Abstract:
:In an effort to improve the activities and bioavailabilities of stromal cell-derived factor-1 (SDF-1, CXCL12) sdf-(1-67)-OH (1), we have prepared a linear peptide analogue [sdf-(1-31)-NH(2) (2)] and two lactam analogues [cyclo(Lys(20)-Glu(24))-sdf-(1-31)-NH(2) (3) and cyclo(Glu(24)-Lys(28))-sdf-(1-31)-NH(2) (4)], consisting of the N-terminal region (amino acids 1-14) joined by a four-glycine linker to the C-terminal region (amino acids 56-67) of 1. Analogues 2 and 4 had eight residues of alpha-helix, as estimated from its circular dichroism (CD) spectra, in contrast to 10 residues in analogue 3. Cyclization of analogue 2 at residues 20 and 24 to give analogue 3 resulted in only a slight change to the theta;(222)/theta;(209) ratio (0.81 to 0.86, where 1.09 is considered a perfect alpha-helix), although an increase in the alpha-helix length of analogue 3 was observed. In contrast, cyclization between residues 24 and 28 by lactamization to give analogue 4 only slightly affected the helical content but clearly resulted in a more classical alpha-helical structure (theta;(222)/theta;(209) = 0.98). Cyclization of the linear analogue 2 enhanced the SDF-1 receptor CXCR4 binding approximately 114-fold, where the IC(50) values derived from (125)I-SDF-1 competitive binding assays with CEM cells were found to be 39.5 +/- 5.9 nM, 28.9 +/- 6.3 microM, 225.8 +/- 11.8 nM, and 254.1 +/- 5.4 nM for analogues 1-4, respectively. Intracellular calcium mobilization ([Ca(2+)](i)) induced after interaction with CXCR4, as measured by EC(50), was significantly reduced in analogue 4 compared to 3, and approached the EC(50) of native SDF-1, indicating a correlation between the degree of alpha-helix and biological activity. Therefore, the biological activity of small peptide SDF-1 analogues is highly dependent on the conformation of its C-terminal region.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Tudan C,Willick GE,Chahal S,Arab L,Law P,Salari H,Merzouk Adoi
10.1021/jm0104015keywords:
subject
Has Abstractpub_date
2002-05-09 00:00:00pages
2024-31issue
10eissn
0022-2623issn
1520-4804pii
jm0104015journal_volume
45pub_type
杂志文章abstract::We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. A...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm400369q
更新日期:2013-06-27 00:00:00
abstract::We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970065l
更新日期:1998-01-01 00:00:00
abstract::Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual M...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b01582
更新日期:2020-01-23 00:00:00
abstract::To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been de...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020839k
更新日期:2002-09-12 00:00:00
abstract::An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM,...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00186a020
更新日期:1980-12-01 00:00:00
abstract::The synthesis of analogues of the antipsychotic drug butaclamol bearing chloro substituents on the benzene rings is described. On the basis of a perceived topographical similarity of a putative chlorophenylethylamine pharmacophore present in these analogues and in VUFB-10032 and doclothepin, agents related to octoclot...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00210a011
更新日期:1978-12-01 00:00:00
abstract::A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant toward beta-disposed s...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00002a009
更新日期:1995-01-20 00:00:00
abstract::A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl s...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b00986
更新日期:2018-09-27 00:00:00
abstract::We have derivatized Momordica saponins (MS) I and II through their coupling at C3 glucuronic acid site with dodecylamine. The derivatives show significantly different immunostimulant activity profiles from their respective natural parent saponins. In particular, adjuvant VSA-1 (5), the derivative of MS I, potentiates ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b01511
更新日期:2019-11-14 00:00:00
abstract::There is growing interest in using tumor associated antigens presented by class I major histocompatibility complex (MHC-I) proteins as cancer vaccines. As native peptides are poorly stable in biological fluids, researchers have sought to engineer synthetic peptidomimetics with greater biostability. Here, we demonstrat...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100683p
更新日期:2010-10-14 00:00:00
abstract::9,11-Secoestradiol (9) and 11-hydroxy-9,11-secoestradiol (12) have been synthesized starting from 17-acetoxyestradiol 3-methyl ether (1) and found to possess significant antifertility activity in rats. 3-Methoxy-9,11-seco-9-oxo-17beta-acetoxyestra-1,3,5(10)-trien-11-oic acid (2), prepared by CrO3 oxidation of 1, on h...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00241a026
更新日期:1975-07-01 00:00:00
abstract::Various hydrophilic pyrazine-bis(carboxamides) derived from 3,5-diamino-pyrazine-2,5-dicarboxylic acid bearing neutral and anionic groups were prepared and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, the dianionic d-serine pyrazine derivatives 2d and 2j, and the neutra...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200257k
更新日期:2011-07-28 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::Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isox...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020989v
更新日期:2003-01-16 00:00:00
abstract::Representatives of three types of side-chain analogues of distamycin A (1) were synthesized. These were tested for cytotoxicity, inhibition of herpes simplex virus (HSV) replication in cultured cells, effects on the synthesis of HSV DNA in isolated nuclei in vitro, as well as on DNA synthesis by purified HSV DNA polym...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00197a004
更新日期:1979-11-01 00:00:00
abstract::(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple f...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00121a034
更新日期:1989-01-01 00:00:00
abstract::The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0494873
更新日期:2004-12-02 00:00:00
abstract::Several known alpha-amino acid analogues and a new compound, N-chloroacetylphosphoramidate, a carbamyl phosphate analogue, were screened as antitumor agents. All gave 50% growth inhibition of cultures of human epidemeroid carcinoma of the nasopharynx at dosage levels of 2-8 mug/ml while showing no activity against L12...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00213a026
更新日期:1977-03-01 00:00:00
abstract::Angiotensin-converting enzyme 2 (ACE2), a recently identified human homologue of angiotensin-converting enzyme, is a zinc metallocarboxypeptidase which may play a unique role in cardiovascular and renal function. Here we report the discovery of potent and selective inhibitors of ACE2, which have been identified by eva...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701275z
更新日期:2008-04-10 00:00:00
abstract::Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. O...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0105777
更新日期:2002-05-23 00:00:00
abstract::Screening of our internal chemical collection against the neuropeptide Y5 (NPY Y5) receptor allowed the identification of a benzoxazine derivative 5f as a hit that showed moderate affinity (IC(50) = 300 nM). With the aim of improving the in vitro potency, a series of 2-benzoxazinone derivatives have been synthesized a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049599u
更新日期:2005-03-24 00:00:00
abstract::The effect of incorporation of an eleostearoyl group into molecules of aralkylhydrazines on their monoamine oxidase inhibitory potency was investigated in vitro and in vivo. The results showed that on a molar basis the hydrazides possessed an in vitro potency lower than and an in vivo potency and acute toxicity compar...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00235a004
更新日期:1975-01-01 00:00:00
abstract::The programmed cell death or apoptosis plays both physiological and pathological roles in biology. Anomalous activation of apoptosis has been associated with malignancies. The intrinsic mitochondrial pathway of apoptosis activation occurs through a multiprotein complex named the apoptosome. We have discovered molecule...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701195j
更新日期:2008-02-14 00:00:00
abstract::The gold(I) complexes of the general formula [Au(L(n))(PPh(3))]·xH(2)O (1-8; n = 1-8 and x = 0-1.5), where L(n) stands for a deprotonated form of the benzyl-substituted derivatives of 6-benzylaminopurine, were prepared, thoroughly characterized (elemental analyses, FT-IR, Raman and multinuclear NMR spectroscopy, ESI+ ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm201416p
更新日期:2012-05-24 00:00:00
abstract::New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangos...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01348
更新日期:2017-12-28 00:00:00
abstract::Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibito...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01869
更新日期:2018-04-26 00:00:00
abstract::We disclose the first selective, nonpeptidic, small-molecule somatostatin receptor subtype 5 (SST5R) antagonists that were identified by a chemogenomics approach based on the analysis of the homology of amino acids defining the putative consensus drug binding site of SST5R. With this strategy, opioid, histamine, dopam...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701143p
更新日期:2007-12-13 00:00:00
abstract::Whereas the 2-propyl- and 2-butyl-5,6-(methylenedioxy)indene calcium antagonists reversed the spasmogenic action of several agonists including PGF2alpha and acetylcholine at 5 X 10(-5) to 10(-4) M on the rat ileum, the corresponding 5,6-dimethoxy analogues exhibited spasmogenic activity at higher concentration (10(-4)...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00210a028
更新日期:1978-12-01 00:00:00
abstract::The synthesis of substituted [[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids (1) is described. 3-[(Carbobenzyloxy)amino]-N-hydroxy-2-azetidinones (13a,b), prepared from serine and threonine, were alkylated with 2-(trimethylsilyl)ethyl bromoacetate in the presence of potassium carbonate in THF/H2O. Alkylation wi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00148a013
更新日期:1985-10-01 00:00:00
abstract::A series of dithiocarbamates were prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as gl...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300031j
更新日期:2012-02-23 00:00:00