Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives |
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Authors: | Ching-Huang ChenYi-Wen Lin Rajesh KakadiyaAmit Kumar Yu-Ting ChenTe-Chang Lee Tsann-Long Su |
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Institution: | a Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan b Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan |
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Abstract: | A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido3,2,1-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-dioxopyrido3,2,1-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 pyrido3,2,1-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-oxopyrido3,2,1-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. |
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Keywords: | Acridine Acronycine Eaton&rsquo s reagent Ullmann condensation Cyclization |
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