Structure optimization of an F-indole-chalcone (FC116) on 4-methoxyphenyl group and therapeutic potential against colorectal cancers with low cytotoxicity

Du, Bolin; Liu, Xiaoxia; Luan, Xin; Zhang, Weidong; Zhuang, Chunlin

doi:10.1016/j.bioorg.2023.106531

Cited by 4 publications

(8 citation statements)

References 22 publications

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“…In vivo experiments showed that compound 85 could significantly inhibit tumor growth, which was higher than that of paclitaxel. 127…”

Section: Flavonoid-indole Derivativesmentioning

confidence: 99%

“…In vivo experiments showed that compound 85 could significantly inhibit tumor growth, which was higher than that of paclitaxel. 127 Chrysin is a natural flavonoid present in the seeds and stem bark of Oroxylum indicum and has pharmacological activities such as anti-inflammatory and analgesic activities. 128 Researchers synthesized chrysin linked indole derivatives in the hope to obtain promising antiinflammatory and analgesic drugs.…”

Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 99%

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Research status of indole-modified natural products

Duan,

Song,

Guo

et al. 2023

RSC Med. Chem.

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“…In vivo experiments showed that compound 85 could significantly inhibit tumor growth, which was higher than that of paclitaxel. 127…”

Section: Flavonoid-indole Derivativesmentioning

confidence: 99%

Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 99%

Research status of indole-modified natural products

Duan,

Song,

Guo

et al. 2023

RSC Med. Chem.

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“…Further SAR study generated the discovery of a representative fluoro-substituted indole-chalcone (FC116, Figure 1). 16,18 This compound has demonstrated high potency against HCT116 and CT26 cell lines, with IC 50 values of 4.52 and 18.69 nM, respectively. In HCT116-xenograft mice, FC116 exhibited a tumor growth inhibition rate of 65.96% at a dose of 3 mg/kg, which is much better than paclitaxel (PTX).…”

mentioning

confidence: 99%

“…In APC min/+ mice, FC116 showed a significant adenoma number inhibition rate of 76.3%. 16 Additional modifications on the 4-methoxyphenyl group led to a water-soluble compound FC11619 (Figure 1) that achieved tumor growth inhibition rates of 65.3% and 73.4% at doses of 5 and 10 mg/kg/d for 21 d. 18 Therefore, indole-chalcone derivatives should be a kind of privileged compound for anticancer study. However, the efficacy of the series of indole-chalcones against resistance to standard therapies has not been investigated.…”

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Structure–Activity Relationship Study of (E)-3-(6-Fluoro-1H-indol-3-Yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (FC116) Against Metastatic Colorectal Cancers Resistant to Oxaliplatin

Wang,

Ge,

Cong

et al. 2024

ACS Pharmacol. Transl. Sci.

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Advanced metastatic colorectal cancer (mCRC) and the development of drug resistance to chemotherapy pose significant challenges in clinical settings. In previous studies, we have demonstrated the potent cytotoxic activity of (E)-3-(6-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (FC116) and related 30 derivatives against mCRC by targeting microtubules. In this study, we aimed to evaluate the efficacy of the 31 compounds and explore the structure−activity relationship (SAR) against oxaliplatin-resistant mCRC. We found that most of the derivatives showed high sensitivity toward the oxaliplatinresistant HCT-116/L cells. Particularly, FC116 exhibited a better GI 50 value against the resistant mCRC cell line, HCT-116/L, compared to standard therapies. We also observed a safer therapeutic window for FC116 and a synergistic effect when it was used in combination with oxaliplatin. Mechanistically, FC116 induced the G2/M phase arrest by downregulating cyclin B1 expression through its interaction with microtubules in resistant colorectal cancer cells. Furthermore, in vivo experiments demonstrated that FC116 significantly suppressed tumor growth, achieving a 78% reduction at a dose of 3 mg/kg, which was superior to the 40% reduction achieved by oxaliplatin treatment. Overall, our findings suggest that the indole-chalcone compound FC116 represents a promising lead for chemotherapy in oxaliplatin-resistant mCRC.

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