Abstract
The natural nucleoside antibiotic, bredinin, exhibits antiviral and other biological activities. While various nucleosides related to bredinin have been synthesized, its carbocyclic analog has remained unknown. Synthesis of this heretofore unknown analog of bredinin is described. The key precursor, (3aS,4R,6R,6aR)-6-((methoxy-methoxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (5), was prepared from the commercially available compound, (1R,4S)-2-azabicyclo[2.2.1] hept-5-en-3-one (4). Our initial approach used intermediate 6, derived in three transformations from 5, for the key photolytic step to produce the desired ring-opened precursor to the target compound. This photochemical transformation was unsuccessful. However, an appropriately protected and related precursor was synthesized from 5 through the following side-chain functional group transformations: elaboration of the amino group through malonyl ester formation, oximation at the central carbon, conversion of ester to amide and catalytic reduction of the oxime group. This precursor, on treatment with triethylorthoformate and catalytic acetic acid in ethanol, underwent cyclization to produce the desired 4-carbamoyl-imidazolium-5-olate ring. Deprotection of the latter product proceeded smoothly to give the carbocyclic analog of bredinin. This target molecule exhibits antiviral activity, albeit low, against a number of RNA viruses. Further biological evaluations are in progress.
Highlights
Bredinin (1; zwitterion form 2, Figure 1) is an imidazole nucleoside antibiotic, which was originally isolated from the culture filtrates of Eupenicillium brefeldianum [1]
EC50 values in the submicromolar range were observed with some of these viruses. This natural compound exhibits a synergistic effect against the bovine viral diarrhea virus (BVDV) in combination with IFN-α
We provide a methodology for the synthesis of 1-((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-5-hydroxy-1Himidazole-4-carboxamide (3), the heretofore unknown carbocyclic analog of bredinin
Summary
Bredinin (1; zwitterion form 2, Figure 1) is an imidazole nucleoside antibiotic, which was originally isolated from the culture filtrates of Eupenicillium brefeldianum [1]. This compound shows activity against the vaccinia virus [1] and the human cytomegalovirus, HCMV [7] It has been approved in Japan for use in the prevention of organ allograft rejection, and in the treatment of rheumatoid arthritis, primary nephrosis, lupus nephritis, dermatomyositis and autoimmune dermatoses [8]. The mechanism of its antiviral activity appears to be associated with inhibition of IMPDH by bredinin monophosphate [12,13] (Scheme 1). Consistent with this suggestion is the observation that the activities of bredinin against viruses can be reversed by guanosine and guanosine monophosphate [2]. Transition state in the conversion of IMP to XMP catalyzed by IMPDH [12]
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