Novel tertiary sulfonamides as potent anti-cancer agents

Okolotowicz, Karl J.; Dwyer, Mary A.; Ryan, David L.; Cheng, Jiongjia; Cashman, Emily A.; Moore, Stephanie; Mercola, Mark; Cashman, John R.

doi:10.1016/j.bmc.2018.07.042

Cited by 25 publications

(22 citation statements)

References 34 publications

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“…Considering the selectivity and toxicity problems of Wnt inhibitors, development of inhibitors targeting downstream Wnt transcription effectors (i.e., b-Catenin/TCF complex) is of great interest. Compound 2 works downstream of b-catenin by regulating disengagement of TCF proteins from chromatin (19,20) and may overcome the selectivity and toxicity issues observed for other Wnt inhibitors. Colorectal cancer cell proliferation inhibition by compound 2 was independent of APC mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the design of compound 2 for targeting multiple pathways to modulate cross-talk between additional pathways may be key to colorectal cancer treatment strategy (13). Because homeodomain interacting protein kinase 2 (HIPK2) phosphorylates p53 at Ser46 (40), leading to p53 activation, HIPK2 inhibition of Wnt transcription via phosphorylation of TCF proteins (40,41) links the mechanism of compound 2 to both Wnt inhibition and p53 activation (19,20). This linkage was observed in HCT-116 cells but not the p53 null cells ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…1; refs. 19,20). Chemicals and reagents used in this study were described in Supplementary Materials and Methods.…”

Section: Compoundsmentioning

confidence: 99%

“…1) was identified as an inhibitor of canonical Wnt/b-catenin-dependent transcription in a highthroughput screen of 76,000 compounds (19,20). Chemical synthesis of >130 analogs of compound 1 using dynamic medicinal chemistry (24) afforded compounds with greater Wnt transcription inhibitor potency and improved pharmaceutical properties (19,20). Compounds 1 to 4 were selected and potently inhibited cell proliferation against the NCI-60 panel of cancer cell lines (GI 50 values range from <10 to $40 nmol/L; Supplementary Table S2).…”

Section: Effect Of Compounds 1 To 4 On Nci-60 Colorectal Cancer Cell mentioning

confidence: 99%

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A Novel Inhibitor Targets Both Wnt Signaling and ATM/p53 in Colorectal Cancer

et al. 2018

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For 2017, the estimated lifetime risk of developing colorectal cancer was 1 in 22. Even though preventative colonoscopy screening and standard-of-care surgery, radiation, and chemotherapy have decreased the death rate from colorectal cancer, new therapies are needed for metastatic colorectal cancer. Here, we developed a novel small molecule, compound , that inhibited proliferation and viability of human colorectal cancer cells (HCT-116, DLD-1, SW480, and 10.1). Compound inhibited cell migration, invasion, and epithelial-mesenchymal transition processes and potently increased cell apoptosis in human colorectal cancer cells. Compound also modulated mitotic stress signaling, leading to both inhibition of Wnt responsiveness and stabilization and activation of p53 to cause cell-cycle arrest. In mouse xenografts, treatment with compound (20 mg/kg/day, i.p.) induced cell death and inhibited tumor growth more than four-fold compared with vehicle at day 34. Neither acute cytotoxicity nor toxicity in animals (up to 1,000 mg/kg, i.p.) were observed for compound To our knowledge, compound is the first reported potent small molecule that inhibits Wnt/β-catenin signaling, activates p53 signaling regardless of p53 mutation status, and binds microtubules without detectable toxicity. Thus, compound offers a novel mechanism of action and a new strategy to treat colorectal cancer. These findings identify a potent small molecule that may be therapeutically useful for colon cancer that works by inhibiting Wnt/β-catenin signaling, activating p53, and binding microtubules without detectable toxicity. .

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…1; refs. 19,20). Chemicals and reagents used in this study were described in Supplementary Materials and Methods.…”

Section: Compoundsmentioning

confidence: 99%

Section: Effect Of Compounds 1 To 4 On Nci-60 Colorectal Cancer Cell mentioning

confidence: 99%

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A Novel Inhibitor Targets Both Wnt Signaling and ATM/p53 in Colorectal Cancer

et al. 2018

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“…On the other hand, derivatives with a sulfonamide structure, having anticancer properties, have already been highlighted in the literature. These anti-cancer therapeutics, act by inhibiting Wnt (Wingless-related integration site) transcription pathway [19]. The use of chitosan-sulfonamide derivatives to prepare nanoparticles for increasing the inhibition capacity of angiogenesis could prove to be an important strategy in future antitumor therapy.…”

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confidence: 99%

Designing of Chitosan Derivatives Nanoparticles with Antiangiogenic Effect for Cancer Therapy

et al. 2020

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Angiogenesis is a physiological process involving the growth of new blood vessels, which provides oxygen and required nutrients for the development of various pathological conditions. In a tumor microenvironment, this process upregulates the growth and proliferation of tumor cells, thus any stage of angiogenesis can be a potential target for cancer therapies. In the present study, chitosan and his derivatives have been used to design novel polymer-based nanoparticles. The therapeutic potential of these newly designed nanoparticles has been evaluated. The antioxidant and MTT assays were performed to know the antioxidant properties and their biocompatibility. The in vivo antiangiogenic properties of the nanoparticles were evaluated by using a chick Chorioallantoic Membrane (CAM) model. The obtained results demonstrate that chitosan derivatives-based nanostructures strongly enhance the therapeutic effect compared to chitosan alone, which also correlates with antitumor activity, demonstrated by the in vitro MTT assay on human epithelial cervical Hep-2 tumor cells. This study opens up new direction for the use of the chitosan derivatives-based nanoparticles for designing of antiangiogenic nanostructured materials, for future cancer therapy.While stimulation of angiogenesis in cancer leads to metastasis, the anti-angiogenic therapy proved to be an important approach against tumor growth. In this respect, it is a well-known fact that the consumption of antioxidants can be recommended to achieve the inhibition of angiogenesis or reversal of unwanted cell-cell adherence [1]. Several studies have been conducted to investigate the connection between antioxidants and pathological angiogenesis, thus leading to mixed conclusions from studies that have been associated with a lower total cancer incidence with the use of antioxidants [2], to studies that have highlighted the lack of any benefit of using antioxidants on the incidence of cancer [3]. All these results are, for certain ones, closely related with the type of antioxidant included in the study (alpha tocopherol, beta-carotene, ascorbic acid) and the investigated tumor location and not least the investigated pharmaceutical formulation. In this context, the use of antioxidants in the form of nanoparticles could improve the efficiency of this therapy due to specific surface area of nanostructures [4], thereby ensuring better contact with cells that would increase the chances of pathological angiogenesis inhibition. However, to have more success in cancer therapy, more studies should be conducted in this direction.Chitosan is a natural cationic polymer exhibits three chemical reactive sites including a primary amine and two primary or secondary hydroxyl groups for further modification [5][6][7]. Nano/microparticles coated with chitosan, synthesized through different techniques for encapsulation (chemical, physical and mechanical techniques), are in continuous development, aiming at the entrapment of bioactive substances, enzymes, hormones, antimicrobial agents, vitamins, mi...

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A Guide for Mono‐Selective N‐Methylation, N‐Ethylation, and N‐n‐Propylation of Primary Amines, Amides, and Sulfonamides and Their Applicability in Late‐Stage Modification

Templ,

Schnürch

2024

Chemistry A European J

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This review provides a comprehensive overview of mono‐alkylation methodologies targeting crucial nitrogen moieties – amines, amides, and sulfonamides – found in organic building blocks and pharmaceuticals. Emphasizing the intersection of chemical precision with drug discovery, the central challenge addressed is achieving one‐pot mono‐selective short‐chain N‐alkylations (methylations, ethylations, and n‐propylations), preventing undesired overalkylation. Additionally, sustainable, safe, and benign alternatives to traditional alkylating agents, including alcohols, carbon dioxide, carboxylic acids, nitriles, alkyl phosphates, quaternary ammonium salts, and alkyl carbonates, are explored. This review, categorized by the nature of the alkylating agent, aids researchers in selecting suitable methods for mono‐selective N‐alkylation.

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Novel tertiary sulfonamides as potent anti-cancer agents

Cited by 25 publications

References 34 publications

A Novel Inhibitor Targets Both Wnt Signaling and ATM/p53 in Colorectal Cancer

A Novel Inhibitor Targets Both Wnt Signaling and ATM/p53 in Colorectal Cancer

Designing of Chitosan Derivatives Nanoparticles with Antiangiogenic Effect for Cancer Therapy

A Guide for Mono‐Selective N‐Methylation, N‐Ethylation, and N‐n‐Propylation of Primary Amines, Amides, and Sulfonamides and Their Applicability in Late‐Stage Modification

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