Design and synthesis of novel tetrahydro-2H-Pyrano[3,2-c]Pyridazin-3(6H)-one derivatives as potential anticancer agents

被引：20
作者：
Al-Tel, Taleb H. [1 ,2 ]
机构：
[1] Univ Sharjah, Dept Med Chem, Coll Pharm, Sharjah, U Arab Emirates
[2] Univ Sharjah, Sharjah Inst Med Res, Canc Div, Sharjah 27272, U Arab Emirates
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 45卷 / 12期
关键词：
Pyrenones; Tetrahydro-2H-pyrano[3,2-c]pyridazin-3 (6H)-one; Synthesis; beta-Ketoesters; Achmatowicz reaction; Anticancer activity; NATURAL-PRODUCTS; ASYMMETRIC-SYNTHESIS; DRUG DISCOVERY; CANCER; ANTAGONISTS; CHEMISTRY; ANALOGS; SPACE; LEADS;
D O I：
10.1016/j.ejmech.2010.09.029
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Polyfunctional tetrahydro-2H-pyranol3,2-clpyridazin-3(6H)-one derivatives were synthesized and biologically evaluated as novel anticancer agents. These motifs were produced by a five-step reaction sequence in which the Achmatowicz oxidative cyclization, is the basic core for such synthesis. Compounds 15f, 16c, and 16d showed antiproliferative activity against the SK-BR-3 breast cancer cell line. Importantly, 16c and 16d showed the highest efficacy, being approximately 30-fold more potent against SK-BR-3 (IC50 0.21 and 0.15 mu M, respectively) compared to other cancer cell lines tested. In addition, 16c and 16d displayed about 295 fold less toxicity against normal breast cell line MCF10A compared to SKBR-3 breast cancer cells. These compounds form the foundation for further investigation in our continuing efforts to develop potent anticancer agents. (C) 2010 Elsevier Masson SAS. All rights reserved.
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收藏
页码：5724 / 5731
页数：8
相关论文
共 39 条
[1]   SYNTHESIS OF METHYL 2,3-DIDEOXY-DL-ALK-2-ENOPYRANOSIDES FROM FURAN COMPOUNDS - GENERAL APPROACH TO TOTAL SYNTHESIS OF MONOSACCHARIDES [J].
ACHMATOWICZ, O ;
BUKOWSKI, P ;
SZECHNER, B ;
ZWIERZCHOWSKA, Z ;
ZAMOJSKI, A .
TETRAHEDRON, 1971, 27 (10) :1973-+
[2]   Tandem Achmatowicz-Knoevenagel protocol: diastereoselective synthesis and anticancer evaluation of cyclopenta[b]pyrane derivatives [J].
Al-Tel, Taleb H. ;
Semreen, Mohammad H. ;
Voelter, Wolfgang .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2010, 8 (23) :5375-5382
[3]   Rational Design and Synthesis of Potent Dibenzazepine Motifs as β-Secretase Inhibitors [J].
Al-Tel, Taleb H. ;
Al-Qawasmeh, Raed A. ;
Schmidt, Marco F. ;
Al-Aboudi, Amal ;
Rao, Shashidhar N. ;
Sabri, Salim S. ;
Voelter, Wolfgang .
JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (20) :6484-6488
[4]   Differential Use of Anhydropyranosides for Enantiopure Routes to Bis-γ-butyrolactones: A New Approach to the Frameworks of Antibiotic and Anticancer Agents Isoavenaciolide and Ethisolide [J].
Al-Tel, Taleb H. ;
Al-Qawasmeh, Raed A. ;
Sabri, Salim S. ;
Voelter, Wolfgang .
JOURNAL OF ORGANIC CHEMISTRY, 2009, 74 (13) :4690-4696
[5]   Anticancer drugs from nature - natural products as a unique source of new microtubule-stabilizing agents [J].
Altmann, Karl-Heinz ;
Gertsch, Juerg .
NATURAL PRODUCT REPORTS, 2007, 24 (02) :327-357
[6]   CYCLOALKANOINDOLES .1. SYNTHESES AND ANTIINFLAMMATORY ACTIONS OF SOME ACIDIC TETRAHYDROCARBAZOLES, CYCLOPENTINDOLES, AND CYCLOHEPTINDOLES [J].
ASSELIN, AA ;
HUMBER, LG ;
DOBSON, TA ;
KOMLOSSY, J ;
MARTEL, RR .
JOURNAL OF MEDICINAL CHEMISTRY, 1976, 19 (06) :787-792
[7]   Drug discovery from medicinal plants [J].
Balunas, MJ ;
Kinghorn, AD .
LIFE SCIENCES, 2005, 78 (05) :431-441
[8]  
BARALDI PG, 1994, SYNTHESIS-STUTTGART, P1158
[9]   Phenylpiperazinylalkylamino substituted pyridazinones as potent α1 adrenoceptor antagonists [J].
Barlocco, D ;
Cignarella, G ;
Dal Piaz, V ;
Giovannoni, MP ;
De Benedetti, PG ;
Fanelli, F ;
Montesano, F ;
Poggesi, E ;
Leonardi, A .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (15) :2403-2410
[10]   Molecular similarity: a key technique in molecular informatics [J].
Bender, A ;
Glen, RC .
ORGANIC & BIOMOLECULAR CHEMISTRY, 2004, 2 (22) :3204-3218
1234