Endogenous Metabolite
Uracil is a natural pyrimidine nucleobase found in RNA. In itself, it is not a drug with a specific protein target like an enzyme or receptor. Its derivatives and analogs are designed to target various biological processes. This review discusses many uracil derivatives with different targets, but specific target information (e.g., IC50, Ki) for the parent compound uracil is not provided. The derivatives mentioned target enzymes such as thymidine phosphorylase (TP), glycogen phosphorylase (GP), Plasmodium falciparum dUTPase (PfdUTPase), HIV-1 reverse transcriptase, and others. [1]

本文综述了近年来尿嘧啶衍生物的研究进展。本文还旨在讨论开发用于各种生物靶标的更强效、更特异的尿嘧啶类似物的潜在未来方向。尿嘧啶被认为是药物发现中的特权结构，具有广泛的生物活性和合成可及性。抗病毒和抗肿瘤是尿嘧啶类似物最广泛报道的两种活性，但它们也具有除草、杀虫和杀菌活性。它们的抗病毒潜力是基于对病毒复制途径中关键步骤的抑制，从而产生对HIV、乙型肝炎和丙型肝炎、疱疹病毒等的有效活性。尿嘧啶衍生物，如5-氟尿嘧啶或5-氯尿嘧啶是第一个产生的药理学活性衍生物。选择性差限制了其治疗应用，导致胃肠道或中枢神经毒性的高发生率。为了解决这些问题，已经对尿嘧啶结构进行了大量的修饰，从而开发出具有更好的药理学和药代动力学特性的衍生物，包括增加的生物活性、选择性、代谢稳定性、吸收和低毒性。作为生物活性剂的新型尿嘧啶和稠合尿嘧啶衍生物的研究涉及嘧啶环N（1）、N（3）、C（5）和C（6）位取代基的修饰。特别介绍了这类类似物的合成方法和生物学研究，如：5-氟尿嘧啶或5-氯尿嘧啶衍生物、替加富尔类似物、尿嘧啶的阿拉伯吡喃单核糖苷、尿嘧啶吡喃葡糖双核糖苷、脂质多霉素、caprazamycin或膜霉素、三丁基尿苷类似物、脲嘧啶的硝基或氰基衍生物、尿嘧啶喹唑啉酮、尿嘧啶吲哚或尿嘧啶-靛蓝偶联物、桥接多亚甲基链中含有一个或两个尿嘧啶单元和氮原子的嘧啶类化合物等。本文还讨论了具有与其他杂环环化的尿嘧啶环的融合尿嘧啶的合成和生物学活性[1]。

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本文是一篇综述文章，总结了众多尿嘧啶衍生物的生物学活性。综述重点在于其修饰类似物的活性。例如，5-氟尿嘧啶（5-FU）抑制RNA复制酶。许多合成的尿嘧啶衍生物在细胞实验中显示出抗癌、抗病毒、抗菌和抗寄生虫活性。[1]
提及了一项关于人胸腺嘧啶DNA糖基化酶（hTDG）从DNA中切除尿嘧啶及其卤代衍生物（5-氟尿嘧啶/FU、5-氯尿嘧啶/CIU、5-溴尿嘧啶/BrU）的研究。从GX底物中切除这些碱基的活性（kmax）显著依赖于5'侧翼碱基对。例如，与CpGCIU相比，从TpGCIU、GpGCIU和ApGCIU序列中切除CIU的kmax分别降低了6倍、11倍和82倍。从任何5'侧翼序列的G FU、GCIU和GBrU中切除的活性达到或超过了从CpG T序列中切除的活性。[1]

文中提及了一些衍生物的体内数据，例如尿嘧啶衍生物（6-氨基-1-甲基-5-亚硝基尿嘧啶，MANU）的金(I)配合物在实验性神经胶质瘤动物模型中，治疗七天后将肿瘤生长抑制至约十分之一。[1]

描述了用于评估尿嘧啶衍生物的改良胸苷磷酸化酶（TP）生物测定法。该测定使用在大肠杆菌中表达的重组大肠杆菌TP作为酶，胸苷作为底物。使用该测定评估合成化合物的抑制活性。例如，一个5-氯尿嘧啶连接的吡唑并[1,5-a][1,3,5]三嗪衍生物（化合物262，R = 4-F5S-苯基）的IC50为0.04 µM，在相同条件下比先导化合物7-脱氮黄嘌呤（7DX，IC50 = 32 µM）强约800倍。该化合物被发现是非竞争性抑制剂。[1]
提及了用于评估恶性疟原虫和硕大利什曼原虫dUTP酶以及人酶抑制剂的测定法。化合物针对重组酶进行测试以衡量选择性。例如，一个三苯甲基化的脱氧尿苷类似物（5'-三苯甲氨基-2',5'-二脱氧尿苷 124，X=OH）对恶性疟原虫dUTP酶的Ki为0.2 µM，与人酶相比选择性超过200倍。[1]
提及了评估尿嘧啶衍生物作为糖原磷酸化酶（GP）抑制剂的动力学实验。鉴定出的最佳抑制剂是1-(β-D-吡喃葡萄糖基)-5-乙炔基尿嘧啶（99），其Ki为4.7 µM。[1]

提及了磺酰罗丹明B（SRB）法用于评估细胞毒性活性。化合物针对人癌细胞系进行测试，如宫颈癌（HeLa）、口腔癌（KB）和乳腺癌（MCF-7）。例如，一个3'-叠氮-2',3'-双脱氧-5-氟尿苷的磷酰胺衍生物（25，R = CH2CH3）在所有测试的癌细胞中显示出最高的活性，远高于母体核苷。[1]
提及了MTT法用于对人癌细胞系（如HeLa、MCF-7、DU145）进行细胞毒性评估。例如，尿嘧啶-靛红结合物（107）经过评估，其中一些对DU145细胞的IC50值低至13.90 µM。[1]
描述了抗病毒活性测定。化合物针对病毒进行测试，如1型单纯疱疹病毒（HSV-1）、水痘-带状疱疹病毒（VZV）、人巨细胞病毒（HCMV）、登革热病毒（DENV）和黄热病毒（YFV），使用适当的细胞系（例如，CCL-81用于HSV，AD-169用于HCMV，MDCK用于流感）。例如，5-(噻吩-2-基)-2'-脱氧尿苷（40）对HSV-1表现出显著的活性，一些卤代类似物（41）与溴夫定（BVDU）效力相当。一个氟环丙基尿嘧啶核苷（55）显示出中度的抗HCMV活性（在AD-169株中为10.61 µg/mL）。[1]
对一些不饱和尿嘧啶核苷测量了在正常人肠细胞系（H4）和肿瘤细胞系（Caco-2、黑色素瘤、MCF-7）上的细胞毒性（CC50）。发现化合物65在MCF-7乳腺癌细胞系中有效。[1]
对于尿嘧啶衍生的嘧啶环芳烃，研究了其对革兰氏阴性菌（铜绿假单胞菌、大肠杆菌）、革兰氏阳性菌（金黄色葡萄球菌、枯草芽孢杆菌、粪肠球菌）、病原真菌（黑曲霉、须毛癣菌、烟曲霉）和酵母（白色念珠菌）的抗菌和抗真菌活性。活性随聚亚甲基链长度的增加而增加，并在引入正癸基取代基时显著增强。[1]

The review describes an in vivo study for a gold(I) complex of a uracil derivative (6-amino-1-methyl-5-nitrosouracil, MANU) in an animal model of experimental glioma. The result mentioned was that after seven days of treatment, the gold compound decreased tumor growth to about one-tenth compared to vehicle-treated animals. [1]

The review points out that 5-fluorouracil (5-FU, a uracil derivative) has poor selectivity, short half-life, and wide distribution, which limits its therapeutic application. However, the review does not provide specific ADME/PK parameters (absorption, distribution, metabolism, excretion, half-life, bioavailability) of the parent compound uracil. [1]
For some triphenylmethylated uracil analogs developed as dUTPase inhibitors of Plasmodium falciparum, preliminary ADME studies have shown that some lead compounds have drug activity. However, the review also does not provide specific parameters. [1]

The review points out that 5-fluorouracil (5-FU) has side effects such as gastrointestinal or central nervous system toxicity due to its poor selectivity. [1]
For a series of uracil-benzodioxane hybrids (cyclic and acyclic 5-FU O,N-acetal 150, 151), the IC50 values of all compounds against MCF-7 cells were in the micromolar range. One of the compounds (151, R1=NO2, R2=H) was the most cytotoxic. Another compound (151, R1=R2=H) induced apoptosis and G0/G1 cell cycle arrest in MCF-7 cells. [1]
In the study of 5-[1-(2-haloethyl (or nitro)ethoxy-2-iodoethyl)]-2'-deoxyuridine (46), all compounds showed low host cell toxicity. [1]
Serum parameter analysis of the MANU gold(I) complex indicated fewer adverse reactions after treatment. [1]
Structure-activity relationship analysis of 5,6-substituted 1-[(2-hydroxyethoxy)methyl]uracil showed that cytotoxicity depended on lipophilicity and steric hindrance parameters. [1]

[1]. In search of uracil derivatives as bioactive agents. Uracils and fused uracils: Synthesis, biological activity and applications. Eur J Med Chem. 2015 Jun 5;97:582-611.

Uracil is a common naturally occurring pyrimidine nucleobase, with its pyrimidine ring substituted at positions 2 and 4 by two oxo groups. It is present in RNA, pairs with adenine, and substitutes for thymine during DNA transcription. Uracil has multiple functions, including as a prodrug, a human metabolite, a Daphnia magna metabolite, a Saccharomyces cerevisiae metabolite, an Escherichia coli metabolite, a mouse metabolite, and an allergen. It is both a pyrimidine nucleobase and a pyrimidinone. It is a tautomer of (4S)-4-hydroxy-3,4-dihydropyrimidin-2(1H)-one. Uracil is a metabolite found or produced in Escherichia coli (K12 strain, MG1655 strain). Uracil has been reported in Hamigela avilania, Micrococcus microcarpa, and other organisms with relevant data.
Uracil is a metabolite found or produced in Saccharomyces cerevisiae.
It is one of the four nucleotide bases in RNA.
See also: Pyrimidine (subclass).

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Background: Uracil is a common natural pyrimidine derivative and one of the four nucleotide bases in RNA that binds to adenine. In DNA, it is replaced by thymine. It can be considered a demethylated form of thymine. Uracil undergoes amide-imine (lactam-lactam) tautomerism, with the lactam form being predominant at pH 7. Uracil is a weak acid. [1]
Preferred structure: Uracil is considered a preferred structure in drug discovery due to its broad bioactivity, ease of synthesis, and the ability to impart drug-like properties upon modification at N1, N3, C5, and C6 sites. [1]
Derivative activity: Uracil analogs are most commonly reported to have antiviral and antitumor activities, but also herbicidal, insecticidal, and bactericidal activities. [1]
Mechanism analysis (e.g., 5-fluorouracil): 5-fluorouracil (5-FU) is an anti-metabolic pyrimidine analog. Due to its similar structure to uracil but different chemical properties, it can inhibit RNA replicase, thereby blocking RNA synthesis and inhibiting cancer cell growth. [1]
Metabolic transformation: This review describes the specific chemical transformation of uracil derivatives (β-hydroxy-N-methylvaline/βHOMeVal in basidiomycin A) under alkaline conditions, involving reverse aldol condensation or dehydration reactions, but this is not the general metabolic pathway of uracil itself. [1]

C4H4N2O2

112.0868

112.027

C, 42.86; H, 3.60; N, 24.99; O, 28.55

66-22-8

66-22-8 (uracil); 3083-77-0 [1-beta-D-Arabinofuranosyluracil (Uracil 1-β-D-arabinofuranoside)]; 462-88-4 (Ureidopropionic acid); 504-07-4 (5,6-Dihydrouracil); 66-75-1 (Uramustine, Uracil mustard); 141-90-2 (2-Thiouracil); 58-96-8 (Uridin; β-Uridine)

1174

Typically exists as white to light yellow solids at room temperature

1.5±0.1 g/cm3

440.5±37.0 °C at 760 mmHg

330°C

220.2±26.5 °C

0.0±1.1 mmHg at 25°C

1.640

-2.55

65.72

2

2

0

8

161

0

O=C1N([H])C([H])=C([H])C(N1[H])=O

ISAKRJDGNUQOIC-UHFFFAOYSA-N

InChI=1S/C4H4N2O2/c7-3-1-2-5-4(8)6-3/h1-2H,(H2,5,6,7,8)

Pyrimidine-2,4(1H,3H)-dione

2,4-Dioxopyrimidine; 2,4-Pyrimidinedione; Pirod; uracil; 66-22-8; 2,4-Dihydroxypyrimidine; 2,4(1H,3H)-Pyrimidinedione; pyrimidine-2,4(1H,3H)-dione; pyrimidine-2,4-diol; Pyrod; 2,4-Pyrimidinediol; Pyrod.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 25 mg/mL (~223.04 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (22.30 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (22.30 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (22.30 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。