Synthesis and Antitumor Activity of Camptothecin Analogs

Wall, Monore E.

Abstract

The synthesis of a number of new analogs of camptothecin are proposed, which incorporate the requisite Alpha-hydroxy lactone moiety in ring E with ring substituents which should confer greater water solubility on the compounds. Thus, referrring to the basic structure of camptothecin, it is planned to synthesize all possible combinations of mono- and dihydroxy or mono- and diamino substituents involving positions 9, 10, 11, 12. Other monofunctional groups in ring A planned are -COOH, CH2OH, CH2NH2. Other structural types are planned. If the basic structures are active in L1210, then syntheses which include water solubilizing substituents will be conducted. The syntheses will be oriented toward obtaining 50-200 mg quantities for initial SAR evaluation in vitro and in vivo.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Research Project (R01)
• Project #: 5R01CA038996-02
• Application #: 3177586
• Study Section: Medicinal Chemistry Study Section (MCHA)
• Project Start: 1984-12-01
• Project End: 1987-11-30
• Budget Start: 1985-12-01
• Budget End: 1986-11-30
• Support Year: 2
• Fiscal Year: 1986

Institution

• Name: Research Triangle Institute
• DUNS #: 131606022
• City: Research Triangle Park
• State: NC
• Country: United States
• Zip Code: 27709

Publications

Pantazis, P; Kozielski, A; Rodriguez, R et al. (1994) Therapeutic efficacy of camptothecin derivatives against human malignant melanoma xenografts. Melanoma Res 4:5-10

Wall, M E; Wani, M C; Nicholas, A W et al. (1993) Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs. J Med Chem 36:2689-700

Nicholas, A W; Wani, M C; Manikumar, G et al. (1990) Plant antitumor agents. 29. Synthesis and biological activity of ring D and ring E modified analogues of camptothecin. J Med Chem 33:972-8

Wani, M C; Nicholas, A W; Manikumar, G et al. (1987) Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations. J Med Chem 30:1774-9

Wani, M C; Nicholas, A W; Wall, M E (1987) Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5'(RS)-1,5-dioxo-5'-ethyl-5'-hydroxy-2'H,5'H,6'H-6'-oxopyrano[3' ,4'- f]delta 6,8-tetrahydro-indolizine: total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecin. J Med Chem 30:2317-9

Wani, M C; Nicholas, A W; Wall, M E (1986) Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues. J Med Chem 29:2358-63