Validamine
[CAS# 32780-32-8]

Identification

• Classification: Biochemical >> Amino acids and their derivatives >> Other amino acid derivatives
• Name: Validamine
• Synonyms: 6-Amino-4-(hydroxymethyl)-4-cyclohexane-[4H,5H]-1,2,3-triol; (1R,2S,3S,4S,6R)-4-Amino-6-(hydroxymethyl)cyclohexane-1,2,3-triol
• Molecular Formula: C₇H₁₅NO₄
• Molecular Weight: 177.20
• CAS Registry Number: 32780-32-8
• SMILES: C1[C@@H]([C@H]([C@@H]([C@H]([C@H]1N)O)O)O)CO

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 345.6±42.0 ºC 760 mmHg (Calc.)^*
• Flash point: 162.8±27.9 ºC (Calc.)^*
• Index of refraction: 1.599 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P280-P301+P312-P302+P352-P305+P351+P338

Discovory and Applicatios

Validamine is a naturally occurring aminocyclitol compound that was discovered in the course of investigations into the biosynthesis of validamycin A, an antifungal antibiotic produced by *Streptomyces hygroscopicus* var. *limoneus*. The interest in validamine arose from its role as a structural component and biosynthetic precursor in the formation of validamycin derivatives. The discovery of validamine contributed significantly to the understanding of aminocyclitol biosynthesis, especially in relation to C₇-cyclitol-based antibiotics.

Chemically, validamine is classified as a 1-amino-1-deoxy-1,3,4,6-tetradeoxy-scyllo-inositol. It is structurally related to other aminocyclitols, such as valienamine and 1-deoxynojirimycin. Validamine contains a cyclohexane ring with hydroxyl and amino functional groups arranged in specific stereochemistry, which is crucial for its biological activity and its participation in biosynthetic pathways. In the case of validamycin A, validamine is biosynthesized from a keto-intermediate and subsequently reacts with valienone to form validoxylamine A, which then undergoes further glycosylation to yield the final antibiotic product.

Experimental studies using isotopically labeled intermediates supported the hypothesis that validamine is formed via a specific amination of a keto precursor. Although early biosynthetic feeding studies with radiolabeled validamine did not result in incorporation into validamycin A, it was concluded that this was due to limited uptake by the producing organisms rather than invalidity of the pathway. Subsequent studies confirmed the presence of validamine in the biosynthetic sequence through enzymatic and biochemical analysis. Its identification provided a clear route for the generation of validamycin analogs and offered insights into the enzymatic machinery of *Streptomyces* species.

Beyond its role as a biosynthetic intermediate, validamine has attracted attention due to its biological activity. It is known to inhibit β-glucosidase enzymes in a competitive manner, with inhibition characterized as pH-dependent and concentration-dependent. This property has positioned validamine as a useful tool in the study of carbohydrate metabolism and glycosidase function. The inhibition of β-glucosidase is relevant in various biological contexts, including digestion, lysosomal storage disorders, and modulation of glycoprotein processing.

A notable application of validamine in industrial microbiology involves its role in enhancing the production of acarbose, an α-glucosidase inhibitor used in the treatment of type 2 diabetes. In fermentation studies involving *Actinoplanes utahensis*, the addition of validamine was found to increase the yield of acarbose while simultaneously reducing the formation of impurity C, a structurally related by-product. This effect improved the overall efficiency and cost-effectiveness of acarbose production, making validamine a valuable auxiliary in biotechnological processes.

Validamine's ability to improve product yield and purity in microbial fermentations highlights its importance not only in fundamental biosynthetic pathways but also in applied biotechnology. Moreover, the availability of validamine and its analogs has enabled structure–activity relationship studies for the development of novel glycosidase inhibitors, which continue to be of pharmaceutical interest.

In conclusion, validamine is a key compound in natural product biosynthesis and enzymatic inhibition. Its discovery has elucidated crucial aspects of aminocyclitol biosynthesis and has found applications in both fundamental research and industrial-scale antibiotic and antidiabetic compound production. The integration of validamine in biosynthetic and fermentation processes underscores its multifaceted utility and significance in microbial chemistry and pharmaceutical development.

References

1984. Microbial degradation of validamycin A by Flavobacterium saccharophilum. Enzymatic cleavage of C-N linkage in validoxylamine A. The Journal of Antibiotics, 37(8).
DOI: 10.7164/antibiotics.37.859

1990. Inhibitory effect of validamine, valienamine and valiolamine on activities of carbohydrases in rat small intestinal brush border membranes. Chemical and Pharmaceutical Bulletin, 38(7).
DOI: 10.1248/cpb.38.1970

2013. Enhanced Production of Acarbose and Concurrently Reduced Formation of Impurity C by Addition of Validamine in Fermentation of Actinoplanes utahensis ZJB-08196. BioMed Research International, 2013.
DOI: 10.1155/2013/705418