Synthesis, in vitro, and in vivo evaluation of novel functionalized quaternary ammonium curcuminoids as potential anti-cancer agents

Solano, Lucas N.; Nelson, Grady L.; Ronayne, Conor T.; Lueth, Erica A.; Foxley, Melissa A.; Jonnalagadda, Sravan K.; Gurrapu, Shirisha; Mereddy, Venkatram R.

doi:10.1016/j.bmcl.2015.10.061

Cited by 11 publications

(8 citation statements)

References 34 publications

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“…3-(Trimethylsilyl)-1-propanesulfonic acid sodium salt (NaDSS) (TCI Chemicals), methanol- d 3 (Acros), methanol- d 4 (Cambridge Isotope Laboratories), potassium hydroxide (Mallinckrodt), tetrabutylammonium bromide ( 7 ), and tetradecyltrimethylammonium bromide ( 8 ) (Sigma-Aldrich) were all used as received. The model compounds were prepared according to literature procedures: 1-benzylquinuclidin-1-ium bromide ( 1 ); benzyltrimethylammonium bromide ( 2 ); 1-benzyl-1,4-diazabicyclo[2.2.2]octan-1-ium bromide ( 3 ); 4-benzyl-4-methylmorpholin-4-ium bromide ( 4 ); N -benzyl- N -cyclohexyl- N -methylcyclohexanaminium bromide ( 5 ); 1-hexyl-1-methylpiperidin-1-ium bromide ( 6 ); 1-ethyl-1-methylpyrrolidin-1-ium bromide ( 9 ); 6-azaspiro[5.5]undecan-6-ium bromide ( 10 ); 5-azaspiro[4.5]decan-5-ium bromide ( 13 ); 1,3-di- n- butyl-2-(2,6-dimethylphenyl)-4,5-diphenylimidazolium iodide ( 15 ); 1-benzyl-2-(2,6-dimethylphenyl)-3-methyl-4,5-diphenylimidazolium ( 16 ); 1-benzyl-2,3-dimethylimidazolium bromide ( 17 ); 1-benzyl-3-methylimidazolium bromide ( 18 ); 1,3-dimethyl-2-mesityl-1 H -benzimidazolium iodide ( 19 ); 1-benzylpyridin-1-ium chloride ( 21 ); N -[bis(dimethylamino)methylene]- N -methyl-1-phenylmethanaminium iodide ( 22 ); tetrakis[cyclohexyl(methyl)amino]phosphonium hexafluorophosphate ( 23 ), tetrakis(pyrrolidin-1-yl)phosphonium hexafluorophosphate ( 24 ); benzyl-tris(2,4,6-trimethoxyphenyl)phosphonium bromide ( 25 ); and benzyltrimethylphosphonium bromide ( 26 ) …”

Section: Methodsmentioning

confidence: 99%

Degradation of Organic Cations under Alkaline Conditions

et al. 2020

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Understanding the degradation mechanisms of organic cations under basic conditions is extremely important for the development of durable alkaline energy conversion devices. Cations are key functional groups in alkaline anion exchange membranes (AAEMs), and AAEMs are critical components to conduct hydroxide anions in alkaline fuel cells. Previously, we have established a standard protocol to evaluate cation alkaline stability within KOH/CD 3 OH solution at 80 °C. Herein, we are using the protocol to compare 26 model compounds, including benzylammonium, tetraalkylammonium, spirocyclicammonium, imidazolium, benzimidazolium, triazolium, pyridinium, guanidinium, and phosphonium cations. The goal is not only to evaluate their degradation rate, but also to identify their degradation pathways and lead to the advancement of cations with improved alkaline stabilities.

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Section: Methodsmentioning

confidence: 99%

Degradation of Organic Cations under Alkaline Conditions

et al. 2020

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“…However, due to its poor bioavailability, curcumin has only been shown to be effective in in vitro studies and is not currently utilized as an adjuvant to common chemotherapeutics for treating PC . Given this problem, significant efforts have been made to modify curcumin synthetically and producing other curcumin analogs, in order to generate compounds with greater bioavailability and efficacy in vivo . Among these efforts, our group has developed various structural analogues of curcumin (polyenolic zinc‐binding agents; PEZBINs), including the current lead compound, CMC2.24 (Figure A), which has higher bioactivity, better solubility, and no evidence of toxicity even at very high doses …”

Section: Introductionmentioning

confidence: 99%

“…11 Given this problem, significant efforts have been made to modify curcumin synthetically and producing other curcumin analogs, in order to generate compounds with greater bioavailability and efficacy in vivo. [12][13][14] Among these efforts, our group has developed various structural analogues of curcumin (polyenolic zinc-binding agents; PEZBINs), including the current lead compound, CMC2. 24 [15][16][17][18][19][20] (Figure 1A), which has higher bioactivity, better solubility, and no evidence of toxicity even at very high doses.…”

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confidence: 99%

A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras

Mallangada

Vargas

Thomas

et al. 2018

Molecular Carcinogenesis

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Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (P < 0.02), and the growth of a human patient-derived tumor xenograft by 47.5% (P < 0.03 vs vehicle control). Mechanistically, CMC2.24 inhibited the Ras-RAF-MEK-ERK pathway. Based on Ras Pull-Down Assays, CMC2.24 inhibited Ras-GTP, the active form of Ras, in MIA PaCa-2 cells and in pancreatic acinar explants isolated from Kras mutant mice, by 90.3% and 89.1%, respectively (P < 0.01, for both). The inhibition of active Ras led to an inhibition of c-RAF, MEK, and ERK phosphorylation by 93%, 91%, and 87%, respectively (P < 0.02, for all) in PC xenografts. Furthermore, c-RAF overexpression partially rescued MIA PaCa-2 cells from the cell growth inhibition by CMC2.24. In addition, downstream of ERK, CMC2.24 inhibited STAT3 phosphorylation levels at the serine 727 residue, enhanced the levels of superoxide anion in mitochondria, and induced intrinsic apoptosis as shown by the release of cytochrome c from the mitochondria to the cytosol and the further cleavage of caspase 9 in PC cells. In conclusion, CMC2.24, a potential Ras inhibitor, is an efficacious agent for PC treatment in preclinical models, deserving further evaluation.

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“…BH reaction template also offers high tunability at three different places. This reaction has been extensively investigated for various types of pharmaceutical development [ 17 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Baylis-Hillman Reaction Derived Imidazole and Triazole Cinnamates as Antifungal Agents

Nelson

Williams

Jonnalagadda

et al. 2018

International Journal of Medicinal Chemistry

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Allylic acetates derived from Baylis-Hillman reaction undergo efficient nucleophilic isomerization with imidazoles and triazoles to provide imidazolylmethyl and triazolylmethyl cinnamates stereoselectively. Antifungal evaluation of these derivatives against Cryptococcus neoformans exhibits good minimum inhibitory concentration values. These compounds exhibit low toxicity in proliferating MCF-7 breast cancer cell line. Structure activity relationship studies indicate that halogenated aromatic derivatives provide better antifungal activity.

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Synthesis, in vitro, and in vivo evaluation of novel functionalized quaternary ammonium curcuminoids as potential anti-cancer agents

Cited by 11 publications

References 34 publications

Degradation of Organic Cations under Alkaline Conditions

Degradation of Organic Cations under Alkaline Conditions

A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras

Synthesis and Evaluation of Baylis-Hillman Reaction Derived Imidazole and Triazole Cinnamates as Antifungal Agents

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