基质金属蛋白酶-2(MMP-2)的过表达与白血病特别是慢性粒细胞白血病(CML)具有相关性。然而,迄今为止,市场上还没有这种MMP-2抑制剂用于治疗白血病。在这项研究中,合成,生物学评价,并对一组联苯磺酰胺衍生物作为有前途的MMP-2抑制剂进行了分子建模研究,关注它们作为抗白血病疗法的潜在应用。化合物DH-18和DH-19发挥最有效的MMP-2抑制作用(IC50为139.45nM和115.16nM,分别)对CML细胞系K562具有有效的抗白血病功效(IC50为0.338µM和0.398µM,分别)。前导分子DH-18和DH-19使MMP-2的表达分别降低了21.3%和17.8%,分别具有有效的凋亡诱导(45.4%和39.8%,分别)在K562细胞系中。此外,这两种化合物都显著阻止了细胞周期的不同阶段。再一次,这两种分子在ACHN细胞系中都显示了有希望的抗血管生成功效.然而,分子对接和分子动力学(MD)模拟研究表明,DH-18通过异羟肟酸锌结合基团(ZBG)与催化Zn2离子形成强二齿螯合。除此之外,MD模拟研究还揭示了DH-18和MMP-2的稳定结合相互作用,以及与活性位点氨基酸残基His120,Glu121,His124,His130,Pro140和Tyr142的关键相互作用.简而言之,这项研究强调了以联苯磺酰胺为基础的新型且有前景的MMP-2抑制剂对于为潜在的CML治疗开辟新途径的重要性.
Overexpression of matrix metalloproteinase-2 (MMP-2) possesses a correlation with leukemia especially chronic myeloid leukemia (CML). However, no such MMP-2 inhibitor has come out in the market to date for treating leukemia. In this study, synthesis, biological evaluation, and molecular modeling studies of a set of biphenylsulfonamide derivatives as promising MMP-2 inhibitors were performed, focusing on their potential applications as antileukemic therapeutics. Compounds DH-18 and DH-19 exerted the most effective MMP-2 inhibition (IC50 of 139.45 nM and 115.16 nM, respectively) with potent antileukemic efficacy against the CML cell line K562 (IC50 of 0.338 µM and 0.398 µM, respectively). The lead molecules DH-18 and DH-19 reduced the MMP-2 expression by 21.3% and 17.8%, respectively with effective apoptotic induction (45.4% and 39.8%, respectively) in the K562 cell line. Moreover, both these compounds significantly arrested different phases of the cell cycle. Again, both these molecules depicted promising antiangiogenic efficacy in the ACHN cell line. Nevertheless, the molecular docking and molecular dynamics (MD) simulation studies revealed that DH-18 formed strong bidentate chelation with the catalytic Zn2+ ion through the hydroxamate zinc binding group (ZBG). Apart from that, the MD simulation study also disclosed stable binding interactions of DH-18 and MMP-2 along with crucial interactions with active site amino acid residues namely His120, Glu121, His124, His130, Pro140, and Tyr142. In a nutshell, this study highlighted the importance of biphenylsulfonamide-based novel and promising MMP-2 inhibitors to open up a new avenue for potential therapy against CML.