Title:Synthesis, Cytotoxicity and Antimicrobial Activity of New Enmein-type Kauranoid Diterpenoid Derivatives
VOLUME: 17 ISSUE: 12
Author(s):Dahong Li, Tong Han, Xu Hu, Kangtao Tian, Shengtao Xu, Tingting Zhou, Keguang Cheng, Zhanlin Li, Huiming Hua and Jinyi Xu*
Affiliation:Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, and School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing
Keywords:Antiproliferative, antimicrobial, enmein-type, diterpenoid, SAR, derivatives.
Abstract:Background: Recently, we devoted to disclosing the antibacterial activities of enmein-type
6,7-seco-ent-kauranoid derivatives.
Objective: Eleven new enmein-type diterpenoid derivatives with different substituents and drug-like properties
were designed and synthesized.
Method: The antimicrobial activities against E. coli, S. aureus, B. subtilis and M. albicans were disclosed. The
antiproliferative activities against human cancer Bel-7402, K562, MGC-803 and CaEs-17 cells and non-cancerous
L-02 cells were also measured by MTT method.
Results: The results revealed that enmein-type diterpenoids showed more promising activities against tested
gram-positive bacteria than gram-negative bacterium and fungus. Compound 9 with R of 2-quinolyl group
exhibited the strongest antimicrobial activities with MIC values of 7.81 µg/ml and 0.98 µg/ml against S. aureus and
B. subtilis, respectively. All the target derivatives exhibited superior cytotoxic activities to compounds 1 and 2
against tumor cells, and slight selectivity between cancerous cells and normal liver cells. Compound 12 with R of
3-(2-chloropyridyl) group and IC50 values of 0.7 µM, 0.9 µM, 0.8 µM and 2.0 µM agaist four tumor cells,
respectively, was selected for further mechanism study in Bel-7402 cell line.
Conclusion: Compound 12 could induce S phase cell cycle arrest and apoptosis at low concentrations via
mitochondria-related pathways. The effects of compound 12 on some apoptosis related proteins showed that CDK2
was up regulated and ATM and cyclin A1 were down-regulated which confirmed the apoptosis and cell cycle effects.
