Identification and characterization of CW108F, a Novel β-carboline compound that promotes cardiomyogenesis of stem cells

Oh, Seung Joon; Kim, Bora; Jeon, Sejin; Go, Du Min; Kim, Min Kyoung; Baek, Kyoung Min; Oh, Goo Taeg; Kim, Dae Yong

doi:10.1016/j.lfs.2013.07.016

Cited by 3 publications

(5 citation statements)

References 30 publications

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“…These compounds showed increased potency relative to 1 and other published small molecule inducers. 11 In addition, 31, 44 and 75 trended toward improved drug-like properties, compared to 1 . Thus, in the 1,5-disubstituted benzimidazole series examined herein, 1, 31, 44 and 75 constituted compounds that are useful and reliable molecular tools to direct cardiomyogenesis in mESCs.…”

Section: Discussionmentioning

confidence: 98%

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1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells

Okolotowicz¹,

Bushway²,

Lanier³

et al. 2015

Bioorganic & Medicinal Chemistry

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Cardiomyopathy is the leading cause of death worldwide. Despite progress in medical treatments, heart transplantation is one of the only current options for those with infarcted heart muscle. Stem cell differentiation technology may afford cell-based therapeutics that may lead to the generation of new, healthy heart muscle cells from undifferentiated stem cells. Our approach is to use small molecules to stimulate stem cell differentiation. Herein, we describe a novel class of 1,5-disubstituted benzimidazoles that induce differentiation of stem cells into cardiac cells. We report on the evaluation in vitro for cardiomyocyte differentiation and describe structure–activity relationship results that led to molecules with drug-like properties. The results of this study show the promise of small molecules to direct stem cell lineage commitment, to probe signaling pathways and to develop compounds for the stimulation of stem cells to repair damaged heart tissue.

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Section: Discussionmentioning

confidence: 98%

“…7–10 In addition, other groups have reported on small molecule inducers of cardiomyogenesis. 11–13 Herein, we describe potent and selective 1,5-disubstituted benzimidazoles that represent a new class of small molecules that instruct stem cell differentiation to cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells

Okolotowicz¹,

Bushway²,

Lanier³

et al. 2015

Bioorganic & Medicinal Chemistry

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show abstract

“…carbolines have been reported to inhibit NO production in macrophages (Lee et al, 2000;Yoon et al, 2005) and other cell types (Newton et al, 2007;Shen et al, 2011;Wong et al, 2011), this biologic activity has typically been associated with suppressed NF-kB activity (Lee et al, 2000;Yoon et al, 2005;Wen et al, 2006;Newton et al, 2007;Shen et al, 2011;Oh et al, 2013) and reduced expression of cytokines and other inflammatory genes transcriptionally regulated by NF-kB (Newton et al, 2007;Oh et al, 2013). A recent screen of 50 functionalized tetrahydro-b-carboline derivatives (Shen et al, 2011) reported that the most potent carboline derivative had IC 50 values for inhibition of NF-kB activity and NO production of 4.8 and 2.8 mM, respectively.…”

Section: -Gly Carb Inhibits No Formation In Macrophagesmentioning

confidence: 99%

“…A number of naturally occurring and modified carbolines have been reported to alter NF-kB activation (Lee et al, 2000;Yoon et al, 2005;Oh et al, 2013;Tran et al, 2014). The 6-chloro-b-carboline derivative ML-102B [N-(6-chloro-7-methoxy-9H-b-carbolin-8-yl)-2-methylnicotinamide] inhibited the production of TNFa and interleukin-2 cytokines in peripheral blood monocytes by blocking NF-kB nuclear translocation (Wen et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

A Novel Carboline Derivative Inhibits Nitric Oxide Formation in Macrophages Independent of Effects on Tumor Necrosis Factorαand Interleukin-1βExpression

Grodzki

Poola

Pasupuleti

et al. 2014

J Pharmacol Exp Ther

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Neuropathic pain is a maladaptive immune response to peripheral nerve injury that causes a chronic painful condition refractory to most analgesics. Nitric oxide (NO), which is produced by nitric oxide synthases (NOSs), has been implicated as a key factor in the pathogenesis of neuropathic pain. b-Carbolines are a large group of natural and synthetic indole alkaloids, some of which block activation of nuclear factor k-light-chain-enhancer of activated B cells (NF-kB), a predominant transcriptional regulator of NOS expression. Here, we characterize the inhibitory effects of a novel 6-chloro-8-(glycinyl)-amino-b-carboline (8-Gly carb) on NO formation and NF-kB activation in macrophages. 8-Gly carb was significantly more potent than the NOS inhibitor NG-nitro-Larginine methyl ester in inhibiting constitutive and inducible NO formation in primary rat macrophages. 8-Gly carb interfered with NF-kB-mediated gene expression in differentiated THP1-XBlue cells, a human NF-kB reporter macrophage cell line, but only at concentrations severalfold higher than needed to significantly inhibit NO production. 8-Gly carb also had no effect on tumor necrosis factor a (TNFa)-induced phosphorylation of the p38 mitogenactivated protein kinase in differentiated THP1 cells, and did not inhibit lipopolysaccharide-or TNFa-stimulated expression of TNFa and interleukin-1b. These data demonstrate that relative to other carbolines and pharmacologic inhibitors of NOS, 8-Gly carb exhibits a unique pharmacological profile by inhibiting constitutive and inducible NO formation independent of NF-kB activation and cytokine expression. Thus, this novel carboline derivative holds promise as a parent compound, leading to therapeutic agents that prevent the development of neuropathic pain mediated by macrophage-derived NO without interfering with cytokine expression required for neural recovery following peripheral nerve injury.

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“…This can be at the level of whole cells, such as professional antigen presenting cells, B-cells or T-cells, or at the level of whole organs, from lymph nodes upwards. Perhaps the clearest example of this is the idea of using drugs to direct stems to differentiate within the immune environment, as has been done in other areas, [23][24][25] and the potential of unwanted immunogenicity of stem cell therapeutics. 26,27 Hand-in-hand with the idea of the immune system as a hierarchy of targets is the concept of polypharmacy directed at many immune targets.…”

mentioning

confidence: 99%

The Immune System as Drug Target

Flower

2013

Immunol Immunogenet Insights

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ABSTRACT:The immune system is perhaps the largest yet most diffuse and distributed somatic system in vertebrates. It plays vital roles in fighting infection and in the homeostatic control of chronic disease. As such, the immune system in both pathological and healthy states is a prime target for therapeutic interventions by drugs-both small-molecule and biologic. Comprising both the innate and adaptive immune systems, human immunity is awash with potential unexploited molecular targets. Key examples include the pattern recognition receptors of the innate immune system and the major histocompatibility complex of the adaptive immune system. Moreover, the immune system is also the source of many current and, hopefully, future drugs, of which the prime example is the monoclonal antibody, the most exciting and profitable type of present-day drug moiety. This brief review explores the identity and synergies of the hierarchy of drug targets represented by the human immune system, with particular emphasis on the emerging paradigm of systems pharmacology.

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Identification and characterization of CW108F, a Novel β-carboline compound that promotes cardiomyogenesis of stem cells

Cited by 3 publications

References 30 publications

1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells

1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells

A Novel Carboline Derivative Inhibits Nitric Oxide Formation in Macrophages Independent of Effects on Tumor Necrosis Factorαand Interleukin-1βExpression

The Immune System as Drug Target

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