org Lett 10:3769-72
Henderson, James A; Phillips, Andrew J (2008) Total synthesis of aburatubolactam A. Angew Chem Int Ed Engl 47:8499-501
Henderson, James A; Jackson, Katrina L; Phillips, Andrew J (2007) Highly functionalized pyranopyrans from furans: a synthesis of the C27-C38 and C44-C53 subunits of norhalichondrin B. Org Lett 9:5299-302
Keaton, Katie A; Phillips, Andrew J (2006) Titanium(II)-mediated cyclizations of (silyloxy)enynes: a total synthesis of (-)-7-demethylpiericidin A1. J Am Chem Soc 128:408-9
Hart, Amy C; Phillips, Andrew J (2006) Total synthesis of (+)-cylindramide A. J Am Chem Soc 128:1094-5

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