6-Aminonicotinamide is a potent nicotinamide antimetabolite and a competitive inhibitor of the NADP⁺-dependent enzyme glucose-6-phosphate dehydrogenase (G6PD) (Ki=0.46μM)[1-2]. 6-Aminonicotinamide interferes with glycolysis, leading to ATP depletion, and is widely used in cancer research, such as in prostate cancer and breast cancer studies[3-4].
In vitro, treatment of HepAD38, HepG2-NTCP, and primary human hepatocytes (PHHs) with 6-Aminonicotinamide (12.5–25μM) for 24 hours, 6-Aminonicotinamide significantly inhibits the replication and transcription of hepatitis B virus (HBV), reduces HBsAg secretion, HBV RNA levels, and core DNA levels, and slightly decreases cccDNA[5]. Pretreatment of MYCN-amplified neuroblastoma cells (SJ-N-JF) with 6-Aminonicotinamide (0.8–100μM) for 18 hours, followed by 5-aminolevulinic acid (5-ALA; 250–500μM)-mediated photodynamic therapy (PDT; 633nm, 17.5mW/cm²) for 10–15 minutes, 6-Aminonicotinamide synergistically enhances the cytotoxicity of PDT, induces necrotic cell death, inhibits glucose-6-phosphate dehydrogenase (G6PD) activity, reduces the NADPH/NADP⁺ and GSH/GSSG ratios, and disrupts glutathione redox balance[6].
In vivo, a single intraperitoneal injection of 6-Aminonicotinamide (5–20mg/kg) in pregnant mice (gestational days 7–14), 6-Aminonicotinamide induces developmental abnormalities in the fetuses, including skeletal malformations, cleft palate, micrognathia, and spina bifida[7]. Intraperitoneal injection of 6-Aminonicotinamide (50mg/kg) in newborn mice (postnatal day 1), 6-Aminonicotinamide leads to rapidly progressive hydrocephalus by day 9 after injection, accompanied by aqueductal occlusion due to vacuolization of ependymal cells and periaqueductal gliosis, resulting in ventricular dilation and neurological dysfunction[8].
References:
[1] Ntsala LP, Lemmerer A. 6-Amino-nicotinamide. Acta Crystallogr Sect E Struct Rep Online. 2012 Aug 1;68(Pt 8):o2449.
[2] Johnson WJ, McColl JD. 6-Aminonicotinamide--a Potent Nicotinamide Antagonist. Science. 1955 Oct 28;122(3174):834.
[3] Cheikh IA, Hayar B, Ghanem N, et al. Therapeutic Targeting of the Pentose Phosphate Pathway in Colorectal Cancer Using 6-Aminonicotinamide and 5-Fluorouracil. Mol Carcinog. 2025 Jul;64(7):1222-1235.
[4] Varshney R, Dwarakanath B, Jain V. Radiosensitization by 6-aminonicotinamide and 2-deoxy-D-glucose in human cancer cells. Int J Radiat Biol. 2005 May;81(5):397-408.
[5] Ren F, Yang X, Hu ZW, et al. Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production. EBioMedicine. 2019 Nov;49:232-246.
[6] Okamura SM, Chelakkot VS, Linn Z, et al. 6-Aminonicotinamide enhances the efficacy of 5-aminolevulinic acid-mediated photodynamic therapy for neuroblastoma. BMC Cancer. 2025 Nov 25;25(1):1815.
[7] Curley FJ, Ingalls TH, Zappasodi P. 6-aminonicotinamide-induced skeletal malformations in mice. Arch Environ Health. 1968 Mar;16(3):309-15.
[8] Aikawa H, Suzuki K, Ito N, et al. 6-Aminonicotinamide-induced hydrocephalus in suckling mice. J Neuropathol Exp Neurol. 1984 Sep;43(5):511-21.
6-Aminonicotinamide是一种有效的烟酰胺抗代谢物，是竞争性 NADP+ 依赖性酶葡萄糖-6-磷酸脱氢酶 (G6PD) 的抑制剂(Ki=0.46μM)[1-2]。6-Aminonicotinamide干扰糖酵解，导致ATP耗竭，多被用于癌症（如前列腺癌、乳腺癌）的相关研究[3-4]。
在体外，6-Aminonicotinamide（12.5–25μM）处理HepAD38、HepG2-NTCP和原代人肝细胞（PHHs）24小时后，6-Aminonicotinamide能显著抑制乙型肝炎病毒（HBV）的复制和转录，降低HBsAg分泌、HBV RNA水平和核心DNA水平，并轻微减少cccDNA[5]。6-Aminonicotinamide（0.8–100μM）预处理MYCN扩增的神经母细胞瘤细胞（SJ-N-JF）18小时，随后进行5-氨基乙酰丙酸（5-ALA；250–500μM）介导的光动力疗法（PDT；633nm，17.5mW/cm²）10-15分钟，6-Aminonicotinamide可协同增强PDT的细胞毒性，诱导坏死性细胞死亡，抑制葡萄糖-6-磷酸脱氢酶（G6PD）活性，降低NADPH/NADP+和GSH/GSSG比值，破坏谷胱甘肽氧化还原平衡[6]。
在体内，在孕鼠（妊娠第7–14天）单次腹腔注射6-Aminonicotinamide（5-20mg/kg）处理后，6-Aminonicotinamide可诱导胎鼠出现骨骼畸形、腭裂、小颌畸形及脊柱裂等发育异常 [7]。新生小鼠（出生第1天）腹腔注射6-Aminonicotinamide（50mg/kg），6-Aminonicotinamide在注射后第9天引发快速进展的脑积水，伴随中脑导水管因室管膜细胞空泡化及周围胶质水肿而闭塞，导致脑室扩张、神经功能障碍[8]。