Amphiphilic pyridinium salts block TNF alpha/NF kappa B signaling and constitutive hypersecretion of interleukin-8 (IL-8) from cystic fibrosis lung epithelial cells.
Cystic fibrosis (CF) is a common, lethal genetic disease, which is due to mutations in the CFTR gene. The CF lung expresses a profoundly proinflammatory phenotype, due to constitutive hypersecretion of IL-8 from epithelial cells lining the airways. In a systematic search for candidate drugs that might be used therapeutically to suppress IL-8 secretion from these cells, we have identified a potent and efficacious series of amphiphilic pyridinium salts. The most potent of these salts is MRS2481, an (R)-1-phenylpropionic acid ester, with an IC50 of ca. 1microM. We have synthesized 21 analogues of MRS2481, which have proven sufficient to develop a preliminary structure-activity relationship (SAR). For optimal activity, we have found that the ester must be connected to the pyridinium derivative by an eight-carbon chain. An optical isomer of the lead compound, containing an (S)-1-phenylpropionic acid ester, has been found to be a much less active. The mechanism of action of MRS2481 appears to involve inhibition of signaling of the NF(kappa)B and AP-1 transcription factors to the IL-8 promoter. MRS2481 is a potent inhibitor of TNFalpha-induced phosphorylation and proteosomal destruction of I(kappa)B(alpha). Inasmuch as I(kappa)B(alpha) is the principal inhibitor of the NF(kappa)B signaling pathway, preservation of intact I(kappa)B(alpha) would serve to keep the IL-8 promoter silent. We also find that MRS2481 blocks TNF(alpha)-activated phosphorylation of JNK, the c-JUN kinase. The IL-8 promoter is also activated by an AP-1 site, which requires a phospho-c-JUN/c-FOS dimer for activity. We therefore interpret these data to suggest that the mechanism of MRS2481 action is to inhibit both NF(kappa)B and AP-1 signaling on the IL-8 promoter. Given the medicinally promising properties of water-solubility, potency in the low muM concentration range, and high efficacy, we anticipate that MRS2481, or a further optimized derivative, may find an important place in the armamentarium of pharmaceutical strategies yet to be arrayed against the inflammatory phenotype of the CF lung.
Tchilibon
Susanna
S
Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
Zhang
Jian
J
Yang
Qingfeng
Q
Eidelman
Ofer
O
Kim
Haksung
H
Caohuy
Hung
H
Jacobson
Kenneth A
KA
Pollard
Bette S
BS
Pollard
Harvey B
HB
D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D012492:Salts / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D016209:Interleukin-8; D016328:NF-kappa B; D011726:Pyridinium Compounds; D012492:Salts; D013501:Surface-Active Agents; D014409:Tumor Necrosis Factor-alpha