(R)-Lisofylline

(R)-Lisofyllineは抗炎症特性を持つ低分子化合物であり、リゾホスファチジン酸アシルトランスフェラーゼ阻害剤（IC₅₀ = 0.6µM）として作用する^[1]。(R)-Lisofyllineは、IL-12シグナル伝達媒介のSTAT4の活性化を阻害し、不飽和ホスファチジン酸種の産生を減らす^[2]。(R)-Lisofyllineは、タイプ1の糖尿病と自己免疫疾患の研究に使われ^[3]、実験性アレルギー性脳脊髄炎を改善してきている^[4]。

体外で、p53変異ヒト卵巣癌細胞（SKOV3、SKOV3 CDDP耐性株、OVCAR3とOVCAR432）を(R)-Lisofylline (20–100µM)とCisplatin (CDDP；10-60µM)の併用で5日間処理した結果、CDDPの細胞毒性作用を著しく増強した^[5]。

体内で、高脂肪食誘発の肥満C57BL/6マウスに(R)-Lisofylline (50mg/kg)を3週間連続で腹腔内注射した結果、肥満関連の代謝障害と心臓炎症を著しく改善した^[6]。(R)-Lisofylline (25mg/kg、毎日二回腹腔内注射)で、複数の低用量のストレプトゾトシン誘発のC57BL/6Jマウスを2週間処理した結果、糖尿病の発生率を著しく減らした^[7]。

References:
[1] Hybertson BM, Bursten SL, Leff JA, et al. Lisofylline prevents leak, but not neutrophil accumulation, in lungs of rats given IL-1 intratracheally. J Appl Physiol (1985). 1997 Jan;82(1):226-32.
[2] Wyska E, Świerczek A, Pociecha K, et al. Physiologically based modeling of lisofylline pharmacokinetics following intravenous administration in mice. Eur J Drug Metab Pharmacokinet. 2016 Aug;41(4):403-12.
[3] Cui P, Macdonald TL, Chen M, et al. Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes. Bioorg Med Chem Lett. 2006 Jul 1;16(13):3401-5.
[4] Bright JJ, Sriram S. Immunotherapy of inflammatory demyelinating diseases of the central nervous system. Immunol Res. 2001;23(2-3):245-52.
[5] Husain A, Rosales N, Schwartz GK, et al. Lisofylline sensitizes p53 mutant human ovarian carcinoma cells to the cytotoxic effects of cis-diamminedichloroplatinum (II). Gynecol Oncol. 1998 Jul;70(1):17-22.
[6] Ali M, Bakr MH, Abdelzaher LA, et al. Lisofylline mitigates cardiac inflammation in a mouse model of obesity through improving insulin secretion and activating cardiac AMPK signaling pathway. Cytokine. 2021 Feb;138:155398.
[7] Yang Z, Chen M, Fialkow LB, et al. The novel anti-inflammatory compound, lisofylline, prevents diabetes in multiple low-dose streptozotocin-treated mice. Pancreas. 2003 May;26(4):e99-104.