Synthesis and Biological Evaluation of Novel Sulfonanilide Compounds as Antiproliferative Agents for Breast Cancer

Su, Bin; Darby, Michael V.; Brueggemeier, Robert W.

doi:10.1021/cc700138n

Cited by 26 publications

(37 citation statements)

References 20 publications

(57 reference statements)

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“…1) is a lead compound from the nimesulide derivative pool [25,39]. It selectively inhibited the proliferation of SK-BR-3 and BT474 breast cancer cells which all express Her2 protein in previous studies [39]. We hypothesize that the compound might be able to inhibit LTEDaro breast cancer cell growth since the cells depend on the elevated Her2 signal for proliferation.…”

Section: Compound Jcc76 Significantly Inhibited Ltedaro Cell Growthmentioning

confidence: 91%

“…Compound JCC76 (Fig. 1) is a lead compound from the nimesulide derivative pool [25,39]. It selectively inhibited the proliferation of SK-BR-3 and BT474 breast cancer cells which all express Her2 protein in previous studies [39].…”

Section: Compound Jcc76 Significantly Inhibited Ltedaro Cell Growthmentioning

confidence: 93%

“…It is more like a general cytotoxic agent to the cancer cells. Interestingly, its analogs selectively inhibited Her2 over-expressing breast cancer cell growth [26,39]. Since Her2 is unregulated in AI resistant breast cancer cells, it is very likely that nimesulide analogs are able to overcome AI resistance.…”

Section: Compound Jcc76 Significantly Inhibited Ltedaro Cell Growthmentioning

confidence: 99%

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In vitro and in vivo effects of a cyclooxygenase-2 inhibitor nimesulide analog JCC76 in aromatase inhibitors-insensitive breast cancer cells

Zhong

Cai

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

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Third generation aromatase inhibitors (AIs) are more effective than tamoxifen in the treatment of estrogen receptor (ER) positive breast cancer. However, long-term use of AIs commonly results in resistance. We examined whether compound JCC76{Cyclohexanecarboxylic acid [3-(2,5-dimethyl-benzyloxy)-4-(methanesulfonyl-methyl-amino)-phenyl]-amide}, an analog of Cyclooxygenase-2 (COX-2) inhibitor nimesulide, can inhibit the growth of AI-insensitive breast cancer cells and the mechanisms by which the compound affects cell proliferation. LTEDaro (long term estrogen deprived MCF-7aro cell) cells, which are a model for AI resistance, were used in this study. JCC76 effectively inhibited LTEDaro cell proliferation with an IC(50) of 2.75 ± 0.31 μM. Further investigations reveal that the compound significantly induced apoptosis in LTEDaro cells by decreasing pAKT, BCL-2 and pBad protein levels, which were all up regulated in the cells after long term estrogen deprivation. LTEDaro tumor size and weight were decreased in ovariectomized nude mice treated with the compound, and cell apoptosis in the tumor tissue was increased compared to the control. The animal weight remained almost unchanged which indicated the low toxicity of the compound. These results suggest that JCC76 overcame AI resistance by inducing cell apoptosis as illustrated in the in vitro and in vivo models. Collectively, results from this study provide data to support that nimesulide analog JCC76 may be a new drug candidate to treat AI-resistant breast cancers. It could be also used as a lead to design and synthesize more potent derivatives.

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Section: Compound Jcc76 Significantly Inhibited Ltedaro Cell Growthmentioning

confidence: 91%

Section: Compound Jcc76 Significantly Inhibited Ltedaro Cell Growthmentioning

confidence: 93%

Section: Compound Jcc76 Significantly Inhibited Ltedaro Cell Growthmentioning

confidence: 99%

See 1 more Smart Citation

In vitro and in vivo effects of a cyclooxygenase-2 inhibitor nimesulide analog JCC76 in aromatase inhibitors-insensitive breast cancer cells

Zhong

Cai

et al. 2011

The Journal of Steroid Biochemistry and Molecular Biology

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“…On the structure of nimesulide, several systematic modifications were performed to improve their anti-cancer activity as well as to erase their COX-2 inhibitory activity (Su et al, 2008;Su and Chen, 2009). To inhibit cancer cell growth, critical moieties for the nimesulide analogs are the dimethyl benzyl and methylsulfonamide.…”

Section: Introductionmentioning

confidence: 99%

“…This nimesulide analog is JCC76 which is a non-COX-2 active compound ( Fig. 1) Zhong et al, 2011;Su et al, 2008) and SKBR-3 breast cancer cell growth is inhibited by it with an IC 50 which is more active than nimesulide about 100 folds. The potential COX-2 activity is abolished by the N-methylation of JCC76 which blocks the ionization of its sulfonamide group (Su et al, 2006;Renard et al, 2006;Julemont et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

Choudhury

2014

Med Chem Res

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Growth suppression of many non-COX-2 expressing tumor cells can be exhibited by COX-2 inhibitors, where supplementation of cells with exogenous prostaglandins fails to rescue the cells from growth inhibition. It can, therefore, be speculated that anti-cancer properties of some COX-2 inhibitors may be contributed by the COX-2-independent effects also. Some of the derivatives obtained from certain COX-2 inhibitors which show non-COX-2 inhibitory mechanism have revealed some significant anti-cancer activities. From a COX-2 selective inhibitor nimesulide, an analog JCC76 is derived which is a non-COX-2 active compound and shows inhibition of SKBR-3 breast cancer cell growth. Other JCC76 derived inhibitors also played significant role in SKBR-3 cell inhibition. An analog-based study was done using pharmacophore modeling and 3D-QSAR to provide clues for potential lead compound designing. A five point pharmacophore ADHRR was generated using 39 JCC76-derived SKBR-3 inhibitors. The validated pharmacophore alignment was used for further 3D-QSAR analysis, which presented a good R 2 value of 0.562, 0.982, and 0.848 for atombased QSAR, CoMFA, and CoMSIA model, respectively. All the QSAR models presented good statistical significance and predictivity. The corresponding Q 2 values for each model are 0.513, 0.649, and 0.518, respectively. Both the pharmacophore and CoMSIA results displayed that the H-bond donor and acceptor sites are the key structural feature for JCC76-derived non-COX-2-dependent inhibitors with high activity.

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Synthesis and Biological Evaluation of Novel Indomethacin Derivatives as Potential Anti‐Colon Cancer Agents

Farrag

2016

Archiv der Pharmazie

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The molecular structure of indomethacin was used as a starting scaffold for the synthesis of 20 novel analogs and to study their effects on the proliferation of three human colon cancer cell lines, HCT-116, HT-29, and Caco-2, by MTT assay. The synthesized indomethacin analogs were characterized on the basis of IR, H NMR, C NMR, mass spectral data, and elemental analysis results. Cytotoxicity assay results showed that the indomethacin amide analog 2 was the most potent anticancer agent (IC = 0.78, 0.09, and 0.0127 μg/mL) against the three colon cancer cell lines, respectively, being more potent than the standard 5-fluorouracil (IC = 1.8, 0.75, and 5.45 μg/mL). Interestingly, the indomethacin oxazin analog 3 and the indomethacin amide analog 8 displayed very potent anticancer activity against the HCT-116 cell line with IC = 0.421 and 0.27 μg/mL, respectively, much better than the reference (IC = 1.8 μg/mL). Additionally, analogs 3, 4b, 11, 12c, and 13a exhibited excellent antitumor activity against Caco-2 cells, with IC ranging from 1.5 to 4.5 μg/mL. Furthermore, analogs 2 and 8 were additionally examined for their effect on the cell cycle of HCT-116 and HT-29 cells, respectively, using flow cytometric analysis. Analog 2 arrested the cell cycle of HT-29 cells at the S phase, while 8 was found to arrest the cell cycle of HCT-116 cells at the G0/G1 phase.

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Synthesis and Biological Evaluation of Novel Sulfonanilide Compounds as Antiproliferative Agents for Breast Cancer

Cited by 26 publications

References 20 publications

In vitro and in vivo effects of a cyclooxygenase-2 inhibitor nimesulide analog JCC76 in aromatase inhibitors-insensitive breast cancer cells

In vitro and in vivo effects of a cyclooxygenase-2 inhibitor nimesulide analog JCC76 in aromatase inhibitors-insensitive breast cancer cells

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

Synthesis and Biological Evaluation of Novel Indomethacin Derivatives as Potential Anti‐Colon Cancer Agents

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