Synthesis And Biological Evaluation Of Dihydropyridin Containing Thiazolinone Derivatives

As the research moves along, cancer chemotherapy ushers in a new period of vigorous development: molecular-targeted therapeutics have emerged which are highly selective and less toxic compared to the traditional drags. Receptor protein tyrosine kinases (RPTKs) play a fundamental role in signal transduction pathways that mediate malignant cell transformation. Epidermal growth factor receptor kinase (EGFR), a transmembrane PTK that is activated by ligand-induced dimerization, plays a key role in the formation and development of many types of solid tumors, including head and neck, lung, breast, bladder, prostate, and kidney cancers. Therefore, EGFR tyrosine kinase represents an attractive target for the development of novel anticancer agents. (EGFR) and the homologous HER-2 kinases, which are members of the type 1 or erbB/HER receptor tyrosine kinase (RTK) family, have emerged as the most viable anticancer molecular targets in this family of four members, EGFR (HER-1/ErbB-1), HER-2 (ErbB-2/neu), HER-3 (ErbB-3), and HER-4 (ErbB-4). Among them, EGFR and HER-2 are the hottest targets in current cancer research and their overexpression or abnormal activation often cause cell malignant transformation, such as non small cell lung cancer (NSCLC), prostate, breast, stomach, colon, and ovarian cancers. Compounds that inhibit the kinase activity of EGFR and/or HER-2 after binding of its ATP binding site are of potential interest as new therapeutic antitumor agents. Several EGFR inhibitors, the first-generation EGFR inhibitors Gefitinib (IressaTM) and Erlotinib (TarcevaTM) have been approved by US FDA for treatment of patients with non small cell lung cancer (NSCLC). And Lapatinib as a dual reversible EGFR/HER2 inhibitor was approved for breast cancer therapy. Two candidate drugs Afatinib and Dacomitinib, which could bond with a unique cysteine797 residue located at the lip of the ATP binding cleft, as the most promising second generation EGFR kinase inhibitors, have been being evaluated in respective phase III study.In previous study, pyridine derivatives have been selected as pharmacological agents due to their biological activities and their potential applications. The application of this heterocycle is widespread due to its antiviral/antitumor, antibacterial, antiinflamatory, fungistatic, and anti-hyperglycemic activity.Furthermore, special attention has been placed recently on the use of pyrazole for anticancer. Recently, a series of novel pyrazole derivatives containing thiourea skeleton were discovered as potent anticancer agents targeting EGFR in our group, and some of them had demonstrated potent antitumor activity.Thiazolinone and their derivatives have attracted continuing interest over the years because of their varied biological activities, such as anti-inflammatory, antimicrobial, antiproliferative, antiviral, anticonvulsant, antifungal, and antibacterial. Recent years, thiazolinone derivatives with their antitumor activity have become a new hot spot. For example, thiazolinone containing benzothiazole moiety has been shown to exert its anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancers cell lines by Dmytro Havrylyuk et al. Besides these, many pyrazole or thiazolinone derivatives have also been reported potent biological activities and low toxicities. Encouraged by these observations we designed and synthesized newer anticancer compound derivatives which contains pyridine, pyrazole and thiazolinone.A series of dihydropyridin containing thiazolinone derivatives (4a-4r) have been designed, synthesized and their biological activities were also evaluated as potential EGFR and HER-2 kinase inhibitors and tumor cell antiproliferation. All these synthesized compounds were determined by’H-NMR and ESI-MS. In addition,4m compounds were scrutinized by X-ray structure analysis. Among them, compound 4r displayed the most potent inhibitory activity IC50=0.099μM for EGFR and IC50= 3.26μM for HER-2 (positive control Erlotinib IC50= 0.03 μM for EGFR and IC50= 0.14 μM for HER-2). Antiproliferative assay results indicated that compound 4r owned high antiproliferative activity against B16-F10, Hela and MCF-7 in vitro, with IC50 value of 0.09 μM,0.29 μM, and 0.56 μM (positive control Gefitinib and Celecoxib against B16-F10, Hela and MCF-7 in vitro, with IC50 value of 0.10 μM, 1.59 μM,6.70 μM and 5.28 μM,7.51 μM,7.01 μM), respectively. Docking simulation was further performed to position compounds into the EGFR active site to determine the probable binding model the 3D-QSAR models were built for reasonable design of EGFR/HER-2 inhibitors at present and in future, and the results are reported in this paper.