Santacruzamate A (CAY10683), a natural carbamate derivative, inhibits HDAC2 and HDAC6 with IC50 values of 0.119 and 434nM, respectively [1]. Santacruzamate A exhibits immunomodulatory and cell proliferation inhibitory activities and modulates the synaptic function in neurons by inhibiting microglial activation[2]. Santacruzamate A has been widely used in the development of a series of related derivatives aimed at inhibiting HDAC isoenzymes[3].
In vitro, Santacruzamate A treatment for 24 hours significantly inhibited the viability of NCM460 cells, with an IC50 value of 315.7nM[4]. Santacruzamate A treatment at 50µM for 6 hours inhibited the invasion and migration of NUCKS1-overexpressing colorectal cancer (CRC) cells, reduced the expression of HDAC2 protein without affecting the expression of NUCKS1 protein[5]. Treatment with 10µM Santacruzamate A for 24 hours significantly inhibited the cell viability of BV2 microglial cells, suppressed the expression of HDAC2 and increased the acetylation level of histone H3, accompanied by a decrease in the expression of IL-1β and TNF-α[6].
In vivo, Santacruzamate, administered via intraperitoneal injection (2mg/kg every other day) for 6 weeks, resulted in an increase in the expression of GLT-1, p-GluN2B and p-GluA1 in the hippocampal tissue of the mouse model of subarachnoid hemorrhage (SAH), alleviating the depressive symptoms of the SAH mice[7]. Intravenous injection of Santacruzamate A (3mg/kg) every three days for 35 days inhibited the distant metastasis of the tumor in the xenograft mouse model of SW620 cells[8].
References:
[1] Pavlik C M, Wong C Y B, Ononye S, et al. Santacruzamate A, a potent and selective histone deacetylase inhibitor from the Panamanian marine cyanobacterium cf. Symploca sp[J]. Journal of natural products, 2013, 76(11): 2026-2033.
[2] Zhou H, Cai Y, Liu D, et al. Pharmacological or transcriptional inhibition of both HDAC 1 and 2 leads to cell cycle blockage and apoptosis via p21Waf1/Cip1 and p19INK4d upregulation in hepatocellular carcinoma[J]. Cell proliferation, 2018, 51(3): e12447.
[3] Randino R, Gazzerro P, Mazitschek R, et al. Synthesis and biological evaluation of Santacruzamate-A based analogues[J]. Bioorganic & Medicinal Chemistry, 2017, 25(24): 6486-6491.
[4] Wang Y, Chen H, Chen Q, et al. The protective mechanism of CAY10683 on intestinal mucosal barrier in acute liver failure through LPS/TLR4/MyD88 pathway[J]. Mediators of Inflammation, 2018, 2018(1): 7859601.
[5]Zhu L, Zhao T, Su H, et al. NUCKS1 promotes invasion and metastasis of colorectal cancer by stabilizing HDAC2 and activating AKT[J]. Oncogenesis, 2025, 14(1): 19.
[6] Jiao F Z, Wang Y, Zhang H Y, et al. Histone deacetylase 2 inhibitor CAY10683 alleviates lipopolysaccharide induced neuroinflammation through attenuating TLR4/NF-κB signaling pathway[J]. Neurochemical research, 2018, 43(6): 1161-1170.
[7] Tao K, Cai Q, Zhang X, et al. Astrocytic histone deacetylase 2 facilitates delayed depression and memory impairment after subarachnoid hemorrhage by negatively regulating glutamate transporter-1[J]. Annals of Translational Medicine, 2020, 8(11): 691.
[8] Zheng Y, Dai M, Dong Y, et al. ZEB2/TWIST1/PRMT5/NuRD multicomplex contributes to the epigenetic regulation of EMT and metastasis in colorectal carcinoma[J]. Cancers, 2022, 14(14): 3426.
Santacruzamate A (CAY10683)是一种天然氨基甲酸酯衍生物，可抑制HDAC2和HDAC6活性，IC50值分别为0.119nM和434nM[1]。Santacruzamate A具有免疫调节和细胞增殖抑制活性，并通过抑制小胶质细胞活化调节神经元突触功能[2]。Santacruzamate A已被广泛作为先导化合物用于开发靶向HDAC同工酶的系列衍生物[3]。
在体外，Santacruzamate A处理24小时可显著抑制NCM460细胞活力，IC50值为315.7nM[4]。50µM的Santacruzamate A处理6小时能抑制NUCKS1过表达结直肠癌（CRC）细胞的侵袭和迁移，降低HDAC2蛋白表达且不影响NUCKS1蛋白水平[5]。10µM的Santacruzamate A处理BV2小胶质细胞24小时可显著抑制细胞活力，下调HDAC2表达并提高组蛋白H3乙酰化水平，同时降低IL-1β和TNF-α表达[6]。
在体内，蛛网膜下腔出血（SAH）小鼠模型隔日腹腔注射Santacruzamate A（2mg/kg；持续6周）可增加海马组织中GLT-1、p-GluN2B和p-GluA1表达，缓解小鼠抑郁症状[7]。SW620细胞异种移植瘤小鼠模型每三天静脉注射3mg/kg剂量的Santacruzamate A（持续35天）能抑制肿瘤远处转移[8]。