This grant application describes the proposed total syntheses of a number of potent antitumor agents of natural origin, namely lomaiviticins A and B, cytoskyrin A, amphidinolide N and caribenolide I, as well as a number of related molecules for biological screening. The proposed total synthesis of the lomaiviticins would involve the dimerization of an advanced a-halo enone intermediate to generate the C2-symmetric polycyclic framework. Further elaboration of the sterically crowded central core would then be facilitated by the temporary incorporation of a bridging cyclic tether. Two alternative such tethers have been devised, namely a tetrahydrothiophene and a carbocycle bearing a pendant ester group, increasing the flexibility of the overall strategy. Once the required structural motifs are installed, either of these bridges could be oxidatively cleaved to reveal the necessary functionalities for completion of the target molecules. For cytoskyrin A, a biomimetic cascade process to furnish the cage-like framework of the target molecule has been experimentally demonstrated. Involving the acid-catalyzed dimerization of an anthraquinone derivative followed by a bis-enolization/ double intramolecular Michael addition sequence, careful monitoring of this cascade allows for the selective generation of the central core of not only cytoskyrin A, but also that of a number of other structurally related biologically active natural products. This cascade process would be amenable to the production of not only these natural products themselves, but also to that of specifically targeted analogs, which would be screened for antitumor activity. The proposed syntheses of amphidinolide N and caribenolide I feature a unified, highly convergent strategy involving the sequential asymmetric alkylation of a chiral 1,3-dihydroxyacetone equivalent to establish the complete carbon framework of the target molecules, followed by a highly selective macrolactonization to generate the 26-membered ring in each case. The significance of the proposed work will lie specifically in the area of cancer chemotherapy research, and in the development of new synthetic strategies and technologies for general use in the drug discovery and development process.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100101-05
Application #
7768452
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2006-04-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$517,388
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Nicolaou, K C; Lu, Min; Totokotsopoulos, Sotirios et al. (2012) Synthesis and biological evaluation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines: synthetic methodology, enantioselective total synthesis of epicoccin G, 8,8'-epi-ent-rostratin B, gliotoxin, gliotoxin G, emethallicin E, and haematoc J Am Chem Soc 134:17320-32
Nicolaou, K C; Jiang, Xuefeng; Lindsay-Scott, Peter J et al. (2011) Total synthesis and biological evaluation of monorhizopodin and 16-epi-monorhizopodin. Angew Chem Int Ed Engl 50:1139-44
Nicolaou, K C; Ellery, Shelby P; Rivas, Fatima et al. (2011) Synthesis and biological evaluation of 2',4'- and 3',4'-bridged nucleoside analogues. Bioorg Med Chem 19:5648-69
Nicolaou, K C; Kiappes, J L; Tian, Weiwei et al. (2011) Synthesis of the carboline disaccharide domain of shishijimicin A. Org Lett 13:3924-7
Nicolaou, K C; Totokotsopoulos, Sotirios; Giguere, Denis et al. (2011) Total synthesis of epicoccin G. J Am Chem Soc 133:8150-3
Saielli, Giacomo; Nicolaou, K C; Ortiz, Adrian et al. (2011) Addressing the stereochemistry of complex organic molecules by density functional theory-NMR: vannusal B in retrospective. J Am Chem Soc 133:6072-7
Nicolaou, K C; Sun, Ya-Ping; Korman, Henry et al. (2010) Asymmetric total synthesis of cylindrocyclophanes A and F through cyclodimerization and a Ramberg-B├Ącklund reaction. Angew Chem Int Ed Engl 49:5875-8
Nicolaou, K C; Ortiz, Adrian; Zhang, Hongjun et al. (2010) Total synthesis and structural revision of vannusals A and B: synthesis of the true structures of vannusals A and B. J Am Chem Soc 132:7153-76
Hayden, Amy E; Paton, Robert S; Becker, Jochen et al. (2010) Origins of regioselectivity of Diels-Alder reactions for the synthesis of bisanthraquinone antibiotic BE-43472B. J Org Chem 75:922-8
Nicolaou, K C; Ortiz, Adrian; Zhang, Hongjun et al. (2010) Total synthesis and structural revision of vannusals A and B: synthesis of the originally assigned structure of vannusal B. J Am Chem Soc 132:7138-52

Showing the most recent 10 out of 22 publications