Epigenetic targeting of different cancers by inhibiting particular histone deacetylase (HDAC) isozymes is a promising treatment approach against cancer. Development of locally-implantable molecular inhibitors of HDAC (henceforth called HDACi) promises high tumour site concentration and reduced systemic degradation of the HDACi. Herein, we report the design of such implantable HDACi based on amphiphilic derivatives of hydrophobic amino acids endowed with a hydroxamic acid (hxa)-based zinc-binding residue. The amino acids present in HDACi influenced the HDAC isozyme that could be inhibited most effectively; the L-phenylalanine derivative 4e inhibited the HDAC6 isozyme most potently (IC₅₀ ∼ 88 nM), while the L-isoleucine derivative 4h was most effective against the isozyme HDAC2 (IC₅₀ ∼ 94 nM). We also noticed that the L-Phe derivative 4e was up to 5× more potent towards inhibiting HDAC6 than its optical antipode 4f derived from D-Phe. This was rationalized in terms of the varying extent of penetration of the enantiomeric inhibitors inside the catalytic tunnel of the enzyme. Since the isozymes HDAC6 and HDAC2 are overexpressed in different cancer cells, 4e and 4h elicited selective anticancer activity in different cancer cell lines. Additive therapeutic action of the combination therapy of 4e and 4h was observed on lung cancer cells that overexpress both these isozymes. Further, 4e formed implantable self-assembled hydrogels that achieved sustained and selective killing of cancer cells in the vicinity of implantation.

中文翻译：

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疏水性氨基酸衍生的可植入HDAC抑制化学疗法用于局部抗癌治疗

通过抑制特定的组蛋白脱乙酰基酶（HDAC）同工酶，表观遗传靶向不同的癌症是一种有前途的抗癌治疗方法。HDAC的局部植入分子抑制剂（以下称为HDACi）的开发有望提高肿瘤部位的浓度，并减少HDACi的全身降解。在这里，我们报告基于疏水性氨基酸的两亲衍生物的这种可植入的HDACi的设计，该衍生物具有基于异羟肟酸（hxa）的锌结合残基。HDACi中存在的氨基酸影响可以最有效抑制的HDAC同工酶。的大号-苯丙氨酸衍生物4E抑制HDAC6同工酶是有效地（IC ₅₀〜88纳米），而大号-异亮氨酸衍生物4H是最有效的对抗同工酶HDAC2（IC ₅₀〜94纳米）。我们还注意到，L- Phe衍生物4e抑制HDAC6的能力比其衍生自D -Phe的光学对映体4f高5倍。根据对映异构体抑制剂在酶催化通道内的渗透程度的不同，这是合理的。由于同功酶HDAC6和HDAC2在不同的癌细胞中过表达，因此4e和4h在不同的癌细胞系中引起选择性的抗癌活性。4e和4e联合治疗的加和治疗作用在过表达这两种同功酶的肺癌细胞上观察到4小时。此外，4e形成了可植入的自组装水凝胶，该凝胶在植入附近实现了对癌细胞的持续和选择性杀伤。