Design and synthesis of dimethylaminomethyl-substituted curcumin derivatives/analogues: Potent antitumor and antioxidant activity, improved stability and aqueous solubility compared with curcumin

Fang, Xubin; Fang, Lei; Gou, Shaohua; Cheng, Lin

doi:10.1016/j.bmcl.2012.12.098

Cited by 65 publications

(53 citation statements)

References 16 publications

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“…Isoxazole (2), N-substituted pyrazoles (3)(4)(5)(6)(7)(8)(9), and pyrimidine ring (10-12) containing curcumin derivatives were synthesized by interaction of curcumin with hydroxyl amine hydrochloride, hydrazine hydrate, phenyl hydrazine, 2,4-dinitrophenyl hydrazine, furoic hydrazide, isoniazid, semicarbazide, thiosemicarbazide, urea, thiourea, and guanidine, respectively. Synthetic route and structure of these curcumin derivatives are presented in Scheme 1, while the physiochemical data of synthesized compounds are shown in Table 1 (analytical data, see supplementary information, Table S1).…”

Section: S C H E M Ementioning

confidence: 99%

“…Active methylene and keto moiety are believed to be responsible for its rapid metabolism. In order to circumvent the problem of rapid metabolism and to improve its pharmacokinetics profile, several synthetic modifications have been studied on carbonyl and active methylene moiety [9] . In present study, isoxazole, N-substituted pyrazoles, and pyrimidine ring were incorporated in this focused segment of curcumin.…”

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confidence: 99%

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Screening of curcumin‐derived isoxazole, pyrazoles, and pyrimidines for their anti‐inflammatory, antinociceptive, and cyclooxygenase‐2 inhibition

et al. 2017

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Curcumin has shown pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its numerous derivatives for diverse and improved therapeutic roles. In this study, we have synthesized curcumin derivatives containing isoxazole, pyrazoles, and pyrimidines and then the synthesized molecules were evaluated for their anti-inflammatory and antinociceptive activities in experimental animal models. Acute toxicity of synthesized molecules was evaluated in albino mice by oral administration. Any behavioral and neurological changes were observed at dose of 10 mg/kg body weight.Additionally, cyclooxygenase-2 (COX-2) enzyme inhibition studies were performed through in vitro assays. In vivo anti-inflammatory studies showed that curcumin with pyrimidines was the most potent anti-inflammatory agent which inhibited induced edema from 74.7% to 75.9%. Compounds 7, 9, and 12 exhibited relatively higher prevention of writhing episodes than any other compound with antinociceptive activity of 73.2%, 74.9%, and 71.8%, respectively. This was better than diclofenac sodium (reference drug, 67.1% inhibition). Similarly, COX-2 in vitro inhibition assays results revealed that compound 12 (75.3% inhibition) was the most potent compound.Molecular docking studies of 10, 11, and 12 compounds in human COX-2 binding site revealed the similar binding modes as that of other COX-2-selective inhibitors. K E Y W O R D Santi-inflammatory, COX-2 inhibition, curcumin derivatives, molecular modeling Chemically curcumin is diferuloylmethane which has attracted much attention of medicinal chemists for various diseases and therapeutic agents development. It has shown its pharmacological safety and wide range of biological activities such as antibacterial to anticancer agent [1][2][3][4] . Currently, curcumin is acclaimed to be one of the most widely researched naturally occurring chemopreventive agent which is cytoprotective to healthy human cells [5][6][7] . In spite of important therapeutic application, limited therapeutic utility concerns are associated with curcumin because of its poor absorption and fast metabolism under physiological conditions [8] . Active methylene and keto moiety are believed to be responsible for its rapid metabolism. In order to circumvent the problem of rapid metabolism and to improve its pharmacokinetics profile, several synthetic modifications have been studied on carbonyl and active methylene moiety [9] . In present study, isoxazole, N-substituted pyrazoles, and pyrimidine ring were incorporated in this focused segment of curcumin. Nitrogen heterocyclic moieties such as pyrazoles and pyrimidines containing derivatives gained considerable attention in medicinal chemistry for

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Section: S C H E M Ementioning

confidence: 99%

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confidence: 99%

Screening of curcumin‐derived isoxazole, pyrazoles, and pyrimidines for their anti‐inflammatory, antinociceptive, and cyclooxygenase‐2 inhibition

et al. 2017

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“…In addition, modification on the phenolic hydroxy groups might be of benefit to physical stability as well as metabolism behavior, 5) and introduction of the terminal hydrophilic amino groups in the side chains was carried out in anticipation of improved water solubility or/and antitumor activity. 26,27) …”

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confidence: 99%

Synthesis and Antiproliferative Effect of Novel Curcumin Analogues

Liu

Xia

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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Novel curcumin analogues with α,β-unsaturated ketone moiety and/or α,β-saturated ketone structure were synthesized from curcumin via alkylation at the central carbon and the phenolic hydroxy groups, and hydrogenation of α,β-unsaturated ketone moiety. The antiproliferative activities were tested in five human solid tumor cell lines in vitro. Most of the compounds exhibited increased antiproliferative activities comparing with that of curcumin. Structure-activity relationship (SAR) analysis revealed that the α,β-unsaturated ketone structure was not required for antiproliferative activity of these curcumin analogues. Among these compounds, 1,7-bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16f) was the most effective one with IC 50 value below 1 µm, which was 9-to 81-fold more potent than curcumin.

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“…Chemotherapy is the main treatment for advanced lung cancer patients, but many patients are resistant to chemotherapy (Dempke et al, 2010;Starakis et al, 2012) .Therefore, the development of new chemotherapy drug for the treatment of lung cancer is particularly imminent. The exploitation of chemotherapy drugs based on natural product is a common way to develop new drugs (Afaq et al, 2002;Zhang et al, 2012;Fang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Curcumin Analogue A501 induces G2/M Arrest and Apoptosis in Non-small Cell Lung Cancer Cells

Xia¹,

Wei²,

Li³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Curcumin and its analogues have been reported to exert anti-cancer activity against a variety of tumors. Here, we reported A501, a new curcumin analogue. The effect of A501 on cell viability was detected by MTT assay, the result showed that A501 had a better inhibiting effect on the four non-small cell lung cancer (NSCLC) cells than that of curcumin. Moreover, Colony forming experiment showed A501 significant restrained cell proliferation. Flow cytometry displayed A501 can cause G2/M arrest and induce apoptosis. Western blotting showed that A501 decreased the expression of cyclinB1, cdc-2, bcl-2, while increased the expression of p53, cleaved caspase-3 and bax. In conclusion, curcumin analogues A501 played antitumor activity by inhibiting cell proliferation and inducing apoptosis of NSCLC cells. And it was likely to be a promising starting point for the development of curcumin-based anticancer drugs.

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Design and synthesis of dimethylaminomethyl-substituted curcumin derivatives/analogues: Potent antitumor and antioxidant activity, improved stability and aqueous solubility compared with curcumin

Cited by 65 publications

References 16 publications

Screening of curcumin‐derived isoxazole, pyrazoles, and pyrimidines for their anti‐inflammatory, antinociceptive, and cyclooxygenase‐2 inhibition

Screening of curcumin‐derived isoxazole, pyrazoles, and pyrimidines for their anti‐inflammatory, antinociceptive, and cyclooxygenase‐2 inhibition

Synthesis and Antiproliferative Effect of Novel Curcumin Analogues

Curcumin Analogue A501 induces G2/M Arrest and Apoptosis in Non-small Cell Lung Cancer Cells

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