The overall objective of this research program is the development of efficient procedures for the construction of architecturally novel antitumor agents.
Specific aims for the 14-18 years will be to complete the total synthesis of breynogenin and stubomycin. The structure of breynogenin closely resembles that of the aglycone of phyllanthoside, and as such is an ideal synthetic target in that it will provide additional analogs of the phyllanthoside-phyllanthostatin class of antitumor agents. (Note that during the 10-13 year of this program, we completed the first, and to this date the only, total syntheses of three of the four members of the phyllanthoside-phyllanthostatin family.) Stubomycin, on the other hand, possesses a novel macrocyclic lactam skeleton; it has been reported to display potent anitumor activity against the sarcoma 180, IMC-carcinoma and meth-A tumor cell lines. As new tragets in the antitumor area, we have chosen calyculin A and the trienomycins A, B and C. Our interest in calyculin A stems from the (6.5) spiroketal system, common to the phyllanthocin-breynogenin aglycones. Calyculin A displays both potent inhibitory activity against the development of starfish embryos (0.01 mu g /mL) and strong cytotoxic activity against the L1210 cell line (IC50 1.75 x 10-3 mu g/mL). The trienomycins, all of which display strong cytotoxic activity against HeLa S3 cells in vitro, represent a natural extension of our stubomycin work. In addition to the above quite specific synthetic goals, a more general underlying and long range aim of this research program is the development of a better understanding of the molecular architecture responsible for the antitumor properties of these and related system. Thus, as we develop our method of procedure for each of the above targets, we will also introduce various analog systems which will be amenable to construction and subsequent testing, such that in the end we will be able to dissect out the critical structural feature or features responsible for the observed antitumor properties. Once such features are identified, the design of new and possibly more effective antitumor drugs should be feasible.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA019033-14
Application #
3165078
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1976-06-30
Project End
1992-05-31
Budget Start
1989-09-21
Budget End
1990-05-31
Support Year
14
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Nazari, Mohamad; Serrill, Jeffrey D; Wan, Xuemei et al. (2017) New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors. J Med Chem 60:7850-7862
Nguyen, Minh H; Imanishi, Masashi; Kurogi, Taichi et al. (2016) Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol. J Am Chem Soc 138:3675-8
Adams, Gregory L; Smith 3rd, Amos B (2016) The Chemistry of the Akuammiline Alkaloids. Alkaloids Chem Biol 76:171-257

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