Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Health Sciences Center, Kuwait University, Safat 13110, Kuwait.
Cancer Cell Int. 2013 Aug 19;13(1):82. doi: 10.1186/1475-2867-13-82.
It has been shown that proteasome inhibition leads to growth arrest in the G1 phase of the cell cycle and/or induction of apoptosis. However, it was found that some of these inhibitors do not induce apoptosis in several human normal cell lines. This selective activity makes proteasome inhibition a promising target for new generation of anticancer drugs. Clinical validation of the proteasome, as a therapeutic target in oncology, has been provided by the dipeptide boronic acid derivative; bortezomib. Bortezomib has proven to be effective as a single agent in multiple myeloma and some forms of non-Hodgkin's lymphoma. Syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid, 1), a known phenolic acid, was isolated from the methanol extract of Tamarix aucheriana and was shown to possess proteasome inhibitory activity.
Using Surflex-Dock program interfaced with SYBYL, the docking affinities of syringic acid and its proposed derivatives to 20S proteasome were studied. Several derivatives were virtually proposed, however, five derivatives: benzyl 4-hydroxy-3,5-dimethoxybenzoate (2), benzyl 4-(benzyloxy)-3,5-dimethoxybenzoate (3), 3'-methoxybenzyl 3,5-dimethoxy-4-(3'-methoxybenzyloxy)benzoate (4), 3'-methoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (5) and 3',5'-dimethoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (6), were selected based on high docking scores, synthesized, and tested for their anti-mitogenic activity against human colorectal, breast and malignant melanoma cells as well as normal human fibroblast cells.
Derivatives 2, 5, and 6 showed selective dose-dependent anti-mitogenic effect against human malignant melanoma cell lines HTB66 and HTB68 with minimal cytotoxicity on colorectal and breast cancer cells as well as normal human fibroblast cells. Derivatives 2, 5 and 6 significantly (p ≤ 0.0001) inhibited the various proteasomal chymotrypsin, PGPH, and trypsin like activities. They growth arrested the growth of HTB66 cells at G1 and G2-phases. They also arrested the growth of HTB68 cells at S- and G2-phase, respectively. Moreover, derivatives 2, 5, and 6 markedly induced apoptosis (≥ 90%) in both HTB66 and HTB68.
Computer-derived syringic acid derivatives possess selective anti-mitogenic activity on human malignant melanoma cells that may be attributed to perturbation of cell cycle, induction of apoptosis and inhibition of various 26S proteasomal activities.
已证实蛋白酶体抑制会导致细胞周期 G1 期的生长停滞和/或诱导细胞凋亡。然而，人们发现，这些抑制剂中的一些不会诱导几种人正常细胞系发生细胞凋亡。这种选择性活性使蛋白酶体抑制成为新一代抗癌药物的有希望的靶标。在肿瘤学中，二肽硼酸衍生物硼替佐米对蛋白酶体作为治疗靶点的临床验证已经提供。硼替佐米已被证明作为单一药物在多发性骨髓瘤和一些非霍奇金淋巴瘤中有效。丁香酸（4-羟基-3,5-二甲氧基苯甲酸，1），一种已知的酚酸，从柽柳甲醇提取物中分离出来，并显示出具有蛋白酶体抑制活性。
使用 Surflex-Dock 程序与 SYBYL 接口，研究了丁香酸及其拟议衍生物对 20S 蛋白酶体的对接亲和力。虚拟提出了几种衍生物，但基于高对接分数，选择了五种衍生物：苄基 4-羟基-3,5-二甲氧基苯甲酸酯（2）、苄基 4-（苄氧基）-3,5-二甲氧基苯甲酸酯（3）、3'-甲氧基苄基 3,5-二甲氧基-4-（3'-甲氧基苄氧基）苯甲酸酯（4）、3'-甲氧基苄基 4-羟基-3,5-二甲氧基苯甲酸酯（5）和 3',5'-二甲氧基苄基 4-羟基-3,5-二甲氧基苯甲酸酯（6），合成并测试了它们对人结直肠、乳腺和恶性黑素瘤细胞以及正常成纤维细胞的抗有丝分裂活性。
衍生物 2、5 和 6 对人恶性黑素瘤细胞系 HTB66 和 HTB68 表现出选择性的剂量依赖性抗有丝分裂作用，对结直肠和乳腺癌细胞以及正常成纤维细胞的细胞毒性最小。衍生物 2、5 和 6 显著（p≤0.0001）抑制了各种蛋白酶体糜蛋白酶、PGPH 和胰蛋白酶样活性。它们使 HTB66 细胞的生长在 G1 和 G2 期停滞。它们还分别使 HTB68 细胞的生长在 S 和 G2 期停滞。此外，衍生物 2、5 和 6 明显（≥90%）诱导 HTB66 和 HTB68 细胞凋亡。
计算机衍生的丁香酸衍生物对人恶性黑素瘤细胞具有选择性的抗有丝分裂活性，这可能归因于细胞周期的改变、细胞凋亡的诱导和各种 26S 蛋白酶体活性的抑制。
