Abstract：
:Target identification is a high-priority, albeit challenging, aspect of drug discovery. Diazirine-based photoaffinity probes (PAPs) can facilitate the process by covalently capturing transient molecular interactions. This can help identify target proteins and map the ligand's interactome. Diazirine probes have even been incorporated by cellular machinery into proteins. Embarking on the synthesis of customized PAPs, containing either an aliphatic or trifluoromethyl phenyl diazirine, can be a considerable endeavor, particularly for medicinal chemists and chemical biologists new to the field. This review takes a synthetic focus, aiming to summarize available routes, propose new avenues, and illuminate recent advances in diazirine synthesis. Select examples of diazirine photoaffinity labeling applications have been included throughout to provide instructive definition of the advantages and limitations of the technology while simultaneously highlighting how these reagents can be applied in a practical sense.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Hill JR,Robertson AABdoi
10.1021/acs.jmedchem.7b01561subject
Has Abstractpub_date
2018-08-23 00:00:00pages
6945-6963issue
16eissn
0022-2623issn
1520-4804journal_volume
61pub_type
杂志文章,评审abstract：:Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction networ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01290
更新日期：2020-11-25 00:00:00
abstract：:In our search for new therapeutic agents against chronic hepatitis C, a ribonucleoside analogue, 2'-C-methylcytidine, was discovered to be a potent and selective inhibitor in cell culture of a number of RNA viruses, including the pestivirus bovine viral diarrhea virus, a surrogate model for hepatitis C virus (HCV), an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0603623
更新日期：2006-11-02 00:00:00
abstract：:The synthesis and some biological activities of [4-beta-(2-thienyl)-L-alanine]oxytocin are reported. This analogue has been studied in an ongoing exploration of the biological effects of introducing amino acid residues with bulky hydrophobic side chains into the second corner position of the beta turn present in the c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00199a022
更新日期：1978-01-01 00:00:00
abstract：:Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin co...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01957
更新日期：2020-03-26 00:00:00
abstract：:Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by the indocyanine gre...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01682
更新日期：2019-02-28 00:00:00
abstract：:Accumulation of beta-amyloid aggregates (Abeta) in the brain is linked to the pathogenesis of Alzheimer's disease (AD). We report a novel approach for producing 1,4-diphenyltriazoles as probes for targeting Abeta aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070467l
更新日期：2007-07-12 00:00:00
abstract：:In a previous study, we described affinity labeling of the lamb uterine estrogen receptor by 17 alpha-[(bromoacetoxy)alkyl/alkynyl]estradiols. However, the intrinsic receptor-alkylating activities of these compounds were probably very hampered by their poor hydrolytic stability in estrogen receptor-containing tissue e...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00013a011
更新日期：1995-06-23 00:00:00
abstract：:Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand ef...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500155b
更新日期：2014-04-24 00:00:00
abstract：:Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300509y
更新日期：2012-08-23 00:00:00
abstract：:Bivalent molecules containing two beta-turn mimics with side chains that correspond to hot-spots on the neurotrophin NT-3 were prepared. Binding assays showed the mimetics to be selective TrkC ligands, and biological assays showed one mimetic to be an antagonist of the TrkC receptor. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100148d
更新日期：2010-07-08 00:00:00
abstract：:Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01720
更新日期：2020-05-14 00:00:00
abstract：:Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Le...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9704917
更新日期：1998-03-26 00:00:00
abstract：:The ecteinascidins (Ets), which are natural products derived from marine tunicates, exhibit potent antitumor activity. Of the numerous Ets isolated, Et 743 is presently being evaluated in phase II clinical trials. Et 743 binds in the minor groove of DNA and alkylates N2 of guanine. Although structurally similar to saf...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990241l
更新日期：1999-07-15 00:00:00
abstract：:Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and poten...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00982
更新日期：2021-01-14 00:00:00
abstract：:All of the selective COX-2 inhibitors described to date inhibit the isoform by binding tightly but noncovalently at the substrate binding site. Recently, we reported the first account of selective covalent modification of COX-2 by a novel inactivator, 2-acetoxyphenyl hept-2-ynyl sulfide (70) (Science 1998, 280, 1268-1...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980303s
更新日期：1998-11-19 00:00:00
abstract：:The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. We study both aspects in detail with the aim of enabling a more rational use of this class of interactions in medicinal chemistry. On the basis of exhaustive searches in crystal structure databases, we de...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100087s
更新日期：2010-03-25 00:00:00
abstract：:A series of imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo[1,5-alpha]quinoxaline urea series had high affinity for the GABAA/benzodiazepine receptor complex with varying in vitro efficacy, al...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960070+
更新日期：1996-09-13 00:00:00
abstract：:A new class of substituted 1-phenyl-3-piperazinyl-2-propanones with antimuscarinic activity is reported. As part of a structure-activity relationship study of this class, various structural modifications, particularly ones involving substitution of position 1 and the terminal piperazine nitrogen, were investigated. Th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00057a010
更新日期：1993-03-05 00:00:00
abstract：:The nature of the carbonyl and nitrogen substituents of hydroxamic acids has a major influence on the biological profile of these compounds. Hydroxamates with small groups such as methyl appended to the carbonyl and relatively large nitrogen substituents generally have longer duration in vivo, produce greater plasma c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00118a016
更新日期：1988-10-01 00:00:00
abstract：:5-Bromotryptophan (5-BrTrp) is the most potent amino acid derivative reported in the literature to inhibit the gelation of hemoglobin S (from sickle cell anemia patients). Trp-Trp is also more potent than Trp as an antigelation agent. Therefore, we have prepared a series of dipeptides containing 5-BrTrp and evaluated ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00174a008
更新日期：1990-12-01 00:00:00
abstract：:7-(Aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661, 1) is a potent inhibitor of the enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). In contrast to other inhibitors of PNMT, it is also highly selective toward PNMT in comparison with its affinity toward the alpha 2-adrenoceptor (PNMT Ki = 0....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960235e
更新日期：1997-12-05 00:00:00
abstract：:The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and lipoxygenases (LOXs) have been found to be implicated in a variety of cancers, including prostate cancer. To develop new therapeutic treatments, it therefore seemed interesting to design dual COX-2/5-LOX inhibitors. We report here the synthesis and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0407761
更新日期：2004-12-02 00:00:00
abstract：:Twenty homodetic cyclic peptides based on the C-terminal sequence of substance P were prepared (Table I) by a combination of solid-phase techniques and cyclizations using azide coupling procedures. Incorporation of dipeptide mimics based on substituted gamma-lactams were used in some cases to restrict their conformati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00053a001
更新日期：1993-01-08 00:00:00
abstract：:The understanding of the physiological role of the G-protein coupled serotonin 5-HT(7) receptor is largely rudimentary. Therefore, selective and potent pharmacological tools will add to the understanding of serotonergic effects mediated through this receptor. In this report, we describe two compound classes, chromans ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0498102
更新日期：2004-07-29 00:00:00
abstract：:2-Hydroxy-5-(3,4-dichlorophenyl)-6,7-bis(hydroxymethyl)-2,3-dihydro-1H- pyrrolizine bis(2-propylcarbamate) (11) was prepared in a multistep synthesis. The 2-hydroxy group was used to prepare ester prodrugs 14 and 15, and the antineoplastic activities of 11, 14, and 15a were compared to 1 (the 2-deoxy analogue of 11) i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00363a023
更新日期：1983-09-01 00:00:00
abstract：:The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0211218
更新日期：2003-05-22 00:00:00
abstract：:A four-step synthesis of 2-chlorodopamine (2b) is presented as well as methods for the syntheses of the N-methyl, ethyl, and n-propyl analogues (2c-e). Compounds 2b and 2c were essentially equipotent to dopamine for increasing renal blood flow in anesthetized dogs that had been treated with the alpha-adrenergic antago...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00159a005
更新日期：1986-09-01 00:00:00
abstract：:Treatment of 14 beta-nitrocodeinone with sodium borohydride gave the codeine derivative which was reduced with zinc dust in acetic anhydride-acetic acid solution to give 14 beta-acetamidocodeine 6-acetate. 14 beta-Thiocyanatocodeinone was obtained from the reaction of thebaine with thiocyanogen and was reduced to 14 b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00176a011
更新日期：1980-02-01 00:00:00
abstract：:An imidazo[4,5-h]isoquinolin-7,9-dione (1) was identified as an adenosine 5'-triphosphate competitive inhibitor of lck by high throughput screening. Initial structure-activity relationship studies identified the dichlorophenyl ring and the imide NH as important pharmacophores. A binding model was constructed to unders...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020113o
更新日期：2002-08-01 00:00:00
abstract：:Neuropeptide S (NPS) is the endogenous ligand of the previously orphan G-protein coupled receptor now named NPSR. The NPS-NPSR receptor system regulates important biological functions such as sleep/waking, locomotion, anxiety and food intake. Recently, exhaustive Ala scan and d-amino acid scan studies, together with s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0706822
更新日期：2007-09-06 00:00:00
