Toward chelerythrine optimization: Analogues designed by molecular simplification exhibit selective growth inhibition in non-small-cell lung cancer cells

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• 作者：Rosania Yang^a ; ^&dagger ; ; Maurí ; cio T. Tavares^a ; ^&dagger ; ; Sarah F. Teixeira^b ; ^&dagger ; ; Ricardo A. Azevedo^b ; Diego C. Pietro^a ; Thais B. Fernandes^a ; Adilson K. Ferreira^b ; Gustavo H.G. Trossini^d ; José ; A.M. Barbuto^b ; ^c ; Roberto Parise-Filho^a ; ^{roberto.parise@usp.br" class="auth_mail" title="E-mail the corresponding author}
• 关键词：SCLC ; small cell lung cancer ; NSCLC ; non-small-cell lung cancer ; LNCaP ; human prostate adenocarcinoma ; DU-145 ; human prostate carcinoma ; MDA-MB-231 ; human breast adenocarcinoma ; BGC-823 ; human gastric cancer ; SI ; selectivity index ; SAR ; structure&ndash ; activity relationship ; A549 ; human lung adenocarcinoma ; NCI-H1299 ; human lung carcinoma ; NCI-H292 ; mucoepidermoid pulmonary carcinoma ; NCI-H460 ; non-small cell lung carcinoma ; LL24 ; fibroblast lung cells ; HUVEC ; human umbilical vein endothelial ce
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：24
• 期：19
• 页码：4600-4610
• 全文大小：1514 K

文摘

A series of novel chelerythrine analogues was designed and synthesized. Antitumor activity was evaluated against A549, NCI-H1299, NCI-H292, and NCI-H460 non-small-cell lung cancer (NSCLC) cell lines in vitro. The selectivity of the most active analogues and chelerythrine was also evaluated, and we compared their cytotoxicity in NSCLC cells and non-tumorigenic cell lines, including human umbilical vein endothelial cells (HUVECs) and LL24 human lung fibroblasts. In silico studies were performed to establish structure–activity relationships between chelerythrine and the analogues. The results showed that analogue compound 3f induced significant dose-dependent G₀/G₁ cell cycle arrest in A549 and NCI-H1299 cells. Theoretical studies indicated that the molecular arrangement and electron characteristics of compound 3f were closely related to the profile of chelerythrine, supporting its activity. The present study presents a new and simplified chelerythrinoid scaffold with enhanced selectivity against NSCLC tumor cells for further optimization.