Allylic Amines as Key Building Blocks in the Synthesis of (<i>E</i>)-Alkene Peptide Isosteres

Skoda, Erin M.; Davis, Gary C.; Wipf, Peter

doi:10.1021/op2002613

Cited by 105 publications

(76 citation statements)

References 74 publications

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“…The drugs GS-nitroxides (JP4-039 and XJB-5-131) [1, 3], bifunctional sulfoxide (MMS-350) [11], PI3K inhibitor (LY294002) [14], and the triphenylphosphonium mitochondrial targeted imidazole fatty acid (TPP-IOA) [16] have been described. JP4-039, XJB-5-131, MMS-350 [11], BEB55 and MCF-201-89 [3] were synthesized according to published protocols and used after passing Quality Control by Liquid Chromatography/Mass Spectroscopy Standards (purity >92%) [16].…”

Section: Methodsmentioning

confidence: 99%

“…JP4-039, XJB-5-131, MMS-350 [11], BEB55 and MCF-201-89 [3] were synthesized according to published protocols and used after passing Quality Control by Liquid Chromatography/Mass Spectroscopy Standards (purity >92%) [16]. TPP-OFA [13] was synthesized by Dr. Jeffrey Atkinson (Brock University, St Catharines, Ontario, Canada), LY294002 (Enzo Life Sciences, Farmingdale NY), methoxamine, isoproterenol,propranolol and glyburide (Sigma, St. Louis, MO) were purchased.…”

Section: Methodsmentioning

confidence: 99%

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Evaluation of potential ionizing irradiation protectors and mitigators using clonogenic survival of human umbilical cord blood hematopoietic progenitor cells

Goff

Shields

Wang

et al. 2013

Experimental Hematology

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We evaluated the use of colony formation (CFU-GM, BFU-E, and CFU-GEMM) by human umbilical cord blood (CB) hematopoietic progenitor cells for testing novel small molecule ionizing irradiation protectors and mitigators. Each of 11 compounds was added before (protection) or after (mitigation) ionizing irradiation including: GS-nitroxides (JP4-039 and XJB-5-131), the bifunctional sulfoxide MMS-350, the phosphoinositol-3-kinase inhibitor (LY294002), TPP-imidazole fatty acid, (TPP-IOA), the nitric oxide synthase inhibitor (MCF-201-89), the p53/mdm2/mdm4 inhibitor (BEB55), methoxamine, isoproterenol, propanolol, and the ATP sensitive potassium channel blocker (glyburide). The drugs XJB-5-131, JP4-039, and MMS-350 were radiation protectors for CFU-GM. JP4-039 was also a radiation protector for CFU-GEMM. The drugs, XJB-5-131, JP4-039, and MMS-350 were radiation mitigators for BFU-E, MMS-350 and JP4-039 were mitigators for CFU-GM, and MMS350 was a mitigator for CFU-GEMM. In contrast, other drugs that were effective in murine assays: TTP-IOA, LY294002, MCF201-89, BEB55, propranolol, isoproterenol, methoxamine, and glyburide showed no significant protection or mitigation in human CB assays. These data support testing of new candidate clinical radiation protectors and mitigators using human CB clonogenic assays early in the drug discovery process, reducing the need for animal experiments.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Evaluation of potential ionizing irradiation protectors and mitigators using clonogenic survival of human umbilical cord blood hematopoietic progenitor cells

Goff

Shields

Wang

et al. 2013

Experimental Hematology

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“…Because peptides are often plagued by poor bioavailability and rapid hydrolysis in vivo, bioisosteric replacements of the amide bond have been of great interest [57,58]. In order for such a rational design to be successful, the bioisostere must allow for a close match of the geometry of the peptide bond while remaining stable to peptidase cleavage.…”

Section: Gramicidin S Derivativesmentioning

confidence: 99%

Conformational Restriction and Steric Hindrance in Medicinal Chemistry

Wipf

Skoda

Mann

2015

The Practice of Medicinal Chemistry

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“…To improve the intracellular/mitochondrial partitioning of TEMPOL and thereby increase its effective concentration, we conjugated TEMPOL to a fragment of gramicidin S that displays significant affinity for the inner mitochondrial membrane. The resulting 4-amino TEMPOL conjugate, XJB-5-131 (MW 958.2), was further optimized to improve its physicochemical properties, resulting in JP4-039 (MW 424.6) (Bernard et al, 2011; Frantz et al, 2011; Greenberger et al, 2012; Skoda et al, 2012; Wipf et al, 2005). JP4-039 partitions preferentially into mitochondria, resulting in enhanced drug efficiency vs. common antioxidants including TEMPOL (Bernard et al, 2011; Goff et al, 2011; Greenberger et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage

Brand

Epperly

Stottlemyer

et al. 2017

Journal of Investigative Dermatology

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Skin is the largest human organ and provides a first line of defense that includes physical, chemical, and immune mechanisms to combat environmental stress. Radiation is a prevalent environmental stressor. Radiation induced skin damage ranges from photoaging and cutaneous carcinogenesis from UV exposure, to treatment-limiting radiation dermatitis associated with radiotherapy, to cutaneous radiation syndrome, a frequently fatal consequence of exposures from nuclear accidents. The major mechanism of skin injury common to these exposures is radiation induced oxidative stress. Efforts to prevent or mitigate radiation damage have included development of antioxidants capable of reducing reactive oxygen species (ROS). Mitochondria are particularly susceptible to oxidative stress, and mitochondrial dependent apoptosis plays a major role in radiation induced tissue damage. We reasoned that targeting a redox cycling nitroxide to mitochondria could prevent ROS accumulation, limiting downstream oxidative damage and preserving mitochondrial function. Here we show that in both mouse and human skin, topical application of a mitochondrial targeted antioxidant prevents and mitigates radiation induced skin damage characterized by clinical dermatitis, loss of barrier function, inflammation, and fibrosis. Further, damage mitigation is associated with reduced apoptosis, preservation of the skin’s antioxidant capacity, and reduction of irreversible DNA and protein oxidation associated with oxidative stress.

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Allylic Amines as Key Building Blocks in the Synthesis of (E)-Alkene Peptide Isosteres

Cited by 105 publications

References 74 publications

Evaluation of potential ionizing irradiation protectors and mitigators using clonogenic survival of human umbilical cord blood hematopoietic progenitor cells

Evaluation of potential ionizing irradiation protectors and mitigators using clonogenic survival of human umbilical cord blood hematopoietic progenitor cells

Conformational Restriction and Steric Hindrance in Medicinal Chemistry

A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage

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