Total synthesis of enantiomeric sparsomycin

Ottenheijm, H. C. J.; Liskamp, Rob M. J.; Tijhuis, M. W.

doi:10.1016/s0040-4039(01)85978-5

Cited by 10 publications

(10 citation statements)

References 11 publications

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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%

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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Section: Synthesismentioning

confidence: 99%

Sparsomycin – a Review and Re-assessment

Cordell¹,

Daley²

2022

HETEROCYCLES

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“…The absolute configuration of the sulfoxide diastereoisomers was determined by CD spectra using documented method. [22][23][24][25][26] The synthesis of cyclic peptide 16 was described in Fig 3. The linear peptide precursors H-(Boc)Lys-pTyr(OBzl)-Ach-Asn-Val-2-Cl-Trt resin were synthesized by Fmoc SPPS. After the peptides were cleaved from resin, the head-to-tail macrocyclization of the linear peptide was achieved successfully using HATU as the coupling reagent and HOAt as the accelerator 27 and then deprotected with the TFA-TIS-H 2 O cocktail.…”

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confidence: 99%

Discovery of thioether-bridged cyclic pentapeptides binding to Grb2-SH2 domain with high affinity

Jiang

Liao²,

Bindu

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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Blocking the interaction between phosphotyrosine (pTyr)-containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor-bound protein 2 (Grb 2) is considered to be an effective and non-cytotoxic strategy to develop new anti-proliferate agents due to its potential to shut down the Ras activation pathway. In this study, a series of phosphotyrosine containing cyclic pentapeptides were designed and synthesized based upon the phage library derived cyclopeptide, G1TE. A comprehensive SAR study was also carried out to develop potent Grb2-SH2 domain antagonists based upon this novel template. With both the peptidomimetic optimization of the amino acid side-chains and the constraint of the backbone conformation guided by molecular modeling, we developed several potent antagonists with low micromolar range binding affinity, such as cyclic peptide 15 with an K(d)=0.359microM, which is providing a novel template for the development of Grb2-SH2 domain antagonists as potential therapeutics for certain cancers.

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“…[7][8][9][10] These potentially important biological activities have made 3 an attractive target for a potential antineoplastic compound. 11) Since thê rst synthetic study of sparsomycin in 1976, 12) synthetic studies of sparsomycin, [13][14][15] total synthesis, [16][17][18] biosynthesis, 19,20) and structure-activity relationship studies [21][22][23][24][25][26][27] have been widely reported. There have been many reports on the antitumor, antibacterial, antifungal, and antiviral properties; however, normalization of the phenotype of oncogene-transformed cells by 3 and its analogues has not previously been reported.…”

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confidence: 99%