Design, synthesis and bioactivity investigation of tetrandrine derivatives as potential anti-cancer agents

Song, Jiahui; Lan, Junjie; Chen, Chao; Hu, Shengcao; Song, Jialei; Liu, Wulin; Zeng, Xiangbo; Lou, Hua‐Yong; Ben‐David, Yaacov; Pan, Weidong

doi:10.1039/c8md00125a

Cited by 20 publications

(15 citation statements)

References 38 publications

(16 reference statements)

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“…5b, the ultraviolet absorption values at 237 nm and 277 nm after HJNO interacting with BLM 642–1290 helicase were more than the sum of those of HJNO and BLM 642–1290 at the same wavelength. It was caused by the chromophore of BLM helicase flipping to a greater polar domain [25]. The ultraviolet absorption values at 237 nm and 277 nm after HJNO interacting with BLM 642–1290 helicase increased with the increasing of HJNO concentration (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The nitro group in HJNO was then efficiently transformed into an amino group by Pd/C in hydrazine hydrate to afford the amino compound, which was added the RCOCl to afford compounds HL-22, HL-24 and HL-27 [23]. HL-25 were synthesized from the amino compound by adding 4-Methylbenzenesulfonyl chloride in pyridine [25]. Fangchinoline reacted with benzoyl chloride in THF in the presence of 4-dimethylaminopyridine (DMAP) to afford HL-23 [26].…”

Section: Methodsmentioning

confidence: 99%

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Screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting BLM helicase

Zhang¹,

Yang²,

Liu³

et al. 2019

BMC Cancer

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BackgroundThe high expression of BLM (Bloom syndrome) helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to screen potential antiproliferative small molecules from 12 small molecules (the derivatives of bisbenzylisoquinoline alkaloids tetrandrine and fangchinoline) by targeting BLM642–1290 helicase. Then we explore the inhibitory mechanism of those small molecules on proliferation of MDA-MB-435 breast cancer cells.MethodsFluorescence polarization technique was used to screen small molecules which inhibited the DNA binding and unwinding of BLM642–1290 helicase. The effects of positive small molecules on the ATPase and conformation of BLM642–1290 helicase were studied by the malachite green-phosphate ammonium molybdate colorimetry and ultraviolet spectral scanning, respectively. The effects of positive small molecules on growth of MDA-MB-435 cells were studied by MTT method, colony formation and cell counting method. The mRNA and protein levels of BLM helicase in the MDA-MB-435 cells after positive small molecule treatments were examined by RT-PCR and ELISA, respectively.ResultsThe compound HJNO (a tetrandrine derivative) was screened out which inhibited the DNA binding, unwinding and ATPase of BLM642–1290 helicase. That HJNO could bind BLM642–1290helicase to change its conformationcontribute to inhibiting the DNA binding, ATPase and DNA unwinding of BLM642–1290 helicase. In addition, HJNO showed its inhibiting the growth of MDA-MB-435 cells. The values of IC50 after drug treatments for 24 h, 48 h and 72 h were 19.9 μmol/L, 4.1 μmol/L and 10.9 μmol/L, respectively. The mRNA and protein levels of BLM helicase in MDA-MB-435 cells increased after HJNO treatment. Those showed a significant difference (P < 0.05) compared with negative control when the concentrations of HJNO were 5 μmol/L and 10 μmol/L, which might contribute to HJNO inhibiting the DNA binding, ATPase and DNA unwinding of BLM helicase.ConclusionThe small molecule HJNO was screened out by targeting BLM642–1290 helicase. And it showed an inhibition on MDA-MB-435 breast cancer cells expansion.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting BLM helicase

Zhang¹,

Yang²,

Liu³

et al. 2019

BMC Cancer

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“…During apoptosis, PARP is cleaved by Caspase-3 into two fragments of 31 kDa and 85 kDa. This cleavage makes PARP unable to function normally, causing apoptosis [ 40 ]. Survivin belongs to the inhibitor of apoptosis protein (IAP) family and is potentially involved in both facilitating tumor cell proliferation and inhibiting apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Anticancer Activity of Tetrandrine by Inducing Apoptosis in Human Breast Cancer Cell Line MDA‐MB‐231 In Vivo

Wang

Yang

Guo

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Tetrandrine (TET) is an alkaloid extracted from a traditional Chinese medicinal plant. It exerts remarkable anticancer activity and induces apoptotic cell death in various human cancer cells. The present study aimed to investigate the effects of TET on the inhibition of tumor growth and the induction of apoptosis in MDA-MB-231 breast cancer in xenograft mice. Tumor weight and volume were measured. The histopathological changes in the tumor tissue were observed. Immunohistochemistry analysis of Bcl-2-associated X protein (Bax) and B-cell lymphoma/leukemia-2 (Bcl-2) was carried out. The expression of apoptosis-associated genes and proteins, such as cysteine aspartic acid-specific protease-3 (Caspase-3), Survivin, Bax, Bcl-2, BH3-interacting domain death agonist (Bid), and poly ADP-ribose polymerase (PARP), was measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. TET inhibited tumor growth and induced apoptosis in TNBC cell line MDA-MB-231. The mechanism underlying this effect might be mediated by TET-upregulated Caspase-3, Bax, and Bid and downregulated by Bcl-2, Survivin, and PARP. Taken together, this study supported the fact that TET is a promising therapeutic agent for the treatment of TNBC, thereby providing experimental evidence for its use in the treatment of breast cancer.

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“…[ 69 ] In addition, tetrandrine and its derivative compound, 14‐(2‐naphthalene sulfonamide)‐tetrandrine, can stimulate cell apoptosis in pancreatic PANC‐1 and breast cancer MDA‐MB‐231 cells by increasing the activities of caspase‐3, caspase‐8 and caspase‐9, as well as elevating the levels of reactive oxygen species in a dose‐ and time‐dependent manner through both the extrinsic death receptor and intrinsic caspase activation, especially for MDA‐MB‐231 cells with an IC 50 value of 1.18 μ m . [ 70,111 ] Tetrandrine reportedly also induces the apoptosis of A549 lung cancer cells effectively by up‐regulating the expression of PARP, Bax, intercellular adhesion molecule‐1 (ICAM‐1) and vascular endothelial growth factor (VEGF) and suppressing the phosphorylation of Akt and the expression of hypoxia‐inducible factor‐1α (HIF‐1α) through the involvement of the VEGF/HIF‐1α/ICAM‐1 signalling pathway. [ 75 ]…”

Section: The Anticancer Activity Of Tetrandrinementioning

confidence: 99%

Tetrandrine: a review of its anticancer potentials, clinical settings, pharmacokinetics and drug delivery systems

Luan

Zeng

2020

Journal of Pharmacy and Pharmacology

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Objectives Tetrandrine, a natural bisbenzylisoquinoline alkaloid, possesses promising anticancer activities on diverse tumours. This review provides systematically organized information on cancers of tetrandrine in vivo and in vitro, discuss the related molecular mechanisms and put forward some new insights for the future investigations. Key findings Anticancer activities of tetrandrine have been reported comprehensively, including lung cancer, colon cancer, bladder cancer, prostate cancer, ovarian cancer, gastric cancer, breast cancer, pancreatic cancer, cervical cancer and liver cancer. The potential molecular mechanisms corresponding to the anticancer activities of tetrandrine might be related to induce cancer cell apoptosis, autophagy and cell cycle arrest, inhibit cell proliferation, migration and invasion, ameliorate metastasis and suppress tumour cell growth. Pharmaceutical applications of tetrandrine combined with nanoparticle delivery system including liposomes, microspheres and nanoparticles with better therapeutic efficiency have been designed and applied encapsulate tetrandrine to enhance its stability and efficacy in cancer treatment. Summary Tetrandrine was proven to have definite antitumour activities. However, the safety, bioavailability and pharmacokinetic parameter studies on tetrandrine are very limited in animal models, especially in clinical settings. Our present review on anticancer potentials of tetrandrine would be necessary and highly beneficial for providing guidelines and directions for further research of tetrandrine.

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Design, synthesis and bioactivity investigation of tetrandrine derivatives as potential anti-cancer agents

Cited by 20 publications

References 38 publications

Screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting BLM helicase

Screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting BLM helicase

Anticancer Activity of Tetrandrine by Inducing Apoptosis in Human Breast Cancer Cell Line MDA‐MB‐231 In Vivo

Tetrandrine: a review of its anticancer potentials, clinical settings, pharmacokinetics and drug delivery systems

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