Precursor-Directed Generation of Indolocarbazoles with Topoisomerase IIα Inhibitory Activity

Cong Wang; Adeep Monger; Liping Wang; Peng Fu; Pawinee Piyachaturawat; Arthit Chairoungdua; Weiming Zhu

doi:10.3390/md16050168

Precursor-Directed Generation of Indolocarbazoles with Topoisomerase IIα Inhibitory Activity

Mar Drugs. 2018 May 17;16(5):168. doi: 10.3390/md16050168.

Authors

Cong Wang^{1

2}, Adeep Monger³, Liping Wang⁴, Peng Fu⁵, Pawinee Piyachaturawat⁶, Arthit Chairoungdua⁷, Weiming Zhu^{8

9}

Affiliations

¹ Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. wangcong123206@163.com.
² Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, School of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Nanning 530006, China. wangcong123206@163.com.
³ Toxicology Graduate Program, Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand. adeepmonger11@gmail.com.
⁴ Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550002, China. lipingw2006@163.com.
⁵ Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. fupeng@ouc.edu.cn.
⁶ Toxicology Graduate Program, Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand. pawinee.pia@mahidol.ac.th.
⁷ Toxicology Graduate Program, Excellent Center for Drug Discovery (ECDD), Faculty of Science, Mahidol University, Bangkok 10400, Thailand. arthit.chi@mahidol.ac.th.
⁸ Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. weimingzhu@ouc.edu.cn.
⁹ Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China. weimingzhu@ouc.edu.cn.

Abstract

One new indolocarbazole, 3-hydroxy-K252d (3), together with the recently reported 3-hydroxyholyrine A (1) and 3'-N-acetyl-3-hydroxyholyrine A (2), were obtained by feeding a culture of the marine-derived Streptomyces strain OUCMDZ-3118 with 5-hydroxy-l-tryptophan. Their structures were elucidated on the basis of spectroscopic analysis. Compound 1 potently induced apoptosis of gastric cancer cells by inhibiting topoisomerase IIα enzyme activity and reducing the expression of antiapoptosis protein level. Compound 3 displayed moderate cytotoxicity against the A549 and MCF-7 cell lines with IC₅₀ values of 1.2 ± 0.05 μM, 1.6 ± 0.09 μM, respectively.

Keywords: Streptomyces sp. OUCMDZ-3118; cytotoxicities; indolocarbazole; marine-derived Streptomyces; topoisomerase IIα enzyme activity.

MeSH terms

5-Hydroxytryptophan / metabolism
Apoptosis / drug effects
Apoptosis Regulatory Proteins / metabolism
Aquatic Organisms / metabolism*
Carbazoles / isolation & purification
Carbazoles / metabolism*
Carbazoles / pharmacology
Cell Line, Tumor
DNA Topoisomerases, Type II / metabolism
Drug Screening Assays, Antitumor
Enzyme Assays
Humans
Inhibitory Concentration 50
Streptomyces / metabolism*
Topoisomerase II Inhibitors / isolation & purification
Topoisomerase II Inhibitors / metabolism*
Topoisomerase II Inhibitors / pharmacology

Substances

3-hydroxy-K252d
Apoptosis Regulatory Proteins
Carbazoles
Topoisomerase II Inhibitors
5-Hydroxytryptophan
DNA Topoisomerases, Type II