Green Synthesis of a Novel Phytoalexin Derivative: <i>In Silico</i> Profiling, Apoptotic Induction, and Antiproliferative Activity against MCF-7 cells - From Vineyards to Potent Anticancer Drug Molecule

Author(s):

Lairikyengbam Deepti Roy and Jyotsna Kumar*   Pages 66 - 76 ( 11 )

Abstract:

<P>Background: Resveratrol's structural similarity to commercialized anti-breast cancer medications such as Tamoxifen underlines its potential as a promising option for developing successful anti-breast cancer drugs. However, the pharmacokinetic issues associated with resveratrol, such as its low bioavailability, have piqued the attention of researchers in developing novel derivatives. <P> Methods: A novel phytoalexin derivative, RsvD1, was successfully synthesized using resveratrol extracted from green grape peels as a precursor to investigate its anti-breast cancer efficacy on Estrogen receptor (ER) positive and negative breast cancer cells. <P> Results: The comparative analysis revealed that RsvD1 exhibited remarkable radical scavenging ability (IC₅₀ = 2.21 μg/mL), surpassing the control, Trolox (IC₅₀ = 6.3 μg/mL). Furthermore, RsvD1 demonstrated enhanced and selective antiproliferative activity against ER-positive MCF-7 cells (IC₅₀ = 20.09 μg/mL) compared to resveratrol, the parent molecule (IC₅₀ = 30.90 μg/mL). Further investigations unveiled that RsvD1 induced apoptosis and DNA damage in MCF-7 cells, leading to cell cycle arrest at the G₀/G₁ phase after 24 hours of incubation. RTqPCR gene expression analysis indicated that RsvD1 down-regulated the CAXII (ER-dependent) genes. <i>In silico</i> predictions demonstrated that RsvD1 possesses promising potential as a drug candidate due to its drug-like characteristics and favourable ADMET profile. Moreover, molecular docking studies provided insights into the theoretical binding mode between RsvD1 and ERα protein. <P> Conclusion: The study highlights the therapeutic potential of the synthesized resveratrol derivative, RsvD1, positioning it as a promising scaffold for developing novel analogues with improved therapeutic properties and selectivity, specifically targeting ER+ breast cancer cells. Moreover, the compound's non-cytotoxic yet antiproliferative properties, coupled with its capability to induce programmed cell death and cell cycle arrest, enhance its potential as a highly effective drug candidate. As a result, this paves a promising path for the development of innovative and selective inhibitors targeting ER+ breast cancer with enhanced efficacy.</P>

Keywords:

Phytoalexin analogue, resveratrol, molecular docking, ADMET, MTT, Annexin V/PI.

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