Natural products (NP's) are a significant source for both drug discovery and development of synthetic organic chemistry. The current renaissance of interest in NP's originates in technological advances that allow high-throughput screening, sub-nanomole analytical techniques and chemical genetics approaches to exploit minute quantities of naturally occurring compounds for drug discovery. Concurrently, advances in synthetic organic chemistry have demonstrated the applicability of multistep natural product synthesis to 'gram-scale' procurement of complex biologically active NP's, such as the macrolide polyketides phorboxazole and discodermolide, for preclinical and clinical testing. Analytical methods such as microcapillary NMR and mass spectrometry are amenable to NP's that are not suitable for X-ray crystallography, however, methods for determination of stereochemistry are still lacking. In order to capitalize on the convergence of sub-nanomole structure elucidation of anti-tumor natural products and macro-scale synthesis, and subscribe to priorities of the NIH Roadmap in molecular discovery, we propose development of a suite of methods for isolation and elucidation of stereochemistry of natural products at sub- nanomole amounts.
Aim 1 will extend our recently-described method for determining relative and absolute configuration of acyclic 1,n-diols (n greater than or equal to 5) to double-skipped tetraols and pentaols using exciton coupling circular dichroism in nanoscale-liposomes to polyols (e.g. caylobolide A).
Aim 2 will exploit CD methods for stereochemical elucidation of chlorocyclopropane-containing macrolides, such as that found in callipeltosides A-C and the new analogs, phorbasides A-E, at sub-nanomole levels.
AIM 3 will apply a hybrid approach to elucidate multiple contiguous stereocenters in acyclic amino-polyols and polyols using a combination of J- based analysis, semi-synthesis and 'universal NMR database' motifs for configurational analysis of two acyclic polyketide families, represented by zwittermicin A and saggitamide A, and Aim 4 will address apply the methods to isolation of novel proapoptotic compounds from marine invertebrates. The outcome of this work will provide new antitumor compound leads, resolve stereochemical complexity of key NP's, refine analytical tools for stereochemical correlations of specific classes of natural products at sub-nanomole levels, and reveal to the community new stereo-defined antitumor NP targets for total synthesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122256-02
Application #
7265257
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2006-07-22
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$196,965
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Molinski, Tadeusz F; Morinaka, Brandon I (2012) INTEGRATED APPROACHES TO THE CONFIGURATIONAL ASSIGNMENT OF MARINE NATURAL PRODUCTS. Tetrahedron 68:9307-9343
Smith 3rd, Amos B; Hogan, Anne-Marie L; Liu, Zhuqing et al. (2011) Phorboxazole Synthetic Studies: Design, Synthesis and Biological Evaluation of Phorboxazole A and Hemi-Phorboxazole A Related Analogues. Tetrahedron 67:5069-5078
Ko, Jaeyoung; Morinaka, Brandon I; Molinski, Tadeusz F (2011) Faulknerynes A-C from a Bahamian sponge Diplastrella sp.: stereoassignment by critical application of two exciton coupled CD methods. J Org Chem 76:894-901
Flores, Beatris; Molinski, Tadeusz F (2011) Assembly of the isoindolinone core of muironolide A by asymmetric intramolecular Diels-Alder cycloaddition. Org Lett 13:3932-5
Morinaka, Brandon I; Molinski, Tadeusz F (2011) Mollenyne A, a long-chain chlorodibromohydrin amide from the sponge Spirastrella mollis. Org Lett 13:6338-41
Molinski, Tadeusz F; Ko, Jaeyoung; Reynolds, Kirk A et al. (2011) N,N'-methyleno-didemnin A from the ascidian Trididemnum solidum. Complete NMR assignments and confirmation of the imidazolidinone ring by strategic analysis of 1J(CH). J Nat Prod 74:882-7
Morinaka, Brandon I; Molinski, Tadeusz F (2011) Xestoproxamines A-C from Neopetrosia proxima. Assignment of absolute stereostructure of bis-piperidine alkaloids by integrated degradation-CD analysis. J Nat Prod 74:430-40
Dalisay, Doralyn S; Quach, Tim; Molinski, Tadeusz F (2010) Liposomal circular dichroism. Assignment of remote stereocenters in plakinic acids K and L from a Plakortis-Xestospongia sponge association. Org Lett 12:1524-7
Dalisay, Doralyn S; Molinski, Tadeusz F (2010) Structure elucidation at the nanomole scale. 3. Phorbasides G-I from Phorbas sp. J Nat Prod 73:679-82
Molinski, Tadeusz F (2010) NMR of natural products at the 'nanomole-scale'. Nat Prod Rep 27:321-9

Showing the most recent 10 out of 27 publications