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Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands.

Chan M, Hayashi T, Mathewson RD, Nour A, Hayashi Y, Yao S, Tawatao RI, Crain B, Tsigelny IF, Kouznetsova VL, Messer K, Pu M, Corr M, Carson DA, Cottam HB - J. Med. Chem. (2013)

Bottom Line: Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively.Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound.Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex.

View Article: PubMed Central - PubMed

Affiliation: Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0695, USA.

ABSTRACT
A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NFκB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.

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Structure ofhit compound 1.
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fig1: Structure ofhit compound 1.

Mentions: A few structurally diverse libraryscaffolds were identified in these cytokine assays as having reproducibleresponses in mouse and human stimulation assays. Among these scaffolds,the pyrimido[5,4-b]indoles emerged as the most potentand diverse class of compounds in the mouse cell assays with clearevidence of SAR. Within this scaffold cluster, the leading hit fromthe initial primary and secondary screens was a substituted acetamideattached to the pyrimidoindole ring system through a thioether linkage(Figure 1). Thus, compound 1 provideda starting point for structure–activity studies.


Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands.

Chan M, Hayashi T, Mathewson RD, Nour A, Hayashi Y, Yao S, Tawatao RI, Crain B, Tsigelny IF, Kouznetsova VL, Messer K, Pu M, Corr M, Carson DA, Cottam HB - J. Med. Chem. (2013)

Structure ofhit compound 1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3722616&req=5

fig1: Structure ofhit compound 1.
Mentions: A few structurally diverse libraryscaffolds were identified in these cytokine assays as having reproducibleresponses in mouse and human stimulation assays. Among these scaffolds,the pyrimido[5,4-b]indoles emerged as the most potentand diverse class of compounds in the mouse cell assays with clearevidence of SAR. Within this scaffold cluster, the leading hit fromthe initial primary and secondary screens was a substituted acetamideattached to the pyrimidoindole ring system through a thioether linkage(Figure 1). Thus, compound 1 provideda starting point for structure–activity studies.

Bottom Line: Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively.Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound.Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex.

View Article: PubMed Central - PubMed

Affiliation: Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0695, USA.

ABSTRACT
A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NFκB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.

Show MeSH
Related in: MedlinePlus