The Chemical, Spectral, and Biological Properties of Monomethine Cyanine Dyes Containing 1,3-Benzoxazine and Quinazoline Nuclei

Carney, Richard W. J.; Wojtkunski, Janice; Kónopka, E. A.; deStevens, George

doi:10.1021/jm00323a027

Cited by 3 publications

(1 citation statement)

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“…Deployment of this idea will require optimization of its potency and pharmacokinetic properties, as well as overcoming the challenge of blood-brain barrier (BBB) permeability and the renal toxicity that have hindered development of MKT-077 (27, 54, 55). Another difficulty is that rhodacyanines represent a significant obstacle for medicinal chemistry efforts, given their functional group density and light sensitivity (56–59). In addition, due to the promiscuous nature of Hsp70 family members, there are concerns about the potential toxicity of an approach that targets these proteins.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Heat Shock Protein 70 Inhibitors Rapidly Rescue Synaptic Plasticity Deficits by Reducing Aberrant Tau

Abisambra¹,

Jinwal²,

Miyata³

et al. 2013

Biological Psychiatry

119

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Background The microtubule associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer’s disease (AD). One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau’s toxic accretion. Methods Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the Hsp70 family in the brain, Hsc70. The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured. Results Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, over-expression of Hsp40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wildtype mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in from tau transgenic brain slices. Conclusions Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in AD and other tauopathies.

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Section: Discussionmentioning

confidence: 99%

Allosteric Heat Shock Protein 70 Inhibitors Rapidly Rescue Synaptic Plasticity Deficits by Reducing Aberrant Tau

Abisambra¹,

Jinwal²,

Miyata³

et al. 2013

Biological Psychiatry

119

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Cyanine Dyes

Ficken

1971

The Chemistry of Synthetic Dyes

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Efficacy and Mechanism of Action of Low Dose Emetine against Human Cytomegalovirus

Mukhopadhyay¹,

Roy²,

Venkatadri³

et al. 2016

PLoS Pathog

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Infection with human cytomegalovirus (HCMV) is a threat for pregnant women and immunocompromised hosts. Although limited drugs are available, development of new agents against HCMV is desired. Through screening of the LOPAC library, we identified emetine as HCMV inhibitor. Additional studies confirmed its anti-HCMV activities in human foreskin fibroblasts: EC50−40±1.72 nM, CC50−8±0.56 μM, and selectivity index of 200. HCMV inhibition occurred after virus entry, but before DNA replication, and resulted in decreased expression of viral proteins. Synergistic virus inhibition was achieved when emetine was combined with ganciclovir. In a mouse CMV (MCMV) model, emetine was well-tolerated, displayed long half-life, preferential distribution to tissues over plasma, and effectively suppressed MCMV. Since the in vitro anti-HCMV activity of emetine decreased significantly in low-density cells, a mechanism involving cell cycle regulation was suspected. HCMV inhibition by emetine depended on ribosomal processing S14 (RPS14) binding to MDM2, leading to disruption of HCMV-induced MDM2-p53 and MDM2-IE2 interactions. Irrespective of cell density, emetine induced RPS14 translocation into the nucleus during infection. In infected high-density cells, MDM2 was available for interaction with RPS14, resulting in disruption of MDM2-p53 interaction. However, in low-density cells the pre-existing interaction of MDM2-p53 could not be disrupted, and RPS14 could not interact with MDM2. In high-density cells the interaction of MDM2-RPS14 resulted in ubiquitination and degradation of RPS14, which was not observed in low-density cells. In infected-only or in non-infected emetine-treated cells, RPS14 failed to translocate into the nucleus, hence could not interact with MDM2, and was not ubiquitinated. HCMV replicated similarly in RPS14 knockdown or control cells, but emetine did not inhibit virus replication in the former cell line. The interaction of MDM2-p53 was maintained in infected RPS14 knockdown cells despite emetine treatment, confirming a unique mechanism by which emetine exploits RPS14 to disrupt MDM2-p53 interaction. Summarized, emetine may represent a promising candidate for HCMV therapy alone or in combination with ganciclovir through a novel host-dependent mechanism.

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The Chemical, Spectral, and Biological Properties of Monomethine Cyanine Dyes Containing 1,3-Benzoxazine and Quinazoline Nuclei

Cited by 3 publications

References 0 publications

Allosteric Heat Shock Protein 70 Inhibitors Rapidly Rescue Synaptic Plasticity Deficits by Reducing Aberrant Tau

Allosteric Heat Shock Protein 70 Inhibitors Rapidly Rescue Synaptic Plasticity Deficits by Reducing Aberrant Tau

Cyanine Dyes

Efficacy and Mechanism of Action of Low Dose Emetine against Human Cytomegalovirus

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