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Y. Hiraiwa et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6369–6372
Scheme 3. Reagents and conditions: (a) cyclohexanone dimethyl ketal, p-toluenesulfonic acid monohydrate, DMF, 45–48 mmHg, 50 °C; (b) Ac2O,
pyridine, rt; (c) 90% TFA, MeOH, CH2Cl2, rt; (d) TrCl, DMAP, pyridine, 80 °C; (e) Tf2O, pyridine, CH2Cl2, 0 °C; (f) CsOAc, DMF, rt; (g) MsCl,
DMAP, CH2Cl2, rt; (h) CsOAc, DMF, 100 °C; (i) NaOMe, MeOH, rt; (j) 90% TFA, rt.
the 60-N-substituted derivatives showed potent antibac-
terial activity against P. aeruginosa expressing aminogly-
coside-modifying enzyme AAC(60).5 Therefore, to
investigate the antibacterial activity and the stability
against aminoglycoside-modifying enzymes of the 5,400-
diepi ABK 9a, we planned the synthesis of 60-N-methyl
derivatives of 9a. Synthesis of the 5,400-diepi-60-N-methyl
ABK 15 is shown in Scheme 3.
should provide a basis for the development of novel
aminoglycosides directed against clinically relevant
strains of bacteria that are recalcitrant to antibiotic
treatment.
Acknowledgments
We thank Prof. Naomasa Gotoh from Kyoto Pharma-
ceutical University for kindly providing us with Pseudo-
monas aeruginosa PAO1 DmexXY-oprM strain. We
thank also Dr. Makoto Oyama and Ms. Shigeko Miki
(Meiji Seika Kaisha Ltd) for NMR spectroscopic and
mass spectrometric analyses, respectively. We thank
Ms. Erumi Murase for technical assistance.
Treatment of the compound 105 with cyclohexanone
dimethyl acetal and then acetylation of the 200-OH and
200 0-OH groups afforded compound 11. Then, in a similar
procedure to that given in Schemes 1 and 2, compound
14 was obtained from 11 in six steps. Removal of Ac
groups, Tr groups and Boc groups of 14 afforded
5,400-diepi-60-N-methyl ABK 15 in two steps. The anti-
bacterial activity of 5,400-diepi-60-N-methyl ABK 15 is
shown in Table 2. As expected, the 5,400-diepi-60-N-
methyl ABK 15 displayed potent antibacterial activity
against P. aeruginosa GN315 expressing aminoglyco-
side-modifying enzyme AAC(60)-Ib. Our findings indi-
cate that 60-N-methylation of an aminoglycoside results
in increased stability against the aminoglycoside-modify-
ing enzyme AAC(60). Furthermore, we tested the
antibacterial activity of the 5,400-diepi ABK 9a against
54 clinical isolates of MRSA and 54 clinical isolates of
P. aeruginosa. Using the MRSA strains, the MIC50 and
MIC90 of 9a (MIC50, 0.25 lg/mL, MIC90, 0.25 lg/mL)
were more potent than those of ABK (MIC50,
0.5 lg/mL, MIC90, 2.0 lg/mL). Against the P. aeruginosa
strains, antibacterial activity of 9a (MIC50, 1.0 lg/mL,
MIC90, 4.0 lg/mL) was superior to that of ABK
(MIC50, 2.0 lg/mL, MIC90, 16 lg/mL).
References and notes
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according to NCCLS.
In summary, we designed and synthesized 400-deoxy-400-
episubstituted ABK derivatives, hybrid compounds of
5-deoxy-5-episubstituted-400-epi ABK derivatives and
60-N-methyl derivative of 5,400-diepi ABK. Among them,
the 5,400-diepi ABK showed potent antibacterial activity
against both MRSA and P. aeruginosa. This study
7. Masuda, N.; Sakagawa, E.; Ohya, S.; Gotoh, N.; Tsujim-
oto, H.; Nishino, T. Antimicrob. Agents Chemother. 2000,
44, 2242.