488-04-0

Basic information

• Product Name: holomycin
• Synonyms: holomycin;N-(4,5-Dihydro-5-oxo-1,2-dithiolo[4,3-b]pyrrol-6-yl)acetamide;N-Demethylthiolutin;N-(5-oxo-4H-dithiolo[4,3-b]pyrrol-6-yl)acetamide
• CAS NO: 488-04-0
• Molecular Formula: C₇H₆N₂O₂S₂
• Molecular Weight: 214.268
• Mol File: 488-04-0.mol

Chemical Properties

• Melting Point: 268 °C (decomp)
• Boiling Point: 532.1°Cat760mmHg
• Flash Point: 275.6°C
• Appearance: /
• Density: 1.63g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.742
• PKA: 9.33±0.40(Predicted)
• CAS DataBase Reference: holomycin(CAS DataBase Reference)
• NIST Chemistry Reference: holomycin(488-04-0)
• EPA Substance Registry System: holomycin(488-04-0)

Safety Data

• Hazardous Substances Data: 488-04-0(Hazardous Substances Data)

Usage

Synthesis Reference(s)

Journal of the American Chemical Society, 86, p. 5654, 1964 DOI: 10.1021/ja01078a049

InChI:InChI=1/C7H6N2O2S2/c1-3(10)8-5-6-4(2-12-13-6)9-7(5)11/h2H,1H3,(H,8,10)(H,9,11)

Upstream product

• 62698-47-9 6-acetylamino-5-oxo-4,5-dihydro-[1,2]dithiolo[4,3-b]pyrrole-3-carboxylic acid methyl ester 
• 62698-44-6 7-(4-methoxy-benzylamino)-2-(4-methoxy-phenyl)-2-methyl-6-oxo-5,6-dihydro-[1,3]dithiino[5,4-b]pyrrole-4-carboxylic acid methyl ester 
• 62698-43-5 7-methanesulfonyloxy-2-(4-methoxy-phenyl)-2-methyl-6-oxo-5,6-dihydro-[1,3]dithiino[5,4-b]pyrrole-4-carboxylic acid methyl ester 
• 62698-45-7 6-(4-methoxy-benzylamino)-5-oxo-4,5-dihydro-[1,2]dithiolo[4,3-b]pyrrole-3-carboxylic acid methyl ester 
• 62698-42-4 2-(4-methoxy-phenyl)-2-methyl-6,7-dioxo-5,6,7,7a-tetrahydro-[1,3]dithiino[5,4-b]pyrrole-4-carboxylic acid methyl ester 
• 90993-81-0 6-amino-4H-[1,2]dithiolo[4,3-b]pyrrol-5-one hydrochloride 
• 75-36-5 acetyl chloride 
• 64-19-7 acetic acid 

Downstream Products

• 488-03-9 6-amino-4H-[1,2]dithiolo[4,3-b]pyrrol-5-one 

Relevant articles and documents

Inhibition of Isoleucyl-tRNA Synthetase by the Hybrid Antibiotic Thiomarinol

Hybrid antibiotics are an emerging antimicrobial strategy to overcome antibiotic resistance. The natural product thiomarinol A is a hybrid of two antibiotics: holothin, a dithiolopyrrolone (DTP), and marinolic acid, a close analogue of the drug mupirocin that is used to treat methicillin-resistant Staphylococcus aureus (MRSA). DTPs disrupt metal homeostasis by chelating metal ions in cells, whereas mupirocin targets the essential enzyme isoleucyl-tRNA synthetase (IleRS). Thiomarinol A is over 100-fold more potent than mupirocin against mupirocin-sensitive MRSA; however, its mode of action has been unknown. We show that thiomarinol A targets IleRS. A knockdown of the IleRS-encoding gene, ileS, exhibited sensitivity to a synthetic analogue of thiomarinol A in a chemical genomics screen. Thiomarinol A inhibits MRSA IleRS with a picomolar Ki and binds to IleRS with low femtomolar affinity, 1600 times more tightly than mupirocin. We find that thiomarinol A remains effective against high-level mupirocin-resistant MRSA and provide evidence to support a dual mode of action for thiomarinol A that may include both IleRS inhibition and metal chelation. We demonstrate that MRSA develops resistance to thiomarinol A to a substantially lesser degree than mupirocin and the potent activity of thiomarinol A requires hybridity between DTP and mupirocin. Our findings identify a mode of action of a natural hybrid antibiotic and demonstrate the potential of hybrid antibiotics to combat antibiotic resistance.

Reducing Holomycin Thiosulfonate to its Disulfide with Thiols

The dithiolopyrrolone (DTP) natural products contain a unique ene-disulfide that is essential for their antimicrobial and anticancer activities. The ene-disulfide in some DTPs is oxidized to a cyclic thiosulfonate, but it is unknown how the DTP thiosulfonates react with biomolecules. We studied the reactivity of the thiosulfonate derivative of the DTP holomycin, oxo-holomycin, and discovered a unique redox reaction: Oxo-holomycin is reduced to its parent disulfide, while oxidizing small molecule and protein thiols to disulfides. Our work reveals that the DTP core is a privileged scaffold that undergoes unusual redox chemistry. The redox chemistry of the DTP natural products may contribute to their mechanism of action.

Thiomarinol, a new hybrid antimicrobial antibiotic produced by a marine bacterium. Fermentation, isolation, structure, and antimicrobial activity

Thiomarinol, an antimicrobial antibiotic, was isolated from the culture broth of a marine bacterium, Alteromonas rava sp. nov. SANK 73390. Its structure was deduced as a hybrid composed of a pseudomonic acid analogue and holothin by NMR spectral analysis and chemical degradation. Antimicrobial activity against Gram-positive and Gram-negative bacteria of thiomarinol was stronger than both of pseudomonic acids and pyrrothine antibiotics.

Expedient total synthesis of pyrrothine natural products and analogs

This paper describes an expedient and straightforward total synthesis of the two pyrrothine natural products holomycin 1a (7 steps, 11% overall) and xenorhabdin I 1c (7 steps, 11% overall) and analogs thereof via a common late-stage intermediate. The path