Synthesis and antiproliferative activity of new tonantzitlolone-derived diterpene derivatives

Busch, Torsten; Dräger, Gerald; Kunst, Eike; Benson, Hannah; Sasse, Florenz; Siems, Karsten; Kirschning, Andreas

doi:10.1039/c6ob01697a

Cited by 14 publications

(5 citation statements)

References 21 publications

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“…Arg. belonging to the Euphorbiaceae plant family (Busch et al, ; Busch & Kirschning, ; Jasper, Wittenberg, Quitschalle, Jakupovic, & Kirschning, ). TZL has been used as a medical plant in native Mexican, Navajo, and Creek traditional medicine, and importantly, it displays cytotoxicity against certain types of human cancer cell, including renal, ovarian, and breast cancer cells, at nM concentrations.…”

Section: Introductionmentioning

confidence: 99%

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Rubaiy

2019

British J Pharmacology

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Canonical or classical transient receptor potential 4 and 5 proteins (TRPC4 and TRPC5) assemble as homomers or heteromerize with TRPC1 protein to form functional nonselective cationic channels with high calcium permeability. These channel complexes, TRPC1/4/5, are widely expressed in nervous and cardiovascular systems, also in other human tissues and cell types. It is debatable that TRPC1 protein is able to form a functional ion channel on its own. A recent explosion of molecular information about TRPC1/4/5 has emerged including knowledge of their distribution, function, and regulation suggesting these three members of the TRPC subfamily of TRP channels play crucial roles in human physiology and pathology. Therefore, these ion channels represent potential drug targets for cancer, epilepsy, anxiety, pain, and cardiac remodelling. In recent years, a number of highly selective small-molecule modulators of TRPC1/4/5 channels have been identified as being potent with improved pharmacological properties. This review will focus on recent remarkable small-molecule agonists: (−)-englerin A and tonantzitlolone and antagonists: Pico145 and HC7090, of TPRC1/4/5 channels. In addition, this work highlights other recently identified modulators of these channels such as the benzothiadiazine derivative, riluzole, ML204, clemizole, and AC1903. Together, these treasure troves of agonists and antagonists of TRPC1/4/5 channels provide valuable hints to comprehend the functional importance of these ion channels in native cells and in vivo animal models. Importantly, human diseases and disorders mediated by these proteins can be studied using these compounds to perhaps initiate drug discovery efforts to develop novel therapeutic agents.

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Section: Introductionmentioning

confidence: 99%

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Rubaiy

2019

British J Pharmacology

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“…These diterpenes are considered uncommon, because of the presence of a macrocyclic flexibilene ring with 15 carbons. Examples of these compounds were found to exhibit cytotoxic activity against human kidney and lung cancer cell lines. , In recent years, studies have involved the synthesis of these diterpenes, antiviral and cytotoxic assays, and inhibition tests of the enzyme kinesin-5. ,− …”

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confidence: 99%

Tri- and Diterpenoids from Stillingia loranthacea as Inhibitors of Zika Virus Replication

et al. 2019

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This study represents the first phytochemical analysis of Stillingia loranthacea (S. loranthacea) and describes new terpenoids obtained from the root bark of this species. The fractionation of the hexane extract from the root bark led to the isolation of two new 28-nor-taraxarenes derivatives, loranthones A and B (1 and 2), four new tigliane diterpenes (5−8), three known tigliane diterpenes (9−11), and three known flexibilene diterpenes, tonantzitlolones A−C (12−14). The investigation of these compounds and the use of a molecular networking-based prioritization approach afforded two other new 28-nor-taraxarenes, loranthones C and D (3 and 4). The cytotoxicity of compounds 1, 2, and 5−14 was evaluated against Vero cells, and their 20% cytotoxic concentration (CC 20 ) values varied from 8.7 to 328 μM; antiviral activity was tested against an epidemic Zika virus (ZIKV) strain circulating in Brazil. Six out of 12 compounds (2, 5, 9−11, and 14) exhibited significant antiviral effects against ZIKV. Specifically, compounds 2 and 5 offered the most promise as lead compounds as they had a 1.7 and 1.8 log 10 TCID 50 /mL reduction in ZIKV replication, respectively. Together, the present findings have identified S. loranthacea terpenoids as potent anti-ZIKV inhibitors and pave the way to the development of possible new treatments against this devastating pathogen.

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“…Arg. [229,230]. Tonantzitlolone has been known to have antiproliferative properties against certain cancer cell lines and possess antitumor activity [229,230].…”

Section: Tonantzitlolonementioning

confidence: 99%

“…[229,230]. Tonantzitlolone has been known to have antiproliferative properties against certain cancer cell lines and possess antitumor activity [229,230]. Sourbier et al [110] investigated cytotoxicity targets and mechanisms of action of tonantzitlolone in clear cell RCC.…”

Section: Tonantzitlolonementioning

confidence: 99%

Phytochemicals for the Prevention and Treatment of Renal Cell Carcinoma: Preclinical and Clinical Evidence and Molecular Mechanisms

Bajalia

Azzouz

Chism

et al. 2022

Cancers

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Renal cell carcinoma (RCC) is associated with about 90% of renal malignancies, and its incidence is increasing globally. Plant-derived compounds have gained significant attention in the scientific community for their preventative and therapeutic effects on cancer. To evaluate the anticancer potential of phytocompounds for RCC, we compiled a comprehensive and systematic review of the available literature. Our work was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. The literature search was performed using scholarly databases such as PubMed, Scopus, and ScienceDirect and keywords such as renal cell carcinoma, phytochemicals, cancer, tumor, proliferation, apoptosis, prevention, treatment, in vitro, in vivo, and clinical studies. Based on in vitro results, various phytochemicals, such as phenolics, terpenoids, alkaloids, and sulfur-containing compounds, suppressed cell viability, proliferation and growth, showed cytotoxic activity, inhibited invasion and migration, and enhanced the efficacy of chemotherapeutic drugs in RCC. In various animal tumor models, phytochemicals suppressed renal tumor growth, reduced tumor size, and hindered angiogenesis and metastasis. The relevant antineoplastic mechanisms involved upregulation of caspases, reduction in cyclin activity, induction of cell cycle arrest and apoptosis via modulation of a plethora of cell signaling pathways. Clinical studies demonstrated a reduced risk for the development of kidney cancer and enhancement of the efficacy of chemotherapeutic drugs. Both preclinical and clinical studies displayed significant promise of utilizing phytochemicals for the prevention and treatment of RCC. Further research, confirming the mechanisms and regulatory pathways, along with randomized controlled trials, are needed to establish the use of phytochemicals in clinical practice.

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Synthesis and antiproliferative activity of new tonantzitlolone-derived diterpene derivatives

Abstract: The synthesis of the diterpene (+)-tonantzitlolone A and a series of derivatives is reported. The study includes the determination of their antiproliferative activities against selected cancer cell lines.

Cited by 14 publications

References 21 publications

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels

Tri- and Diterpenoids from Stillingia loranthacea as Inhibitors of Zika Virus Replication

Phytochemicals for the Prevention and Treatment of Renal Cell Carcinoma: Preclinical and Clinical Evidence and Molecular Mechanisms

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