Abstract：
:The intracellular delivery of nucleic acid molecules is a complex process involving several distinct steps; among these the endosomal escape appeared to be of particular importance for an efficient protein production (or inhibition) into host cells. In the present study, a new series of ionizable vectors, derived from naturally occurring aminoglycoside tobramycin, was prepared using improved synthetic procedures that allow structural variations on the linker and hydrophobic domain levels. Complexes formed between the new ionizable lipids and mRNA, DNA, or siRNA were characterized by cryo-TEM experiments and their transfection potency was evaluated using different cell types. We demonstrated that lead molecule 30, bearing a biodegradable diester linker, formed small complexes with nucleic acids and provided very high transfection efficiency with all nucleic acids and cell types tested. The obtained results suggested that the improved and "universal" delivery properties of 30 resulted from an optimized endosomal escape, through the lipid-mixing mechanism.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Habrant D,Peuziat P,Colombani T,Dallet L,Gehin J,Goudeau E,Evrard B,Lambert O,Haudebourg T,Pitard Bdoi
10.1021/acs.jmedchem.5b01679subject
Has Abstractpub_date
2016-04-14 00:00:00pages
3046-62issue
7eissn
0022-2623issn
1520-4804journal_volume
59pub_type
杂志文章abstract：:Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan pr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01482
更新日期：2015-12-24 00:00:00
abstract：:Structure/activity studies on atrial natriuretic peptide ANP (1-28) have highlighted three portions of the native molecule as necessary for its biological responses. We have linked these three regions and excised the remaining segments to produce a family of small analogues (less than half the size of the parent) whic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00083a003
更新日期：1992-03-06 00:00:00
abstract：:The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01921
更新日期：2018-01-25 00:00:00
abstract：:4-(2-Methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole (5) is a highly potent member of a structurally novel series of selective serotonin-3 receptor antagonists. The synthesis of tritiated 5 and its binding profile in neuroblastoma-glioma 108-15 cells are described. Furthermore, in vivo studies in rat with...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00173a017
更新日期：1990-11-01 00:00:00
abstract：:Several pairs of cannabinoid isomers were synthesized and tested for psychotropic activity in rhesus monkeys. Two regularities were observed: (a) In the absence of the other substituents, the equatorial stereochemistry of the substituent at C-1 determines activity. (b) Two groups of THC-type cannabinoids which differ ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00184a002
更新日期：1980-10-01 00:00:00
abstract：:11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine comp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4016729
更新日期：2014-02-13 00:00:00
abstract：:The dedifferentiation agent "reversine" [2-(4-morpholinoanilino)-N(6)-cyclohexyladenine 2] was found to be a moderately potent antagonist for the human A(3) adenosine receptor (AR) with a K(i) value of 0.66 microM. This result prompted an exploration of the structure-activity relationship of related derivatives, synth...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050221l
更新日期：2005-07-28 00:00:00
abstract：:Esophageal adenocarcinoma (EAC) is a molecularly heterogeneous disease that is rising rapidly in incidence and has poor prognosis. We developed a heterobivalent peptide to target detection of early Barrett's neoplasia by combining monomer heptapeptides specific for either EGFR or ErbB2 in a heterodimer configuration. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00405
更新日期：2018-06-28 00:00:00
abstract：:A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0110789
更新日期：2002-04-25 00:00:00
abstract：:The definitive diagnosis of Alzheimer's disease (AD) requires the detection of amyloid plaques in postmortem brain. Although the amount of fibrillar amyloid roughly correlates with the severity of symptoms at the time of death, the temporal relationship between amyloid deposition, neuronal loss, and cognitive decline ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990103w
更新日期：1999-07-29 00:00:00
abstract：:Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2. 1]octanes (DBO, 1) plays an essential role in modulating affinity toward mu opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N(3) propionyl, N(8...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991140q
更新日期：2000-06-01 00:00:00
abstract：:Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a very promiscuous transporter. Herein we used topological polar surface area (TPSA), a descriptor defined as the sum of surfaces of polar atoms in a molecule, to analyze drug transport by MRP1. We suggested that compounds with high TPSA are transported while t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801389m
更新日期：2009-02-26 00:00:00
abstract：:Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm7009233
更新日期：2007-12-13 00:00:00
abstract：:Twenty-three acrylonitriles, substituted at position 2 with either triazoles or benzimidazoles and at position 3 with various substituted furan, thiophene, or phenyl rings, were prepared by Knoevenagel condensation and tested for in vitro cytotoxic potency on 11 human cancer cell lines. X-ray crystal analysis of two r...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0311036
更新日期：2004-06-17 00:00:00
abstract：:Two separate libraries, prepared via parallel synthesis, were employed to identify low-molecular-weight SH2-targeted ligands for the Lck tyrosine protein kinase. These libraries were constructed to furnish non-amino acid analogues of the (1) Glu-Glu and (2) Ile residues of the Lck SH2 domain peptide ligand Ac-pTyr-Glu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990462r
更新日期：2000-03-23 00:00:00
abstract：:Probucol (1) and probucol analogues with the substitutions at the disulfide-linked carbon (2, 3) and an additional substitution at a tert-butyl of each phenolic ring (4) were tested for their ability to lower total serum cholesterol and prevent aortic atherosclerosis in modified Watanabe heritable hyperlipidemic (WHHL...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00105a046
更新日期：1991-01-01 00:00:00
abstract：:The academic setting provides an environment that may foster success in the discovery of certain types of small molecule tools while proving less suitable in others. For example, small molecule probes for poorly understood systems, those that exploit a specific resident expertise, and those whose commercial return is ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm400132d
更新日期：2013-09-26 00:00:00
abstract：:We have previously reported a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-place preference assays in ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00219
更新日期：2019-04-25 00:00:00
abstract：:Some glycine, leucine and phenylalanine dipeptide derivatives of the transport inhibitory, tricycloaliphatic alpha-amino acid, adamantanine (1), have been synthesized using classical methods of peptide synthesis with the aim of improving the latter's bioavailability. Although test doses of glycyladamantanine and L-leu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00242a013
更新日期：1975-08-01 00:00:00
abstract：:KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00228
更新日期：2016-04-28 00:00:00
abstract：:[4-Phenylalanine]oxytocin was prepared from Z-Cys(Bzl)-Tyr(Bzl)-Ile-Phe-Asn-Cys(Bzl)-Pro-Leu-Gly-NG2 (4) by deprotection with Na in NH3 followed by cyclization of the resulting disulfhydryl compound with ICH2CH2I. The protected peptide 4 was prepared from Boc-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 by the stepwise solution metho...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00244a014
更新日期：1975-10-01 00:00:00
abstract：:The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in dept...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3003697
更新日期：2012-05-10 00:00:00
abstract：:In our search for potent and receptor-selective agonists and antagonists, we report here the results of D-amino acid substitution at each position of the short peptide gamma-melanocyte-stimulating hormone (gamma-MSH). The native gamma-MSH shows weak binding at all three receptors (i.e., the human MC3, MC4, and MC5) an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000211e
更新日期：2000-12-28 00:00:00
abstract：:Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferati...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0609925
更新日期：2006-12-14 00:00:00
abstract：:The F9/Yde/Fml pilus, tipped with the FmlH adhesin, has been shown to provide uropathogenic Escherichia coli (UPEC) a fitness advantage in urinary tract infections (UTIs). Here, we used X-ray structure guided design to optimize our previously described ortho-biphenyl Gal and GalNAc FmlH antagonists such as compound 1 ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01561
更新日期：2019-01-24 00:00:00
abstract：:Certain L1210-active bis(guanylhydrazones) have structural and biological properties in common with the DNA minor groove binding, antileukemic, bisquaternary ammonium heterocycles. Monitoring of the DNA binding of the bis(guanylhydrazones), by fluorimetric quantitation of drug displacement of DNA-bound ethidium, shows...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00196a016
更新日期：1979-10-01 00:00:00
abstract：:A series of analogues of the fungal peptaibol type metabolite ampullosporin A containing modifications in the C and N terminus as well as alpha-aminoisobutyric acid (Aib) substitutions in different positions of the peptide were synthesized by solid phase synthesis using the 9-fluorenylmethyloxycarbonyl strategy. Depen...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0208018
更新日期：2002-06-20 00:00:00
abstract：:A series of cyclic pseudopeptides of the formula cyclo(Leu psi[CH2NH]Xaa-Gln-Trp-Phe-beta Ala), where Xaa represents the residue of an alpha-amino acid, has been synthesized in order to establish the role of the Xaa side chain for tachykinin NK-2 receptor antagonist activity. Syntheses have been carried out in solid p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00047a020
更新日期：1994-10-14 00:00:00
abstract：:4-(Phenylamino)-5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 1 and related compounds known as "diaryltubercidin" analogues are potent inhibitors of adenosine kinase (AK) and are orally active in animal models of pain such as the rat formalin paw model (GP3269 ED50= 6.4 mg/kg). However, the utility...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050394a
更新日期：2005-12-01 00:00:00
abstract：:The prevalence of multidrug resistance among clinically significant bacterial pathogens underscores a critical need for the development of new classes of antibiotics with novel mechanisms of action. Here we describe the synthesis and evaluation of a guanidinomethyl biaryl compound {1-((4'-(tert-butyl)-[1,1'-biphenyl]-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm3012728
更新日期：2012-11-26 00:00:00
