Synthesis and biological activity of enantiomeric pairs of 5-[(E)-cycloalk-2-enylidenemethyl]thiolactomycin congeners

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 20, 2008, Pages 5598-5600

  Ohata, Kohei ^a   Terashima, Shiro ^b  

^a KYORIN PHARMACEUTICAL CO LTD   (Japan)

^b SAGAMI CHEMICAL RESEARCH CENTER   (Japan)

Author keywords

5 (E) Cycloalk 2 enylidenemethyl thiolactomycin; Antibiotic; Inhibitor of mammalian type I fatty acid synthase

Indexed keywords

3 NORTHIOLACTOMYCIN; 5 (CYCLOALK 2 ENYLIDENEMETHYL)THIOLACTOMYCIN DERIVATIVE; CYCLOHEPT 2 ENYLIDENEMETHYLTHIOLACTOMYCIN; CYCLOOCT 2 ENYLIDENEMETHYLTHIOLACTOMYCIN; FATTY ACID SYNTHASE; THIOLACTOMYCIN; THIOLACTOMYCIN DERIVATIVE; UNCLASSIFIED DRUG;

ANTIBACTERIAL ACTIVITY; ARTICLE; DRUG ACTIVITY; DRUG POTENCY; DRUG SYNTHESIS; ENANTIOMER; IN VITRO STUDY; NOCARDIA; NONHUMAN;

ANIMALS; ANTI-BACTERIAL AGENTS; ANTI-INFECTIVE AGENTS; CELL LINE; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; FATTY ACID SYNTHETASE COMPLEX; HUMANS; INHIBITORY CONCENTRATION 50; MICROBIAL SENSITIVITY TESTS; MODELS, CHEMICAL; MOLECULAR CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

MAMMALIA;

EID: 53349103022     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.08.103     Document Type: Article

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14. In addition to 4a-c, 5a-c and their enantiomers (ent-4a-c and ent-5a-c), 5-[(E)-cyclopent-2-enylidenemethyl]-TLM congeners (4d, ent-4d, 5d and ent-5d) were designed and their synthesis was attempted following the same synthetic scheme shown in Scheme 1. Although the synthetic scheme smoothly proceeded to the stage of 10 (n = 0), aldehyde 11 (n = 0) derived from 10 (n = 0) was found to be very unstable, probably due to facile isomerization to the cyclopentadiene derivative and subsequent intramolecular Diels-Alder reaction (Ohata, K.; Terashima, S., to be published).{A figure is presented}
15. 1H NMR spectra with that of 7a.
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18. 1H NMR spectra and/or HPLC analysis are as follows: 9:(S)-isomer:(Z)-isomer; 12:1:1 for 9a; 14:1:4 for 9b; 12:1:1 for 9c.
19. 2:solvent; hexane/AcOEt = 4/1 for 9a; hexane/AcOEt = 5/1 for 9b; hexane/AcOEt = 5/1 for 9c) and HPLC. The HPLC conditions were as follows: 9a [Daicel Chiralpak IA, φ 2.0 cm × 25 cm, hexane/EtOH = 90/10, followed by Daicel Chiralpak IA, φ 2.0 cm × 25 cm, hexane/iPrOH = 97/3]; 9b [Daicel Chiralpak IA, φ 2.0 cm × 25 cm, hexane/EtOH = 91/9]; 9c [Daicel Chiralpak IA, φ 2.0 cm × 25 cm, hexane/MTBE/iPrOH = 80:10:10, followed by Daicel Chiralpak IC, φ 2.0 cm × 25 cm, hexane/iPrOH = 75/25].
20. 3): 5.44 ppm [(Me)(SR)C-CH{double bond, long}C] for 9a; 5.50 ppm [(Me)(SR)C-CH{double bond, long}C] for the (S)-diastereomer of 9a; 5.72 ppm [(Me)(SR)C-CH{double bond, long}C] for the synthetic intermediate of 1; 5.77 ppm [(Me)(SR)C-CH{double bond, long}C] for the (S)-diastereomer of the synthetic intermediate of 1.
21. 1H NMR spectra with those of the corresponding isomers of 9a,b.
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24. Determination of MICs by agar dilution methods was performed according to the guidelines M7-A6 of the Clinical and Laboratory Standards Institute, 2003.
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