Novel nitrogen-enriched oridonin analogues with thiazole-fused a-ring: Protecting group-free synthesis, enhanced anticancer profile, and improved aqueous solubility

Chunyong Ding, Yusong Zhang, Haijun Chen, Zhengduo Yang, Christopher Wild, Lili Chu, Huiling Liu, Qiang Shen, Jia Zhou

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Oridonin (1), a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens, has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility, and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them, including compounds 7-11, 13, and 14, exhibited potent antiproliferative effects against breast, pancreatic, and prostate cancer cells with low micromolar to submicromolar IC50 values as well as markedly enhanced aqueous solubility. These new analogues obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo but also effective against drug-resistant ER-positive MCF-7 clones.

Original languageEnglish (US)
Pages (from-to)5048-5058
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number12
DOIs
StatePublished - Jun 27 2013

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Thiazoles
Solubility
Nitrogen
Isodon
Kaurane Diterpenes
Breast Neoplasms
Diterpenes
Biological Products
Pancreatic Neoplasms
Biological Availability
Inhibitory Concentration 50
Neoplasms
Prostatic Neoplasms
Clone Cells
Pharmacology
Apoptosis
Growth
Pharmaceutical Preparations
oridonin
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Novel nitrogen-enriched oridonin analogues with thiazole-fused a-ring : Protecting group-free synthesis, enhanced anticancer profile, and improved aqueous solubility. / Ding, Chunyong; Zhang, Yusong; Chen, Haijun; Yang, Zhengduo; Wild, Christopher; Chu, Lili; Liu, Huiling; Shen, Qiang; Zhou, Jia.

In: Journal of Medicinal Chemistry, Vol. 56, No. 12, 27.06.2013, p. 5048-5058.

Research output: Contribution to journalArticle

Ding, Chunyong ; Zhang, Yusong ; Chen, Haijun ; Yang, Zhengduo ; Wild, Christopher ; Chu, Lili ; Liu, Huiling ; Shen, Qiang ; Zhou, Jia. / Novel nitrogen-enriched oridonin analogues with thiazole-fused a-ring : Protecting group-free synthesis, enhanced anticancer profile, and improved aqueous solubility. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 12. pp. 5048-5058.
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AU - Yang, Zhengduo

AU - Wild, Christopher

AU - Chu, Lili

AU - Liu, Huiling

AU - Shen, Qiang

AU - Zhou, Jia

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