Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties
The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam de...
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| Published in | Journal of medicinal chemistry Vol. 61; no. 3; pp. 760 - 776 |
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| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
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08.02.2018
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| Abstract | The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T 1/2 = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice. |
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| AbstractList | The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T
= 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice. The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T 1/2 = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice. The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T1/2 = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice. |
| Author | Miao, Zehong Tian, Qianting Zhang, Ao Wang, Yingqing Li, Jie Ding, Chunyong Jiao, Mingkun Song, Shanshan |
| AuthorAffiliation | State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory University of Chinese Academy of Sciences |
| AuthorAffiliation_xml | – name: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory – name: State Key Laboratory of Drug Research – name: University of Chinese Academy of Sciences – name: Shanghai Institute of Materia Medica, Chinese Academy of Sciences |
| Author_xml | – sequence: 1 givenname: Chunyong orcidid: 0000-0003-2379-8740 surname: Ding fullname: Ding, Chunyong organization: University of Chinese Academy of Sciences – sequence: 2 givenname: Qianting surname: Tian fullname: Tian, Qianting organization: University of Chinese Academy of Sciences – sequence: 3 givenname: Jie surname: Li fullname: Li, Jie organization: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory – sequence: 4 givenname: Mingkun surname: Jiao fullname: Jiao, Mingkun organization: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory – sequence: 5 givenname: Shanshan surname: Song fullname: Song, Shanshan organization: Shanghai Institute of Materia Medica, Chinese Academy of Sciences – sequence: 6 givenname: Yingqing surname: Wang fullname: Wang, Yingqing email: yqwang@simm.ac.cn organization: University of Chinese Academy of Sciences – sequence: 7 givenname: Zehong surname: Miao fullname: Miao, Zehong email: zhmiao@simm.ac.cn organization: University of Chinese Academy of Sciences – sequence: 8 givenname: Ao orcidid: 0000-0001-7205-9202 surname: Zhang fullname: Zhang, Ao email: aozhang@simm.ac.cn organization: University of Chinese Academy of Sciences |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29294282$$D View this record in MEDLINE/PubMed |
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| Keywords | IIA INHIBITION PHARMACOKINETICS PROSTATE-CANCER CELLS GROWTH SALVIA-MILTIORRHIZA BUNGE DIHYDROTANSHINONE-I INDUCTION CRYPTOTANSHINONE MASS-SPECTROMETRY |
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| Snippet | The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more... |
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| SubjectTerms | Chemistry, Medicinal Life Sciences & Biomedicine Pharmacology & Pharmacy Science & Technology |
| Title | Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties |
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