Synthesis and Activity of Pyrimidinylpropenamide Antibiotics: The Alkyl Analogues of Sparsomycin

Nakajima, Noriyuki; Enomoto, Takeshi; Watanabe, Takeshi; Matsuura, Nobuo; Ubukata, Makoto

doi:10.1271/bbb.67.2556

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…Replication-enhancing effects were also seen by using the chemically-synthesized derivatives of sparsomycin (unpublished data;Nakajima et al, 2003). The replicationboosting effect levelled-out at 500 nM, an approximately 20-fold lower concentration than the 50% toxic dose (TD 50 ) of sparsomycin (Ash et al, 1984).…”

Section: The Structure Of Sparsomycin a Metabolite From Streptomycesmentioning

confidence: 99%

Rapid Propagation of Low-Fitness Drug-Resistant Mutants of Human Immunodeficiency Virus Type 1 by a Streptococcal Metabolite Sparsomycin

Miyauchi

Komano

Myint

et al. 2006

Antivir Chem Chemother

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Here we report that sparsomycin, a streptococcal metabolite, enhances the replication of HIV-1 in multiple human T cell lines at a concentration of 400 nM. In addition to wild-type HIV-1, sparsomycin also accelerated the replication of lowfitness, drug-resistant mutants carrying either D30N or L90M within HIV-1 protease, which are frequently found mutations in HIV-1-infected patients on highly active antiretroviral therapy (HAART). Of particular interest was that replication enhancement appeared profound when HIV-1 such as the L90M-carrying mutant displayed relatively slower replication kinetics. The presence of sparsomycin did not immediately select the fast-replicating HIV-1 mutants in culture. In addition, sparsomycin did not alter the 50% inhibitory concentration (IC 50 ) of antiretroviral drugs directed against HIV-1 including nucleoside reverse transcriptase inhibitors (lamivudine and stavudine), non-nucleoside reverse transcriptase inhibitor (nevirapine) and protease inhibitors (nelfinavir, amprenavir and indinavir). The IC 50 s of both zidovudine and lopinavir against multidrug resistant HIV-1 in the presence of sparsomycin were similar to those in the absence of sparsomycin. The frameshift reporter assay and Western blot analysis revealed that the replication-boosting effect was partly due to the sparsomycin's ability to increase the -1 frameshift efficiency required to produce the Gag-Pol transcript. In conclusion, the use of sparsomycin should be able to facilitate the drug resistance profiling of the clinical isolates and the study on the lowfitness viruses.

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Section: The Structure Of Sparsomycin a Metabolite From Streptomycesmentioning

confidence: 99%

Rapid Propagation of Low-Fitness Drug-Resistant Mutants of Human Immunodeficiency Virus Type 1 by a Streptococcal Metabolite Sparsomycin

Miyauchi

Komano

Myint

et al. 2006

Antivir Chem Chemother

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“…Continuing interest in the biological effects of the alkaloid attracted further synthetic approaches to 1 and eventually its diastereoisomers. 11,[37][38][39][40][41] These efforts were extended to the development of synthetic routes for analogs for additional biological assessment. [41][42][43][44][45][46][47] Two groups published their syntheses of the unnatural RC diastereomer of 1 almost simultaneously, 37,38 in which a convergent approach assembled an acid and an amine to form the amide bond of 1.…”

Section: Synthesismentioning

confidence: 99%

“…11,[37][38][39][40][41] These efforts were extended to the development of synthetic routes for analogs for additional biological assessment. [41][42][43][44][45][46][47] Two groups published their syntheses of the unnatural RC diastereomer of 1 almost simultaneously, 37,38 in which a convergent approach assembled an acid and an amine to form the amide bond of 1. Commencing with 6-methyluracil (12), the requisite acrylic acid 13 37 was formed in four steps through hydroxymethylation at C-5, oxidation to the aldehyde, followed by a Wittig condensation with Ph3P=CHCO2C2H5, and base hydrolysis.…”

Section: Synthesismentioning

confidence: 99%

“…40 When the four S2-alkyl derivatives (with R= -C2H5, -C4H9, -allyl, and -benzyl) were evaluated in the same assay, the ethyl and allyl analogs were only half as active as 1, whereas the other compounds were significantly less active. 41 A summary of the structure-activity relationships for the anticancer activity of 1 (NSC-59729) is shown in Figure 7. Chain extension at S2 increased the hydrophilicity at the carbon chiral center and the pyrimidine ring.…”

Section: Biology and Sar Of Sparsomycinmentioning

confidence: 99%

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Sparsomycin – a Review and Re-assessment

Cordell¹,

Daley²

2022

HETEROCYCLES

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The chemistry, biology, and biosynthesis of the microbial alkaloid sparsomycin (1) are summarized and re-assessed to identify future research initiatives for this biologically significant metabolite. INTRODUCTIONOne of the underexplored facets of natural product chemistry and biology is the further exploration of "old" bioactive metabolites to fill-in important gaps in basic knowledge, or to explore new or underappreciated applications given the contemporary opportunities in biological assessment and mechanistic understanding.The microbial alkaloid sparsomycin is one such example based on its anticancer, antimicrobial, insecticidal, and tRNA:mRNA translocation activities. Sparsomycin was first reported in 1962 by researchers at the Upjohn Co., Kalamazoo, MI, as a cytotoxic and antitumor alkaloid from the soil microorganism Streptomyces sparsogenes var. sparsogenes, 1,2 where it co-occurred with tubercidin. 2 Several years later, the molecular formula was corrected to C13H19N3O5S2 and the planar structure 1 determined through spectral interpretation and chemical degradation. 3,4 Additional isolations of 1 are rare. For example, a soil sample acquired in Kyoto, Japan, Streptomyces cuspidosporus was isolated and culturing yielded sparsomycin (1) and the antitubercular alkaloid tubercidin. 5 A water sample from the Nile River afforded 1 from Streptomyces violaceusniger AZ-NIOFD, 6 and a derivative of sparsomycin with a unit of H2O added was reported from a soil sample of Pseudomonas aeruginosa AZ-SH-B8 collected in the Sharqia Governorate in northern Egypt, 7 although the characterizations of these isolates were incomplete.Sparsomycin (1) has two stereocenters, the chiral carbon derived from an amino acid moiety and the S1sulfoxide unit. The earlier structural studies 2 had established the chiral carbon stereochemistry as

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“…The oxidation of homochiral β-amino sulfides has been employed the most extensively, presumably since the protocol gives the most rapid access to sulfoxide by way of a readily accessible amino sulfide ( D ). ,,− ,,− ,− Surprisingly, despite the presence of the stereogenic carbon, the diastereoselection of oxidation protocols has only rarely exceeded dr values of 90%. ,, In most cases, ratios range from 1:1 to 3:2, ,,,,,,− , and on many occasions, diastereoselectivities are not even reported or acknowledged. ,,,,− In the few instances when an asymmetric oxidizing agent was employed to complement the stereogenic carbon in the substrate, selected de values reach 95% but only for particular substrates and conditions. ,− …”

Section: Introductionmentioning

confidence: 99%

Sulfenate Substitution as a Complement and Alternative to Sulfoxidation in the Diastereoselective Preparation of Chiral β-Substituted β-Amino Sulfoxides

Söderman

Schwan

2013

J. Org. Chem.

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Building from a previous communication, the reaction of sulfenate anions with chiral N-Boc-protected β-substituted β-amino iodides was evaluated as a conceptually different synthetic approach to chiral β-substituted β-amino sulfoxides. Using arenesulfenates, yields typically ranged from 71% to 92%, and dr's were often near 9:1. Alkanesulfenates proved less reactive, delivering lower yields and dr's. 1-Alkenesulfenates demonstrated high reactivity, returning chemical yields of 60-86% and dr's often close to 9:1 and as high as 95:5. (S)-β-Amino iodide electrophiles yielded (R(S),S(C))-β-amino sulfoxides, whereas (R)-amino iodides afford (S(S),R(C))-β-amino sulfoxides. The absolute configuration of the products makes the sulfenate protocol complementary to other existing preparations, including the commonly employed sulfoxidation of β-amino sulfides. The reactivity of N-Boc-protected 2-benzyl-2-aminoethyl iodide was found to be superior to the less sterically encumbered n-butyl iodide. A transition state model is proposed to account for the stereochemistry of the products and also for the high reactivity of the electrophile. Overall, the chemistry represents a new means of introducing sulfur stereogenicity in a molecule.

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Synthesis and Activity of Pyrimidinylpropenamide Antibiotics: The Alkyl Analogues of Sparsomycin

Cited by 7 publications

References 35 publications

Rapid Propagation of Low-Fitness Drug-Resistant Mutants of Human Immunodeficiency Virus Type 1 by a Streptococcal Metabolite Sparsomycin

Rapid Propagation of Low-Fitness Drug-Resistant Mutants of Human Immunodeficiency Virus Type 1 by a Streptococcal Metabolite Sparsomycin

Sparsomycin – a Review and Re-assessment

Sulfenate Substitution as a Complement and Alternative to Sulfoxidation in the Diastereoselective Preparation of Chiral β-Substituted β-Amino Sulfoxides

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