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Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives

Author:
Chen, Ching-Huang, Lin, Yi-Wen, Kakadiya, Rajesh, Kumar, Amit, Chen, Yu-Ting, Lee, Te-Chang, Su, Tsann-Long
Source:
Tetrahedron 2011 v.67 no.33 pp. 5883-5893
ISSN:
0040-4020
Subject:
acridines, cell growth, chemical reactions, chemical structure, cytotoxicity, humans, lymphocytic leukemia, propionic acid, pyridines
Abstract:
A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido[3,2,1-de]acridines were synthesized for antitumor evaluation. These agents can be considered as analogues of glyfoline or (±)1,2-dihydroxyacronycine derivatives. The key intermediates, 3,7-dioxopyrido[3,2,1-de]acridines (15a,b or 24a,b), for constructing the target compounds were synthesized either from 3-(N,N-diphenylamino)propionic acid (14a,b) by treating with Eaton’s reagent (P₂O₅/MsOH) (Method 1) or from (9-oxo-9H-acridin-10-yl)propionic acid (23a–c) via ring cyclization under the same reaction conditions (Method 2). Compounds 15a,b and 24a,b were converted into (±)3-hydroxy derivatives (25a–d), which were then further transformed into pyrido[3,2,1-de]acridin-7-one (28a–d) by treating with methanesulfonic anhydride in pyridine via dehydration. 1,2-Dihydroxylation of 28a–d afforded (±)cis-2,3-dihydroxy-7-oxopyrido[3,2,1-de]acridine (29a–d). Derivatives of (±)3-hydroxy (25a,b) and (±)cis-2,3-dihydroxy (29a–d) were further converted into their O-acetyl congeners 26a,b and 30a–d, respectively. We also synthesized 2,3-cyclic carbonate (31, 32, and 33) from 29a–c. The anti-proliferative study revealed that these agents exhibited low cytotoxicity in inhibiting human lymphoblastic leukemia CCRF-CEM cell growth in culture.
Agid:
1094004