Anti-Cancer Agents in Medicinal Chemistry

Anti-Cancer Agents in Medicinal Chemistry, 2015, 15, 131-136        131

Potential  Anticancer  Agents. I. Synthesis of Isoxazole Moiety Containing  Quinazoline

Derivatives and Preliminarily in vitro Anticancer  Activity

Jian-Ping Yong#, Can-Zhong Lu#,* and Xiaoyuan Wu

Key Laboratory  of Design and Assembly of Functional  Nanostructures, Chinese Academy of Sciences of P. R. China, Fuzhou, 350002, P. R. China[pic 2][pic 3][pic 4][pic 5]

Abstract:  14 new structures of isoxazole-moiety-containing quinazoline derivatives(3a~3n) were synthesized for the first time and characterized by IR, 1H NMR, 13C NMR, ESI-MS. Subsequently, their in vitro anticancer activity against A549, HCT116 and MCF-7 cell lines was preliminarily evaluated using the MTT method. Among them, most compounds showed good to excellent anticancer activity, especially 3d, 3i, 3k and 3m exhibited the more potent anticancer activity against A549, HCT116 and MCF-7 cell lines, which can be regarded as the promising drug candidates for development of anticancer drugs.

Keywords: Anticancer activity, isoxazole moiety, quinazoline derivatives, synthesis.

#Author’s  Profile:  Jian-Ping  Yong  was born in Ningxia,  China. He graduated  in applied  Chemistry  from Ningxia  University  (2002),  and finished his Ph. D. in Organic Chemistry under the supervision of Prof. Haji Akber Aisa at Xinjiang Technical Institute of Physics and Chemistry(2008).  Then,  he worked  as an assistant  professor  in Ningxia  Medical  University  (2009-2011).  After postdoctoral  studies  with Professor  CanzhongLu  at Fujian  Institute  of Research  on the Structure  of Matter (2011-2013),  he joined  prof. Lu’s group  and became  an associate professor in 2014. His interests include drug design and synthesis, Natural Product Chemistry.

#Author’s  Profile:  Prof. Can-Zhong  Lu was born in Fujian, China. He graduated  in Chemistry  from Xiamen  University  (1986).  Then, he worked  in Fujian  Institute of Research  on the Structure  of Matter (1986-1992).  He received  his Ph.D. under the supervision  of Prof. J. R. Dilworth  at the University  of Essex, UK. (1996). After postdoctoral  studies in Department  of Chemistry  at Bielefeld  University,  Germany (1996-1998),  he started his independent academic career at FJIRSM, then became a Full Professor in 2002, and has published more than 250

SCI papers. His current research interests include synthesis, structural characterization  and catalysis of polyoxometalates-based coordination polymer; luminescent materials and devices based on Cu(I); drug design and synthesis.

INTRODUCTION

Cancer  is  the  second  most  lethal  disease  with  the  abnormal cellular  proliferation  and  metastasis,  second  only  to  the cardiovascular  and  cerebrovascular   disease  in  the  world.  Cancer types include lung cancer, gastric cancer, liver cancer, colon cancer, breast cancer and non-small cell lung cancer (NSCLC) etc.. Lung cancer causes a fifth of all cancer-related  deaths [1], while NSCLC accounts for most cases of lung cancer, and it is usually diagnosed in  advanced   stages  [2].  The  great  cancer  incidence   worldwide increases the search for new, safer and efficent anticancer agents, aiming the prevention or the cure of this illness.

Quinazoline   core  is  the  best  scaffolds   for  development   of anticancer agents [3]. Some quinazolines  as anticancer agents have been  used  in  clinics:  Gefitinib(IressaTM,   AstraZeneca),   Erlotinib

(TarcevaTM, Genentech) and Lapatinib(TykerbTM, GlaxoSmithKline) (Fig. 1) have been approved by FDA for treatment of cancer. 4-[(3-

ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline  (Conmana®,

Zhejiang Beta Pharma Co. Ltd., China) (Fig. 1), named as Icotinib, is  another  quinazoline  derivative,  which  mimics  erlotinib  with  a crown ether rused quinazoline  moiety. The phase III clinical study for treatment  of advanced  NSCLC  showed  that Icotinib  exhibited the equal  therapeutic  efficacy  and low  toxicity  to gefitinib  [4]. It has been approved by China Food and Drug Administration(CFDA) in 2011 for treatment of cancer in clinics.

The isoxazole moiety, as a potential functional group, is usually introduced into some drug molecules to improve their biological activities [5-12]; In our previous work, we introduced the isoxazole moiety at C-30 position of glycyrrhetinic acid(GTA) and 11- deoxyglycyrrhetinic   acid(DGTA),   and   synthesized   a   series   of

*Address correspondence to this author at the Key Laboratory of Design and Assembly of Functional Nanostructures, Chinese Academy of Sciences of P. R. China, Fuzhou, 350002, P. R. China; Fax: +86 59183705794;[pic 6]