Compound 82

functional group manipulation. The presence of the powerful electron-withdrawing fluorine atoms next to the hydroxyl group at the 3'-position prevents phosphorylation of this hydroxyl group by aminoglycoside phosphotransferases, which are the cause of clinical resistance to aminoglycoside antibiotics. This compound can be used as a potential inhibitor for aminoglycoside phosphotransferases [APH(3')s] [56].

In a study to explore the mechanism of phosphorylation of aminoglycoside antibiotics by phosphotransferases and to develop potent inhibitors for these en-

nh ho oh kA

n^n i inh2

nh ho oh oh

Compounds 83-86

zymes, the conjoint molecules (compounds 83-86 ) were prepared. These compounds incorporate the structure of neamine to that of adenosine via carbon tethers. These molecules would take advantage of the availability of two distinct binding subunits for ATP and aminoglycosides in the active site of the enzymes. Hence, the conjoint molecules would bind the enzymes more effectively than the individual components for entropic reasons [57].

In another synthesis, neamine was linked by a spacer to a known isoquinoline sulfonamide protein kinase inhibitor to make the conjunct molecule (compound 87). A molecule such as 87 should bind the active site of these enzymes with great affinity [58].

2. Paromamine

Yoshikawa et al. [59] described the preparation of paromamine 92 from d-glucos-amine. They used Pb(OAc)4 for decarboxylation and sodium borohydride for de-acetoxylation in the key steps of the synthesis. The d-glucosamine-derived alcohol 88 was oxidized by the Jones reagent to furnish the corresponding 5-carboxyl analogs, which were decarboxylated with Pb(OAc)4 to give compound 89 as a mixture of a and /3 isomers. Treatment of 89 with CH3NO2 in the presence of 1% NaOMe-MeOH afforded the scy//o-nitrocyclitol glycoside 90. After protection of the hydroxyl groups and acetylation at position 2, this compound was reductively deacetoxylated with NaBH4 in EtOH to furnish 91, which was converted to paromamine 92 by subsequent deprotection, Raney nickel reduction, and catalytic hydrogenation (compounds 88-92).

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