H2S-releasing oridonin derivatives with improved antitumor activity by inhibiting the PI3K/AKT pathway

Haonan Li; Qingyinglu Ma; Yufeng Jia; Chao Wang; Jianfei Wu; Siyuan Wang; Huiming Hua; Jincai Lu; Dahong Li

doi:10.1016/j.bmc.2024.117968

H₂S-releasing oridonin derivatives with improved antitumor activity by inhibiting the PI3K/AKT pathway

Bioorg Med Chem. 2024 Dec 1:115:117968. doi: 10.1016/j.bmc.2024.117968. Epub 2024 Oct 28.

Authors

Haonan Li¹, Qingyinglu Ma¹, Yufeng Jia¹, Chao Wang¹, Jianfei Wu¹, Siyuan Wang², Huiming Hua³, Jincai Lu⁴, Dahong Li⁵

Affiliations

¹ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
² College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, PR China.
³ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: huimhua@163.com.
⁴ School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: jincailu@126.com.
⁵ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: lidahong0203@163.com.

PMID: 39481184
DOI: 10.1016/j.bmc.2024.117968

Abstract

Activating programmed cell death by delivering hydrogen sulfide (H₂S) has emerged as a promising strategy for tumor therapy. Oridonin serves as a lead compound for drug development due to its unique scaffold and wide-ranging biological effects, especially its antitumor properties. Based on the previous structure-activity relationship studies, 33 novel 1-O/14-O H₂S-releasing oridonin derivatives were synthesized. Particularly, 11a exhibited the most potent antiproliferative activity, effectively inhibiting colony formation, migration and invasion in both MCF-7 and MIA-PaCa-2 cells. It also inhibited the PI3K/AKT pathway to regulate the expression of Bax and Bcl-2, thereby initiating the Caspase cascade to activate mitochondrial mediated apoptosis. Furthermore, 11a suppressed tumor growth in breast cancer syngeneic models with no apparent toxicity.

Keywords: Antitumor; Hydrogen sulfide; Oridonin; Structural modification; ent-kaurane.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation* / drug effects
Diterpenes, Kaurane* / chemical synthesis
Diterpenes, Kaurane* / chemistry
Diterpenes, Kaurane* / pharmacology
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Humans
Hydrogen Sulfide* / chemistry
Hydrogen Sulfide* / metabolism
Hydrogen Sulfide* / pharmacology
Mice
Molecular Structure
Phosphatidylinositol 3-Kinases* / metabolism
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
Phosphoinositide-3 Kinase Inhibitors / chemistry
Phosphoinositide-3 Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt* / antagonists & inhibitors
Proto-Oncogene Proteins c-akt* / metabolism
Signal Transduction / drug effects
Structure-Activity Relationship

Substances

Diterpenes, Kaurane
oridonin
Proto-Oncogene Proteins c-akt
Antineoplastic Agents
Phosphatidylinositol 3-Kinases
Hydrogen Sulfide
Phosphoinositide-3 Kinase Inhibitors