Cyclothialidine
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| Category | Enzyme inhibitors |
| Catalog number | BBF-01118 |
| CAS | 147214-63-9 |
| Molecular Weight | 641.65 |
| Molecular Formula | C26H35N5O12S |
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Description
It is produced by the strain of Streptomyces filipinensis NR 0484. It and its homologues inhibit escherichia coli DNA helicases with IC50 of 0.3 μmol/L, and the reference neomycin was 1.2 μmol/L.
Specification
| Synonyms | Cyclothialidine A; (2S)-2-[[(5S,8R)-5-[[(2S,3R)-1-(2-amino-3-hydroxypropanoyl)-3-hydroxypyrrolidine-2-carbonyl]amino]-13,15-dihydroxy-16-methyl-2,6-dioxo3-oxa-10-thia-7-azabicyclo[10.4.0]hexadeca-1(16),12,14-triene-8-carbonyl]amino]propanoic acid; N-[[(4R,7S)-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-7-[[(3R)-3-hydroxy-1-L-seryl-L-prolyl]amino]-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecin-4-yl]carbonyl]-L-alanine |
| IUPAC Name | (2S)-2-[[(5R,8S)-8-[[(2S,3R)-1-(2-amino-3-hydroxypropanoyl)-3-hydroxypyrrolidine-2-carbonyl]amino]-14,16-dihydroxy-13-methyl-7,11-dioxo-10-oxa-3-thia-6-azabicyclo[10.4.0]hexadeca-1(16),12,14-triene-5-carbonyl]amino]propanoic acid |
| Canonical SMILES | CC1=C2C(=C(C=C1O)O)CSCC(NC(=O)C(COC2=O)NC(=O)C3C(CCN3C(=O)C(CO)N)O)C(=O)NC(C)C(=O)O |
| InChI | InChI=1S/C26H35N5O12S/c1-10-17(34)5-18(35)12-8-44-9-15(22(37)28-11(2)25(40)41)30-21(36)14(7-43-26(42)19(10)12)29-23(38)20-16(33)3-4-31(20)24(39)13(27)6-32/h5,11,13-16,20,32-35H,3-4,6-9,27H2,1-2H3,(H,28,37)(H,29,38)(H,30,36)(H,40,41)/t11-,13?,14-,15-,16+,20-/m0/s1 |
| InChI Key | HMHQWJDFNVJCHA-ZPGBQQFCSA-N |
Properties
| Appearance | Pale Yellow Powder |
| Solubility | Soluble in Water, Methanol |
Reference Reading
1. A new DNA gyrase inhibitor subclass of the cyclothialidine family based on a bicyclic dilactam-lactone scaffold. Synthesis and antibacterial properties
Peter Angehrn, Erwin Goetschi, Hans Gmuender, Paul Hebeisen, Michael Hennig, Bernd Kuhn, Thomas Luebbers, Peter Reindl, Fabienne Ricklin, Anne Schmitt-Hoffmann J Med Chem. 2011 Apr 14;54(7):2207-24. doi: 10.1021/jm1014023. Epub 2011 Mar 9.
The DNA gyrase inhibitor cyclothialidine had been shown to be a valuable lead structure for the discovery of new antibacterial classes able to overcome bacterial resistance to clinically used drugs. Bicyclic lactone derivatives containing in their 12-14-membered ring a thioamide functionality were reported previously to exhibit potent antibacterial activity against gram-positive bacteria. Moderate in vivo efficacy, however, was demonstrated only for derivatives bearing hydrophilic substituents, which were found to have a favorable impact on pharmcokinetics, and to reduce metabolic degradation, in particular glucuronidation. The incorporation of an additional amide unit into the 14-membered monolactam-lactone scaffold of cyclothialidine analogues provided a new "dilactam" subclass of DNA gyrase inhibitors of inherently higher polarity. After adjusting their lipophilicity by methyl-halogen exchange at the benzene ring, compounds of this series did not require the thioamide functionality to exert a decent antibacterial potency and consequently exhibited improved pharmacokinetic properties resulting in a pronounced in vivo efficacy in a mouse septicaemia infection model.
2. Cyclothialidine analogs, novel DNA gyrase inhibitors
K Yamaji, M Masubuchi, F Kawahara, Y Nakamura, A Nishio, S Matsukuma, M Fujimori, N Nakada, J Watanabe, T Kamiyama J Antibiot (Tokyo). 1997 May;50(5):402-11. doi: 10.7164/antibiotics.50.402.
DNA gyrase inhibitors, cyclothialidines B, C, D and E were isolated from four Streptomycete strains (NR 0659, NR 0660, NR 0661 and NR 0662). Their structures have been elucidated based on the amino acid analysis of the hydrolysates, NMR and HRFAB-MS experiments and shown to be cyclothialidine analogs. The absolute stereochemistry has been determined by the chiral HPLC analysis of the hydrolysates. Cyclothialidines B, D and E are novel and potent inhibitors of DNA gyrase.
3. Combining molecular docking and QSAR studies for modelling the antigyrase activity of cyclothialidine derivatives
Liane Saíz-Urra, Miguel Ángel Cabrera Pérez, Aliuska Morales Helguera, Matheus Froeyen Eur J Med Chem. 2011 Jul;46(7):2736-47. doi: 10.1016/j.ejmech.2011.03.061. Epub 2011 Apr 5.
DNA gyrase is a well-established antibacterial target consisting of two subunits, GyrA and GyrB, in a heterodimer A(2)B(2), where GyrB catalyzes the hydrolysis of ATP. Cyclothialidine (Ro 09-1437) has been considered as a promising inhibitor whose modifications might lead to more potent compounds against the enzyme. We report here for the first time, QSAR studies regarding to ATPase inhibitors of DNA Gyrase. 1D, 2D and 3D descriptors from DRAGON software were used on a set of 42 cyclothialidine derivatives. Based on the core of the cyclothialidine GR122222X, different conformations were created by using OMEGA. FRED was used to dock these conformers in the cavity of the GyrB subunit to select the best conformations, paying special attention to the 12-membered ring. Three QSAR models were developed considering the dimension of the descriptors. The models were robust, predictive and good in statistical significance, over 70% of the experimental variance was explained. Interpretability of the models was possible by extracting the SAR(s) encoded by these predictive models. Analyzing the compound-enzyme interactions of the complexes obtained by docking allowed us to increase the reliability of the information obtained for the QSAR models.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
