In the course of studies involving the enantioselective synthesis of biologically active alkaloids, we have prepared chiral alpha-sulfinyl ketimines. The anions of these ketimines undergo in situ 1,4-addition/ring closure reactions with alpha-ene esters, 1,3-diiodopropane, and 3-chloro-2- chloromethylpropene. We propose to study the asymmetric addition reactions of the anions of various chiral alpha-sulfinyl ketimines and substituted acyclic and cyclic alpha-ene esters, and other electrophiles, and the stereoselective reduction of the resulted beta-sulfinyl enamides and enamines. The utilization of these reactions in the asymmetric syntheses of indolizidines [e.g., (+)-castanospermine and (-)-slaframine], quinolizidines [e.g., (-)-lupinine], pyrrolizidines [e.g., (+)-yohimbine and 18,19-dihydrousambarine], and beta-carboline alkaloids [e.g., (-)- emetine] will be studies. The synthesized natural products, their synthetic intermediates, and analogs will be tested for antitumor activity using in vitro tissue culture systems in Dr. Dolores Takemoto's laboratory (co-investigator), and anti-AIDS activities in Dr. V.L. Narayanan's laboratory, Drug Synthesis & Chemistry Branch, National Cancer Institute. The proposed synthetic schemes are general and should provide many useful biologically active synthetic intermediates and analogues. The cytotoxic activity in vitro against cancer cells (P388, P815, and L1210 cells), the toxicity towards normal cells, and the mechanism of actions (in vitro; DNA, RNA, and protein inhibitions) of these compounds will be studied.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA051794-01
Application #
3196463
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1990-05-01
Project End
1993-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Kansas State University
Department
Type
Schools of Arts and Sciences
DUNS #
City
Manhattan
State
KS
Country
United States
Zip Code
66506
Robinson, P D; Hua, D H; Good, L A et al. (1993) (4S,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one. Acta Crystallogr C 49 ( Pt 6):1238-40
Robinson, P D; Hua, D H; Wu, X et al. (1992) Ethyl (2R,3R,SR)-3-(ethoxycarbonyloxy)-2-[1-(p-tolylsulfinyl) cyclopropyl]-1-pyrrolidinecarboxylate. Acta Crystallogr C 48 ( Pt 11):2088-90