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1.
Bioorg Med Chem Lett ; 26(12): 2912-2914, 2016 06 15.
Article in English | MEDLINE | ID: mdl-27133483

ABSTRACT

Herein we report the synthesis and anticonvulsant activity of a library of eighteen new compounds that are structural mimics of phenytoin. These class of compounds contain a N-1', N-3'-disubstituted spirohydantoin scaffold, where the N-1' and N-3' positions are modified with an alkyl group or aryl group. Of the eighteen compounds synthesized and tested, compound 5c showed the best anticonvulsant activity. It completely prevented the precursor events of motor seizure in the pilocarpine model of temporal lobe epilepsy. Additionally, ten of the analogs were more effective than phenytoin when compared using the Racine's score in the pilocarpine model. Based on the structure activity relationship (SAR), we concluded that alkyl groups (ethyl, propyl or cyclopropyl) at N-3' position and 4-nitro phenyl group at N-1' position are desirable.


Subject(s)
Anticonvulsants/pharmacology , Epilepsy, Temporal Lobe/drug therapy , Pilocarpine/pharmacology , Seizures/drug therapy , Spiro Compounds/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Pilocarpine/chemical synthesis , Pilocarpine/chemistry , Rats , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity Relationship
2.
Nat Chem Biol ; 9(11): 677-84, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23995768

ABSTRACT

Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90ß, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers.


Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Neoplasms/metabolism , Purines/pharmacology , Receptor, ErbB-2/metabolism , HSP90 Heat-Shock Proteins/chemistry , HSP90 Heat-Shock Proteins/metabolism , Humans , Neoplasms/pathology , Purines/chemical synthesis , Purines/chemistry , Structure-Activity Relationship
3.
Am J Pathol ; 183(2): 422-30, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23770347

ABSTRACT

The proinflammatory response leads to various types of pathologic pathways, including the development of preterm birth. Preterm birth occurs in 12% of deliveries in the United States and causes more than 70% of perinatal morbidity and mortality. The most common cause of spontaneous preterm birth is intrauterine infection in the mother. There is accumulating evidence indicating that the release of proinflammatory cytokines plays a critical role in the pathogenesis of inflammation-associated premature delivery. We found that the common organic solvent, N,N-dimethylacetamide (DMA), prevents endotoxin-induced preterm birth in timed pregnant C57BL/6 embryonic day (E)15.5 mice and rescues their pups from spontaneous abortion at doses many-fold lower than those currently used clinically and in a dose-dependent fashion. We also provide histologic evidence that DMA suppresses the endotoxin-triggered proinflammatory response by significantly attenuating inflammatory cell infiltration of placental tissue. Furthermore, immunoblotting analysis of placental tissue harvested from our murine models revealed DMA-mediated regulation of expression of the proinflammatory cytokines IL-1ß, tumor necrosis factor α, and IL-6, and increased expression of the regulatory inflammatory cytokine IL-10. By using in vitro studies, we provide evidence that DMA suppresses macrophage function and that this small molecule prevents nuclear translocation of nuclear factor-kB. These results suggest that DMA represents a newly discovered, nontoxic therapy for a broad range of inflammatory disorders.


Subject(s)
Acetamides/pharmacology , Anti-Inflammatory Agents/pharmacology , Cytokines/drug effects , Endotoxins/toxicity , Premature Birth/prevention & control , Animals , Female , Lipopolysaccharides/toxicity , Mice , Mice, Inbred C57BL , NF-kappa B/drug effects , Pregnancy , Premature Birth/chemically induced
4.
Life Sci ; 91(13-14): 687-92, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22820174

ABSTRACT

AIM: To investigate the association between vasculopathy and survival during experimental cerebral malaria (ECM), and to determine whether targeting the endothelin-1 (ET-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival. MAIN METHODS: C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were randomly assigned to four groups: no treatment, artemether treated, ET(A) receptor antagonist (HJP-272) treated, or HJP-272 and artemether treated. The uninfected control mice were treated with HJP-272 and artemether. We analyzed survival, cerebral hemorrhage, weight change, blood glucose levels and parasitemia. KEY FINDINGS: Our studies demonstrated decreased brain hemorrhage in PbA-infected (ECM) mice treated when HJP-272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one novel ET(A) receptor antagonist synthesized by our group, is used in conjunction with artemether, an anti-malarial agent. In addition, despite adversely affecting parasitemia and weight in non-artemether treated infected mice, HJP-272, seemed to confer some survival benefit when used as adjunctive therapy, though this did not reach significance. SIGNIFICANCE: Previous studies demonstrate that the endothelin pathway is associated with vasculopathy, neuronal injury and inflammation in ECM. As demonstrated here, components of the ET-1 pathway may be important targets for adjunctive therapy in ECM, and may help in preventing hemorrhage and in improving survival when used as adjunctive therapy during malaria infection. The data presented suggest that our novel agent, HJP-272, may ameliorate alterations in the vasculature which can potentially lead to inflammation, neurological dysfunction, and subsequent death in mice with ECM.


Subject(s)
Artemisinins/pharmacology , Cerebral Hemorrhage/prevention & control , Endothelin A Receptor Antagonists , Hydroxyquinolines/pharmacology , Malaria, Cerebral/drug therapy , Animals , Antimalarials/administration & dosage , Antimalarials/pharmacology , Artemether , Artemisinins/administration & dosage , Cerebral Hemorrhage/parasitology , Drug Synergism , Drug Therapy, Combination , Endothelin-1/metabolism , Female , Hydroxyquinolines/administration & dosage , Malaria, Cerebral/complications , Mice , Mice, Inbred C57BL , Microvessels/pathology , Parasitemia/drug therapy , Plasmodium berghei/isolation & purification , Random Allocation , Survival
6.
Bioorg Med Chem Lett ; 20(22): 6840-4, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20932745

ABSTRACT

A series of 1,3,6-trisubsituted-4-oxo-1,4-dihyroquinoline-2-carboxylic acid analogs (2a-m) were designed and synthesized and their pharmacological activity determined, with the objective to better understand their SAR as potential ET(A) selective inhibitors. Most of the compounds displayed significant ET(A) antagonist activity having IC(50) for inhibition of binding of the [(125)I]ET-1 to ET(A) receptor <10 nM, with good selectivity for ET(A) antagonism over ET(B) receptor. Based on the in vitro results, SAR of this series of compounds requires an alkoxy substituent at the 6-position to be a straight and saturated chain up to three carbons long, since substitution of unsaturated and branched alkyloxy groups results in decrease in ET(A) antagonist activity. In this series, compound 2c (6-O-n-propyl analog) was found to be most potent (IC(50)=0.11 nM) with ET(B)/ET(A) selectivity of 8303.


Subject(s)
Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Endothelin A Receptor Antagonists , Animals , Carboxylic Acids/chemistry , Female , Iodine Radioisotopes/metabolism , Mice , Pregnancy , Receptor, Endothelin A/metabolism , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 16(17): 4644-7, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16793262

ABSTRACT

Thirteen new N-1',N-3'-disubstituted-2'H,3H,5'H-spiro-(2-benzofuran-1,4'-imidazolidine)-2',3,5'-triones were synthesized and their pharmacological activity determined with the objective to better understand their SAR for anticonvulsant activity. The anticonvulsant effects of these compounds were evaluated by standard pentylenetetrazol (scPTZ test) and maximum electroshock seizure (MES test) models in mice. Most of the compounds showed ability to protect against the pentylenetetrazol-induced convulsions. Compound 3o (the N-1'-p-nitrophenyl, N-3'-ethyl derivative) in the N-1'-aryl, N-3'-alkyl disubstituted series exhibited maximum activity with ED(50) of 41.8 mg/kg in scPTZ convulsion model.


Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Benzofurans/chemistry , Benzofurans/pharmacology , Imidazolidines/chemistry , Imidazolidines/pharmacology , Animals , Anticonvulsants/chemistry , Benzofurans/chemical synthesis , Imidazolidines/chemical synthesis , Mice , Molecular Structure , Pentylenetetrazole/pharmacology , Seizures/chemically induced , Seizures/prevention & control , Structure-Activity Relationship
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