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1.
Mark D. Wittman John F. Kadow Kahnie Pham Leung Kinwa Harold A. Mastalerz Dolatrai M. Vyas William C. Rose Wyle Solomon Nada Zein 《Bioorganic & medicinal chemistry letters》1994,4(24):2925-2928
The thiol activation and aromatization of bicyclo[7.1.0]enediynes was found to be dependent of the nature of the propargyl substituent. These effects are correlated to antitumor activity. 相似文献
2.
Monoclonal antibody-beta-lactamase conjugates for the activation of a cephalosporin mustard prodrug.
H P Svensson J F Kadow V M Vrudhula P M Wallace P D Senter 《Bioconjugate chemistry》1992,3(2):176-181
Cephalosporin mustard (CM) was designed as an anticancer prodrug that could be activated in a site-specific manner by monoclonal antibody-beta-lactamase conjugates targeted to antigens present on tumor cell surfaces. Purified beta-lactamases from Bacillus cereus (BC beta L) and Escherichia coli (EC beta L) catalyzed the release of phenylenediamine mustard (PDM) from CM through a fragmentation reaction which occurs after the beta-lactam ring of CM is hydrolyzed. The Km and Vmax values were 5.7 microM and 201 mumol/min per mg for BC beta L and 43 microM and 29 mumol/min per mg for EC beta L, respectively. Conjugates of BC beta L were prepared by combining the F(ab')2 fragments of the maleimide-substituted monoclonal antibodies L6 and 1F5 with thiolated BC beta L. The conjugates showed little loss in enzymatic activity and bound nearly as well as the unmodified F(ab')2 monoclonal antibodies to antigens expressed on the H2981 human lung adenocarcinoma cell line (L6 positive, 1F5 negative). PDM was approximately 50-fold more cytotoxic than CM to H2981 cells. Treatment of the cells with L6-BC beta L followed by CM resulted in a level of cytotoxic activity that was comparable to that of PDM. This was most likely due to activation of CM by conjugate that bound to cell-surface antigens, since pretreatment of H2981 cells with BC beta L or 1F5-BC beta L enhanced the activity of CM to a lesser extent. Thus, we have shown that CM is a prodrug, and that it can be activated with immunological specificity by a monoclonal antibody-beta-lactamase conjugate. 相似文献
3.
Zheng X Hudyma TW Martin SW Bergstrom C Ding M He F Romine J Poss MA Kadow JF Chang CH Wan J Witmer MR Morin P Camac DM Sheriff S Beno BR Rigat KL Wang YK Fridell R Lemm J Qiu D Liu M Voss S Pelosi L Roberts SB Gao M Knipe J Gentles RG 《Bioorganic & medicinal chemistry letters》2011,21(10):2925-2929
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC50 = 0.07 μM, %F = 18), are reported. 相似文献
4.
Fink BE Vite GD Mastalerz H Kadow JF Kim SH Leavitt KJ Du K Crews D Mitt T Wong TW Hunt JT Vyas DM Tokarski JS 《Bioorganic & medicinal chemistry letters》2005,15(21):4774-4779
A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities. 相似文献
5.
Kyle Parcella Andrew Nickel Brett R. Beno Steven Sheriff Changhong Wan Ying-Kai Wang Susan B. Roberts Nicholas A. Meanwell John F. Kadow 《Bioorganic & medicinal chemistry letters》2017,27(2):295-298
Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency. 相似文献
6.
Tao Wang John F. Kadow Zhongxing Zhang Zhiwei Yin Qi Gao Dedong Wu Dawn DiGiugno Parker Zheng Yang Lisa Zadjura Brett A. Robinson Yi-Fei Gong Wade S. Blair Pei-Yong Shi Gregory Yamanaka Pin-Fang Lin Nicholas A. Meanwell 《Bioorganic & medicinal chemistry letters》2009,19(17):5140-5145
4-Fluoro- and 4-methoxy-1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (2 and 3, respectively) have been characterized as potent inhibitors of HIV-1 attachment that interfere with the interaction of viral gp120 with the host cell receptor CD4. As part of an effort to understand fundamental aspects of this pharmacophore, discovered originally using a high throughput cell-based screen, modification and substitution of the piperazine ring was examined in the context of compounds 6a–ah. The piperazine ring was shown to be a critical element of the HIV-1 attachment inhibiting pharmacophore, acting as a scaffold to deploy the indole glyoxamide and benzamide in a topographical relationship that complements the binding site on gp120. 相似文献
7.
Yan-Fung Wong Qing Sheng Janet WL Chung Jacky KF Chan King L Chow 《BMC developmental biology》2010,10(1):82
Background
C. elegans TGF-β-like Sma/Mab signaling pathway regulates both body size and sensory ray patterning. Most of the components in this pathway were initially identified by genetic screens based on the small body phenotype, and many of these mutants display sensory ray patterning defect. At the cellular level, little is known about how and where these components work although ray structural cell has been implicated as one of the targets. Based on the specific ray patterning abnormality, we aim to identify by RNAi approach additional components that function specifically in the ray lineage to elucidate the regulatory role of TGF-β signaling in ray differentiation. 相似文献8.
Synthesis and bioactivity of 2,4-diacyl analogues of paclitaxel 总被引:1,自引:0,他引:1
Chordia MD Yuan H Jagtap PG Kadow JF Long BH Fairchild CR Johnston KA Kingston DG 《Bioorganic & medicinal chemistry》2001,9(1):171-178
The 2,4-diacyl paclitaxel analogues 8a-8r were prepared from paclitaxel by acylation of 4-deacetyl-2-debenzoylpaclitaxel 1,2-carbonate (3) followed either by hydrolysis of the carbonate and acylation or by direct treatment of the carbonate with an aryllithium. Some of the resulting derivatives showed significantly improved tubulin assembly activity and cytotoxicity as compared with paclitaxel; in some cases this improvement was especially significant for paclitaxel-resistant cell lines. 相似文献
9.
Juhi Sardana Cristina Organisti Ilona C. Grunwald Kadow 《Developmental neurobiology》2018,78(9):873-888
Deciphering the mechanisms of sensory neural map formation is a central aim in neurosciences. Failure to form a correct map frequently leads to defects in sensory processing and perception. The olfactory map develops in subsequent steps initially forming a rough and later a precise map of glomeruli in the antennal lobe (AL), mainly consisting of olfactory receptor neuron (ORN) axons and projection neuron (PN) dendrites. The mechanisms underpinning the later stage of class‐specific glomerulus formation are not understood. Recent studies have shown that the important guidance molecule Eph and its ligand ephrin play a role in class‐specific PN targeting. Here, we reveal aspects of the mechanism downstream of Eph signaling during olfactory map formation. We show that the Eph‐specific RhoGEF Ephexin (Exn) is required to fine tune PN dendrite patterning within specific glomeruli. We provide the first report showing an in vivo neurite guidance defect in an exn mutant. Interestingly, the quality of the phenotypes is different between eph and exn mutants; while loss of Eph leads to strong misprojections of DM3/Or47a neurons along the medial–lateral axis of the antennal lobe (AL), loss of Exn induces ventral ectopic innervation of a neighboring glomerulus. Genetic interaction experiments suggest that differential signaling of the small GTPases Rac1 and Cdc42 mediated by Exn‐dependent and ‐independent Eph signaling fine tunes spatial targeting of PN dendrites within the olfactory map. We propose that their distinct activities on the actin cytoskeleton are required for precise navigation of PN dendrites within the olfactory map. Taken together, our results suggest that the precise connectivity of an individual neuron can depend on different modes of signaling downstream of a single guidance receptor. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000–000, 2018 相似文献
10.
Ny Sin Brian L. Venables Keith D. Combrink H. Belgin Gulgeze Kuo-Long Yu Rita L. Civiello Jan Thuring X. Alan Wang Zheng Yang Lisa Zadjura Anthony Marino Kathleen F. Kadow Christopher W. Cianci Junius Clarke Eugene V. Genovesi Ivette Medina Lucinda Lamb Mark Krystal Nicholas A. Meanwell 《Bioorganic & medicinal chemistry letters》2009,19(16):4857-4862
A series of bezimidazole-isatin oximes were prepared and profiled as inhibitors of respiratory syncytial virus (RSV) replication in cell culture. Structure–activity relationship studies were directed toward optimization of antiviral activity, cell permeability and metabolic stability in human liver micorosomes (HLM). Parallel combinatorial synthetic chemistry was employed to functionalize isatin oximes via O-alkylation which quickly identified a subset of small, lipophilic substituents that established good potency for the series. Further optimization of the isatin oxime derivatives focused on introduction of nitrogen atoms to the isatin phenyl ring to provide a series of aza-isatin oximes with significantly improved PK properties. Several aza-isatin oximes analogs displayed targeted metabolic stability in HLM and permeability across a confluent monolayer of CaCo-2 cells. These studies identified several compounds, including 18i, 18j and 18n that demonstrated antiviral activity in the BALB/c mouse model of RSV infection following oral dosing. 相似文献