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SYNTHESIS, CRYSTAL STRUCTURE, ANTI-LUNG CANCER ACTIVITY OF 2-(4-FLUOROPHENYL)-5(5-IODO-2-METHYLBENZYL)THIOPHENE L.-P. Zhou1, F. Qiu2, Z.-F. Zhang3, C.-M. Wang2, Y.-L. Dong4, and J.-P. Liu2*

New heterocycle compound 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (1), designed using 5-iodo-2-methylbenzoic acid (2) as the starting material is successfully obtained via the multiple synthesis route and finally characterized by IR, 1H NMR, and single crystal X-ray crystallography. In addition, the in vitro anticancer activity of compound 1 on three human lung cancer cells (H20, H2227, and H69) is further determined, which suggests that compound 1 may be a potential anticancer agent. DOI: 10.1134/S0022476620070148 Keywords: heterocycles, X-ray, anticancer activity.

INTRODUCTION Cancer is a disease in which cells grow and proliferate in an uncontrolled manner. Cancer evokes a high level of mortality regardless of recent advances in the development of clinically authorized anticancer agents [1, 2]. The development of resistance to chemotherapeutic agents and associated side effects are major obstacles to effectively treat cancer [3, 4]. Thus, it is necessary to identify and develop new anticancer agents with the improved efficacy and reduced side effects to complement the present chemotherapeutic strategies [5]. Type-2 diabetes mellitus is a long-term metabolic disorder and a chronic disease with worldwide prevalence [6]. It is characterized by high blood sugar, resistance to insulin, and a deficiency in insulin secretion [7]. Canagliflozin is an antidiabetic drug of the gliflozin class or subtype 2 sodium-glucose cotransporter 2 (SGLT-2) inhibitors; it is used to improve the glycemic control in patients with type-2 diabetes [8]. 2-(4-Fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (1) being one of the most important intermediates in the synthesis of canagliflozin fascinated us [9]. Thus, much attention has been devoted to the synthesis, characterization, and crystal structure of compound 1 which have never been reported before. The present work deals with the synthesis and characterization of title compound 1. Compound 1 was synthesized by 5-iodo-2-methylbenzoic acid (2) as the starting material yielding 5-iodo-2-methylbenzoyl chloride (3), then reacted with 2-(4-fluorophenyl)thiophene to obtain (5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2- methylphenyl)methanone (4), and title compound 1 was prepared after the reduction of compound 4 with TMDS and AlCl3 (Scheme 1). In addition, the in vitro anticancer activity of compound 1 on three human lung cancer cells (H20, H2227, and H69) was further determined. Finally, molecular docking studies were utilized to further clarify its structure-activity relationship.

1

The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P. R. China. 2The First Clinical Medical of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia, P. R. China; *[email protected]. 3 Tongliao City Hospital, Tongliao, Inner Mongolia, P. R. China. 4Zhejiang Univer