Studies on neplanocin a, new antitumor antibiotic. I. Producing organism, isolation and characterization.

Yaginuma, Satoshi; Muto, Naoki; Tsujino, Masatoshi; Sudate, Yasuhiro; Hayashi, Masahito; Otani, Motoyasu

doi:10.7164/antibiotics.34.359

Cited by 260 publications

(114 citation statements)

References 16 publications

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“…The balance between concentrations of SAM and SAH is referred to as the ''methylation ratio'' (typically maintained at ;10:1), and perturbation of this ratio has been demonstrated to arrest growth of various cell lines (Kramer et al 1990). Because of its central role in metabolism, SAHH has been targeted for drugs against a number of diseases, including hypercholesterolemia (Yamada et al 2007), malaria (Bujnicki et al 2003), and cancer (Yaginuma et al 1981). Additionally, inhibitors of SAHH have also been shown to have antiviral activity against a variety of pox viruses by inhibiting mRNA methylation during the replication cycle (De Clercq et al 1989).…”

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confidence: 99%

“…Although it is down-regulated two-to threefold during starvation conditions in vitro (Betts et al 2002), and is not significantly up-or down-regulated in activated macrophages (Schnappinger et al 2003), it appears to be up-regulated in infected mouse lung tissue (determined using promoter-trap experiments) (Dubnau et al 2005), a condition which also shows up-regulation of other infection-related genes, like isocitrate lyase. SAHH is also considered ''druggable,'' given the large number of nucleoside analogs with activity that have been discovered, such as aristeromycin (ARI) (Wolfe and Borchardt 1991), neplanocin A (Yaginuma et al 1981;Borchardt et al 1984), and other ADO analogs (Guranowski et al 1981). However, these are not considered clinically relevant due to cytotoxicity issues (De Clercq et al 1989).…”

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confidence: 99%

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Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

et al. 2008

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S-adenosylhomocysteine hydrolase (SAHH) is a ubiquitous enzyme that plays a central role in methylation-based processes by maintaining the intracellular balance between S-adenosylhomocysteine (SAH) and S-adenosylmethionine. We report the first prokaryotic crystal structure of SAHH, from Mycobacterium tuberculosis (Mtb), in complex with adenosine (ADO) and nicotinamide adenine dinucleotide. Structures of complexes with three inhibitors are also reported: 39-keto aristeromycin (ARI), 2-fluoroadenosine, and 3-deazaadenosine. The ARI complex is the first reported structure of SAHH complexed with this inhibitor, and confirms the oxidation of the 39 hydroxyl to a planar keto group, consistent with its prediction as a mechanism-based inhibitor. We demonstrate the in vivo enzyme inhibition activity of the three inhibitors and also show that 2-fluoradenosine has bactericidal activity. While most of the residues lining the ADO-binding pocket are identical between Mtb and human SAHH, less is known about the binding mode of the homocysteine (HCY) appendage of the full substrate. We report the 2.0 Å resolution structure of the complex of SAHH cocrystallized with SAH. The most striking change in the structure is that binding of HCY forces a rotation of His363 around the backbone to flip out of contact with the 59 hydroxyl of the ADO and opens access to a nearby channel that leads to the surface. This complex suggests that His363 acts as a switch that opens up to permit binding of substrate, then closes down after release of the cleaved HCY. Differences in the entrance to this access channel between human and Mtb SAHH are identified.

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Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

et al. 2008

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“…Recently, a novel class of carbocyclic analogs of purine nucleosides has been decribed in which the ribose moiety is replaced by a cyclopentene ring (15,16,21,23,24). These compounds were originally isolated from the culture broth of an actinomycete, Ampullarilla regularis A11079, and designated neplanocins.…”

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Antiviral and antimetabolic activities of neplanocins

Clercq¹

1985

Antimicrob Agents Chemother

217

108

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Of a series of carbocyclic analogs of adenosine, in which the ribose moiety was replaced by a cyclopentenyl ring, neplanocin A, or (-)-9-[trans-2, trans-3-dihydroxy-4-(hydroxymethyl)cyclopent-4-enyl]adenine proved particularly effective in inhibiting the multiplication of DNA viruses (i.e., vaccinia), (-)RNA viruses (i.e., parainfluenza, measles, and vesicular stomatitis), and double-stranded RNA viruses (i.e., reo) in vitro in cell culture. Depending on the cells used, the MIC of neplanocin A for these viruses ranged from 0.01 to 4 micrograms/ml, and depending on the parameter used to assess toxicity for the host cell, the specificity index of neplanocin A ranged from 50 to 4,000. As postulated before for other adenosine analogs, neplanocin A may owe its antiviral action to inhibition of S-adenosylhomocysteine hydrolase, hence perturbation of transmethylation reactions. In vivo, neplanocin A afforded only marginal protection against a lethal infection of mice with vesicular stomatitis virus.

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“…(1) 10 and neplanocin A (2), 11 display antibiotic and antitumor activity that sparked the search for other CANs with biological activity (Figure 1). Among the antiviral CANs discovered in the search for agents active against human immunodeficiency virus (HIV), the most promising are carbovir (3), 12 the structurally related abacavir (4) 13 as well as BCA (5).…”

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confidence: 99%

Synthesis and antiviral evaluation of 2-amino-1,6-dihydro-6-oxo-9-[4-bis(hydroxymethyl) -2-cyclopenten-1-yl]-9H-purine: an analog of the anti-HIV compound Carbovir

Sharma

Nair²

2000

Arkivoc

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A novel carbovir analog, (±)-2-amino-1,6-dihydro-6-oxo-9-[4-bis(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purine, was synthesized starting from the γ-lactam, 2-azabicyclo [2.2.1]hept-5-en-3-one (7). The key intermediate, 1-acetamido-4-bis(hydroxymethyl)cyclopent-2-ene (10), was prepared by the Pfitzner-Moffatt oxidation of the hydroxymethyl group of 8, aldol condensation of the resulting aldehyde, followed by a Cannizzaro reaction. The guanine base was constructed on the amino group of 10. The structures of the target molecule and the intermediates were confirmed by NMR, UV and HRMS data. Anti-HIV evaluation results are reported.

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Studies on neplanocin a, new antitumor antibiotic. I. Producing organism, isolation and characterization.

Cited by 260 publications

References 16 publications

Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

Antiviral and antimetabolic activities of neplanocins

Synthesis and antiviral evaluation of 2-amino-1,6-dihydro-6-oxo-9-[4-bis(hydroxymethyl) -2-cyclopenten-1-yl]-9H-purine: an analog of the anti-HIV compound Carbovir

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