Synthesis of novel diterpenoid analogs with in-vivo antitumor activity

A lead compound 7 has antitumor effect, which was discovered by screening our small synthetic natural product-like compound (NPL) library. Based on the lead compound, a series of novel tricyclic diterpene analogs were synthesized and investigated for their activity against the growth of various tumo...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2016-09, Vol.120, p.13-25
Main Authors: Wang, Ying-Ying, He, Yuan, Yang, Lian-Fang, Peng, Shi-Hong, He, Xiao-Long, Wang, Jin-Hua, Lv, Fang, Hao, Yun, Liu, Ming-Yao, Yi, Zhengfang, Qiu, Wen-Wei
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Antitumor
Apoptosis
Apoptosis - drug effects
Cell Line, Tumor
Cell Movement - drug effects
Colony formation
Disease Models, Animal
Diterpenes - chemical synthesis
Diterpenes - pharmacology
Diterpenoids
Drug Screening Assays, Antitumor
Fibroblasts - drug effects
Humans
Inhibitory Concentration 50
Mice
Migration
Structure-Activity Relationship
Tricyclic diterpene
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Summary:A lead compound 7 has antitumor effect, which was discovered by screening our small synthetic natural product-like compound (NPL) library. Based on the lead compound, a series of novel tricyclic diterpene analogs were synthesized and investigated for their activity against the growth of various tumor cell lines using the sulforhodamine B (SRB) assay. To our delight, most aromatic amide compounds exhibited more potent antitumor activity than the lead compound. The most active compound 19 (QW30) showed an average IC50 0.33 μM, which was 15-fold more potent than the lead compound. Most of the compounds with potent antitumor activity displayed less toxic on normal human fibroblasts (HAF) in comparison with the tumor cell lines. Especially 19, its selectivity indexes (SI) between HAF and cancer cell lines was 17.3 times better than the positive control compound podophyllotoxin. The apoptosis, colony formation and transwell migration assays of 7 and 19 were performed on T47D cell line. The in-vivo antitumor effect of 19 was also observed in T47D tumor-bearing mice without obvious toxicity. A series of novel tricyclic diterpene analogs were synthesized and investigated for their in-vitro and in-vivo antitumor activity. [Display omitted] •A series of novel tricyclic diterpene analogs were synthesized.•The antitumor activity was investigated using SRB assay on various tumor cell lines.•Compound 19 displayed potent apoptosis-inducing ability in-vitro.•The migration and colony formation of T47D cells were strongly inhibited by 19.•In vivo antitumor effect of 19 was observed in T47D tumor-bearing mice.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.04.071