synthesis and electrophilic substitution of pyrido[2,3,4-kl]-acridines合成与亲电取代的pyrido[2、3、4-kl]-acridines.pdfVIP

Molecules 2001, 6, 300-322 molecules ISSN 1420-3049 Synthesis and Electrophilic Substitution of Pyrido[2,3,4-kl]- acridines‡ 1 1 2 1,* Avi Koller , Amira Rudi , Marta Garcia Gravalos and Yoel Kashman 1 School of Chemistry, Tel Aviv University, Ramat Aviv 69978, Israel 2 PharmaMar, Tres- Cantos, Madrid, Spain * To whom correspondence should be addressed; E-mail: kashman@post.tau.ac.il; Phone: +972-3-640- 8419. Fax: +972-3-640-9293. ‡ Presented at the 4th Electronic Conference on Synthetic Organic Chemistry, September 1-30, 2000, (Paper A0029). Received: 28 February 2001; in revised form 7 March 2001 / Accepted: 7 March 2001 / Published: 31 March 2001 Abstract: Several new pyrido[2,3,4-kl]acridines were synthesized by reacting naphthoquinone, juglone or cyclohexan-1,3-dione with β,β’-diaminoketones in a biomimetic reaction. The structure of all new compounds was elucidated by NMR and MS spectroscopy. Electrophilic substitution, mainly nitration, of the various compounds was undertaken and the substitution positions determined. A series of derivatives was prepared and their cytotoxicity towards P-388 mouse lymphoma cells analysed. The most cytotoxic derivatives were found to have IC50’s of 0.05 and 0.1 ug/ml. Keywords: Pyrido[2,3,4-kl]acridines; Biomimetic synthesis; NMR; Electrophilic nitration; Cytotoxicity Introduction Over the last 15 years more than 50 pyridoacridine alkaloids, based on the 4H-pyrido[2,3,4- kl]acridone (1) skeleton (Figure 1), have been isolated from marine