Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin

Madadi, Nikhil Reddy; Zong, Hong; Ketkar, Amit; Chen, Zheng; Penthala, Narsimha Reddy; Janganati, Venumadhav; Bommagani, Shobanbabu; Eoff, Robert L.; Guzmán, Mónica L.; Crooks, Peter A.

doi:10.1039/c4md00478g

Cited by 31 publications

(19 citation statements)

References 30 publications

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“…It can be seen from our results that ISO and Rsv have high structural similarities with combretastatin, a colchicine analog known to interact with the colchicine-binding site in tubulin [63,64]. Rsv is well known to interact with tubulin, and therefore ISO may also do so by maintaining its structural similarity with Rsv [26,57,65]. The docking results reconfirmed that ISO and Rsv bind to the colchicine binding site in the same orientation as combretastatin, and with a similar docking score.…”

Section: Discussionsupporting

confidence: 67%

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

Subedi

Teli

Lee

et al. 2019

Cancers

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Isorhapontigenin (ISO), a tetrahydroxylated stilbenoid, is an analog of resveratrol (Rsv). The various biological activities of Rsv and its derivatives have been previously reported in the context of both cancer and inflammation. However, the anti-cancer effect of ISO against breast cancer has not been well established, despite being an orally bioavailable dietary polyphenol. In this study, we determine the anti-cancer effects of ISO against breast cancer using MCF7, T47D, and MDA-MB-231 cell lines. We observed that ISO induces breast cancer cell death, cell cycle arrest, oxidative stress, and the inhibition of cell proliferation. Additionally, sphingosine kinase inhibition by ISO controlled tubulin polymerization and cancer cell growth by regulating MAPK/PI3K-mediated cell cycle arrest in MCF7 cells. Interestingly, SPHK1/2 gene silencing increased oxidative stress, cell death, and tubulin destabilization in MCF7 cells. This suggests that the anti-cancer effect of ISO can be regulated by SPHK/tubulin destabilization pathways. Overall, ISO successfully induced breast cancer cell death and cell growth arrest, suggesting this phytochemical is a better alternative for breast cancer treatment. Further studies in animal models could confirm the potency and usability of ISO over Rsv for targeting breast cancer, potentially posing an alternative candidate for improved therapy in the near future.

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Section: Discussionsupporting

confidence: 67%

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

Subedi

Teli

Lee

et al. 2019

Cancers

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“…The most potent compound 6 (Figure ) with GI 50 values of <10 n m against almost all the cell lines in the human cancer cell panel, was also screened against the acute myeloid leukemia cell line, MV4‐1. Its Z analogue 7 is more potent than 6 at inhibiting tubulin polymerization in MV4‐11 cells; this fact was confirmed by molecular docking studies that indicated a common binding site for 6 and 7 on the α,β‐tubulin heterodimer, with a slightly more favorable binding for 7 relative to 6 , which is consistent with the results from microtubule depolymerization assays …”

Section: Synthetic Anticancer Stilbenessupporting

confidence: 76%

“…Its Z analogue 7 is more potent than 6 at inhibiting tubulin polymerization in MV4-11 cells;t his fact was confirmed by molecular docking studies that indicated ac ommon binding site for 6 and 7 on the a,btubulin heterodimer,w ith as lightly more favorable binding for 7 relative to 6,w hich is consistentw ith the resultsf rom microtubule depolymerization assays. [78] Compound 8 in Figure 4, was largely studied for its apoptotic activity in HL60 myeloblastica cute leukemia cell line inducing ap artial block of cells in Sp hase. [27] Subsequently,c ompound 8 was checked in an in vivo study in immunodeficient mice with HT-29 xenograft.…”

Section: Polymethoxy Stilbenesmentioning

confidence: 99%

Anticancer Activity of Stilbene‐Based Derivatives

et al. 2017

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Stilbene is an abundant structural scaffold in nature, and stilbene-based compounds have been widely reported for their biological activity. Notably, (E)-resveratrol and its natural stilbene-containing derivatives have been extensively investigated as cardioprotective, potent antioxidant, anti-inflammatory, and anticancer agents. Starting from its potent chemotherapeutic activity against a wide variety of cancers, the stilbene scaffold has been subject to synthetic manipulations with the aim of obtaining new analogues with improved anticancer activity and better bioavailability. Within the last decade, the majority of new synthetic stilbene derivatives have demonstrated significant anticancer activity against a large number of cancer cell lines, depending on the type and position of substituents on the stilbene skeleton. This review focuses on the structure-activity relationship of the key compounds containing a stilbene scaffold and describes how the structural modifications affect their anticancer activity.

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“…Growth inhibitory or cytotoxic effects were measured by percentage growth (PG), which is proportional to optical density (OD) [23, 24]. OD measurements of SRB-derived color prior to and 48 hrs after exposure of cells to the test compound or vehicle control were recorded.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of novel 4,5-disubstituted 2H-1,2,3-triazoles as cis-constrained analogues of combretastatin A-4

Madadi

Penthala

Howk

et al. 2015

European Journal of Medicinal Chemistry

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A series of combretastatin A-4 (CA-4) analogues have been prepared from (Z)-substituted diarylacrylonitriles (1a–1p) obtained in a two-step synthesis from appropriate arylaldehydes and acrylonitriles. The resulting 4,5-disubstituted 2H-1,2,3-triazoles were evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The diarylacrylonitrile analogue 2l exhibited the most potent anti-cancer activity in the screening studies, with GI50 values of <10 nM against almost all the cell lines in the human cancer cell panel and TGI values of <10nM against cancer cell lines SF-539, MDA-MB-435, OVCAR-3 and A498. Furthermore, in silico docking studies of compounds 2l, 2e and 2h within the active site of tubulin were carried out in order to rationalize the mechanism of anti-cancer properties of these compounds. From the in silico studies, compound 2e was predicted to have better affinity for the colchicine binding site on tubulin compared to compounds 2l and 2h. Analogue 2e was also evaluated for its anti-cancer activity by colony formation assay against 9LSF rat gliosarcoma cells and afforded an LD50 of 7.5 nM. A cell cycle redistribution assay using analogue 2e was conducted to further understand the mechanism of action of these CA-4 analogues. From this study, analogues 2e and 2l were the most potent anti-cancer agents in this structural class, and were considered lead compounds for further development as anti-cancer drugs.

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Synthesis and evaluation of a series of resveratrol analogues as potent anti-cancer agents that target tubulin

Cited by 31 publications

References 30 publications

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

Anticancer Activity of Stilbene‐Based Derivatives

Synthesis and biological evaluation of novel 4,5-disubstituted 2H-1,2,3-triazoles as cis-constrained analogues of combretastatin A-4

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