The objective of this research is the discovery and chemical study of novel cyototoxic agents from higher plants. A panel of human tumor cell lines (HTLC) (A-549 (lung carcinoma), HT-29 (colon adenocarcinoma), MCF-7 (breast adenocarcinoma), RPMl-7951 (melanoma) and U251MG (glioblastoma multiforme) is utilized to measure in vitro cytotoxicity. Plants from the United States, Mexico, Brazil, Chile, Egypt, Thailand and China will be acquired for screening in the HTCL. Those plants with confirmed activities will be re-collected for large- scale bioactivity-directed fractionation. Plants that are currently under active fractionation and chemical studies include Annona coriacea, Annona muricata, Desmos cochinchinenis, Polytrichum ohioense, and Polytrichum pallidisetum. Structures of purified active compounds will be elucidated by spectroscopic and chemical methods. Current spectroscopic studies involve crystalline actives from Annona coriacea, Desmos cochinchinensis and Polytrichum ohioense. Reisolation or semi-synthesis will be carried out to provide sufficient quantities of selected active lead compounds for further evaluations in the National Cancer Institute (NCI) in vitro human tumor panel and in NCI's and Abbott Laboratories' in vivo tumor models. Two compounds (coriacin and 4- desoxycoriacin from Annona coriacea) have shown significant in vivo activity at Abbott Laboratory. Chemical studies of selected compounds will be initiated to uncover structure-activity relationships. Lead compounds for the chemical studies include the polyketides from Annonaceae, aristolactams from Pararistolochia flos-avis, and vismiones from Psorospermum febrifugum. Projects of this types have significance based on advances achieved in the investigators knowledge of natural product chemistry and the discovery of potent cytotoxic agents which may have unique mechanisms of action. In many cases these compounds find use as interesting biochemical/pharmacological probes to help elucidate basic biological processes in cells. Although the vast majority of cytotoxic agents do not find use as drugs, they do provide interesting activity leads for the development of analogs for further evaluation as potential antineoplastic agents. In addition, by evaluating these cytotoxic agents in appropriate animal tumor models, the potential exists to discover agents which may become candidates for further anticancer drug development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA033326-10A1
Application #
3171252
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1982-09-30
Project End
1995-06-30
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Pharmacy
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Soonthornchareonnon, N; Suwanborirux, K; Bavovada, R et al. (1999) New cytotoxic 1-azaanthraquinones and 3-aminonaphthoquinone from the stem bark of Goniothalamus marcanii. J Nat Prod 62:1390-4
Permana, P A; Ho, D K; Cassady, J M et al. (1994) Mechanism of action of the antileukemic xanthone psorospermin: DNA strand breaks, abasic sites, and protein-DNA cross-links. Cancer Res 54:3191-5
Zheng, G Q; Ho, D K; Elder, P J et al. (1994) Ohioensins and pallidisetins: novel cytotoxic agents from the moss Polytrichum pallidisetum. J Nat Prod 57:32-41
Zennie, T M; Cassady, J M (1990) Funebradiol, a new pyrrole lactone alkaloid from Quararibea funebris flowers. J Nat Prod 53:1611-4
Cassady, J M; Baird, W M; Chang, C J (1990) Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents. J Nat Prod 53:23-41
Habib, A M; Reddy, K S; McCloud, T G et al. (1987) New xanthones from Psorospermum febrifugum. J Nat Prod 50:141-5
Sun, N J; Antoun, M; Chang, C J et al. (1987) New cytotoxic aristolactams from Pararistolochia flos-avis. J Nat Prod 50:843-6
Suwanborirux, K; Chang, C J; Cassady, J M (1987) Novel chromones from Spathelia sorbifolia. J Nat Prod 50:102-7
McCloud, T G; Smith, D L; Chang, C J et al. (1987) Annonacin, a novel, biologically active polyketide from Annona densicoma. Experientia 43:947-9
Pachuta, R R; Cooks, R G; Cassady, J M et al. (1986) Antineoplastic agents from higher plants: application of tandem mass spectrometry to xanthones from Psorospermum febrifugum. J Nat Prod 49:412-23

Showing the most recent 10 out of 11 publications