IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
ChemMedChem. 2010 Jan;5(1):140-7. doi: 10.1002/cmdc.200900367.
The NAD(+)-dependent deacetylases, namely sirtuins, are involved in the regulation of a variety of biological processes such as gene silencing, DNA repair, longevity, metabolism, apoptosis, and development. An enzyme from the parasite Leishmania infantum that belongs to this family, LiSIR2RP1, is a NAD(+)-dependent tubulin deacetylase and an ADP-ribosyltransferase. This enzyme's involvement in L. infantum virulence and survival underscores its potential as a drug target. Our search for selective inhibitors of LiSIR2RP1 has led, for the first time, to the identification of the antiparasitic and anticancer bisnaphthalimidopropyl (BNIP) alkyl di- and triamines (IC(50) values in the single-digit micromolar range for the most potent compounds). Structure-activity studies were conducted with 12 BNIP derivatives that differ in the length of the central alkyl chain, which links the two naphthalimidopropyl moieties. The most active and selective compound is the BNIP diaminononane (BNIPDanon), with IC(50) values of 5.7 and 97.4 microM against the parasite and human forms (SIRT1) of the enzyme, respectively. Furthermore, this compound is an NAD(+)-competitive inhibitor that interacts differently with the parasite and human enzymes, as determined by docking analysis, which might explain its selectivity toward the parasitic enzyme.
NAD(+)依赖性脱乙酰酶，即沉默调节蛋白，参与调节多种生物学过程，如基因沉默、DNA 修复、长寿、代谢、细胞凋亡和发育。属于该家族的寄生虫利什曼原虫中的一种酶，LiSIR2RP1，是一种 NAD(+)依赖性微管脱乙酰酶和 ADP-核糖基转移酶。这种酶参与利什曼原虫的毒力和存活，突出了它作为药物靶点的潜力。我们首次寻找 LiSIR2RP1 的选择性抑制剂，导致发现了具有抗寄生虫和抗癌活性的双萘酰亚胺丙基（BNIP）二烷基和三烷基胺（最有效的化合物的 IC(50)值在个位数微摩尔范围内）。用 12 种 BNIP 衍生物进行了结构活性研究，这些衍生物在连接两个萘酰亚胺丙基部分的中央烷基链的长度上有所不同。最活跃和选择性的化合物是 BNIP 二氨基壬烷（BNIPDanon），对寄生虫和人类形式（SIRT1）的酶的 IC(50)值分别为 5.7 和 97.4 microM。此外，该化合物是一种 NAD(+)竞争性抑制剂，与寄生虫和人类酶的相互作用方式不同，这是通过对接分析确定的，这可能解释了它对寄生酶的选择性。
