2-Aminoisocytosine
[CAS# 100643-27-4]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Aminopyrimidine
• Name: 2-Aminoisocytosine
• Synonyms: 2,6-Diamino-4-Pyrimidinol; 2,4-diamino-6(1H)-pyrimidinone; 2,4-Diamino-6-hydroxypyrimidine; 2,4-Diamino-6-hydroxypyrimidine
• Molecular Formula: C₄H₆N₄O
• Molecular Weight: 126.12
• CAS Registry Number: 100643-27-4
• SMILES: C1=C(N=C(NC1=O)N)N

Properties

• Solubility: soluble 100 mM (DMSO), 50 mM (water) (Expl.)
• Melting point: 285-286 ºC (decomp.) (Expl.)
• Density: 1.6±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.77, Calc.^*
• Boiling Point: 524.0±53.0 ºC (760 mmHg), Calc.^*
• Flash Point: 270.7±30.9 ºC, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS09 Warning
• Hazard Statements: H400-H410
• Precautionary Statements: P273-P391-P501

Discovory and Applicatios

2-Aminoisocytosine is a synthetic nucleobase derivative with the molecular formula C₄H₆N₄O. It is structurally characterized as a 2-amino derivative of isocytosine, which itself is an isomer of the naturally occurring base cytosine. The compound contains a six-membered ring with three heteroatoms (two nitrogen and one oxygen), and the presence of an amino group at the 2-position differentiates it from its isomeric counterparts. Its IUPAC name is 2-amino-3H-pyrimidin-4-one.

The compound was first synthesized during investigations into alternative base-pairing systems in the mid-20th century, particularly within the context of developing non-natural nucleic acid analogues. Studies of 2-amino derivatives of pyrimidines, including 2-aminoisocytosine, were undertaken to explore their pairing properties and potential inclusion in artificial genetic systems. These investigations were motivated by early chemical studies on purine and pyrimidine analogues conducted during foundational research in nucleic acid chemistry and base pairing mechanisms.

2-Aminoisocytosine is particularly noted for its ability to participate in non-canonical base pairing. It can form complementary hydrogen bonds with 5-methylisoguanine, creating a base pair that is structurally similar in geometry to the Watson-Crick G-C pair. These findings have made the compound valuable in the study of expanded genetic alphabets, where researchers seek to create synthetic base pairs that can function alongside natural ones in replication and transcription processes.

One of the well-established applications of 2-aminoisocytosine is in the field of synthetic biology. It has been investigated as part of artificially expanded genetic information systems (AEGIS), which are designed to increase the information density of DNA by introducing novel base pairs. Within these systems, 2-aminoisocytosine has been shown to exhibit selective and stable base-pairing behavior under physiological conditions, making it a suitable candidate for incorporation into synthetic nucleic acid polymers.

In nucleic acid chemistry, the presence of 2-aminoisocytosine within oligonucleotides allows for sequence-specific recognition and binding, contributing to the design of functional nucleic acid architectures with programmable properties. These include aptamers, DNAzymes, and molecular sensors. The compound's distinct hydrogen-bonding capabilities have been exploited to engineer nucleic acid structures with increased specificity and novel recognition patterns not achievable with the natural A-T and G-C pairings alone.

Another area of study involving 2-aminoisocytosine is its potential use in therapeutic oligonucleotides. Research has explored whether non-natural bases such as this one can improve the stability, binding affinity, or enzymatic resistance of antisense oligonucleotides or small interfering RNAs (siRNAs). Although not currently in clinical use, the compound remains of interest for such applications due to its altered base-pairing properties.

Beyond its direct applications in molecular biology, 2-aminoisocytosine has been investigated in theoretical and computational studies aimed at understanding the energetics of hydrogen bonding and base pairing in nucleic acids. Quantum chemical calculations have confirmed its potential for forming stable and selective hydrogen bonds with isoguanine derivatives, further validating experimental observations.

Overall, 2-aminoisocytosine represents an important example of how chemical modification of nucleobases can lead to new tools for biotechnology and synthetic genetics. Its discovery contributed to expanding the conceptual understanding of base pairing and nucleic acid structure, and its application continues to support the design of artificial genetic systems and novel nucleic acid-based materials.

References

2024. Review: synthesis and anticancer activity of pyrimido[4,5-b]quinolines in the last twenty years. Chemical Papers, 78(5).
DOI: 10.1007/s11696-024-03316-6

2023. Multicomponent Reactions Using C,N-Binucleophilic Nature of Aminopyrazoles: Construction of Pyrazole-Fused Heterocycles. Topics in current chemistry (Cham), 381(4).
DOI: 10.1007/s41061-023-00427-8

2023. Developments of pyridodipyrimidine heterocycles and their biological activities. Molecular Diversity, 27(1).
DOI: 10.1007/s11030-023-10623-9