Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2

Abstract

Development of new immunosuppressing agents is necessary in organ transplantation or immune diseases. Because Ppc-1 exhibits a suppressing effect on interleukin-2 (IL2) production in Jurkat cells, we synthesized and screened Ppc-1 derivatives that preserve prenylated quinolinecarboxylic acid (PQA) structure, and identified compound 18 (PQA-18) as a novel molecule with immunosuppressing effect. PQA-18 suppressed not only IL2 but also IL4, IL6, and tumor necrosis factor-α production in human peripheral lymphocytes without affecting cell viability. Two-dimensional gel electrophoresis analysis and in vitro kinase assay revealed that PQA-18 inhibits kinase activity of p21-activated kinase 2 (PAK2). Administration of PQA-18 by intraperitoneal injection suppressed the population of a subset of regulatory T cells and the immunoglobulin (Ig) production against T cell-dependent antigens in mice. Treatment with the PQA-18 ointment on Nc/Nga mice, a model of human atopic dermatitis, improved skin lesions and serum IgE levels. These results suggest that PQA-18 is a unique PAK2 inhibitor with potent immunosuppressing effects in vitro and in vivo. PQA-18 may be a valuable lead for the development of novel immunosuppressants.

Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4

“…Molecular basis of LRRK2 inhibition by PQA-11 remains to be solved. On the other hand, we have previously reported that another PQA compound, PQA-18, suppresses PAK2 activity [24]. PAK is a kinase regulated by p21…”

“…The PQA compounds used in this study were synthesized and purified as previously described [23,24], and the structure and purity were confirmed by 1 H and 13 C NMR spectroscopy and high-resolution mass spectroscopy. The purities of all compounds were greater than 98%.…”

Natural Products from Social Amoebae

“…Prenylation of the latter with prenyl bromide under basic conditions gave Ppc‐1 ( 28 ). Ppc‐1 was shown to be a mitochrondrial uncoupler and derivatives of Ppc‐1 were shown to suppress production of interleukin‐2, an immunoregulatory protein, in Jurkat cells …”

“…The naturalproducts Pt-1-5 (23)(24)(25)(26)(27)were obtained from methanolic extractso ff ruiting bodies of P. tenuissimum;P pc-1 (28) was obtained analogously from fruiting bodies of P. pseudocandidum (Scheme 4). [22] To confirm the structure determined by NMR studies, Pt-4 (26)w as synthesized from 5-methoxyresorcinol (29)( Scheme 4b); installation of the acyl side chain was achieved by Friedel-Crafts acylation with butanoyl chloride.…”

“…Ppc-1 was shown to be am itochrondrial uncoupler [24] and derivatives of Ppc-1 weres hown to suppress production of interleukin-2, an immunoregulatory protein, in Jurkat cells. [25] Dictyobiphenyls and dictyoterphenyls Dictyobiphenyls A( 36)a nd B ( 37), and dictyoterphenyls A( 42) and B( 43), were isolated from fruiting bodies of D. polycephalum (Scheme 5). [11] Many o-terphenyl-type compounds are known in the kingdom of fungi, [26] however,v ery few m-terphenylderivatives occur naturally, furthermore, dictyoterphenyl A( 42)w as the first example of an itrogen-containing m-terphenylnatural product.…”