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1.
J Med Chem ; 60(1): 458-473, 2017 01 12.
Article in English | MEDLINE | ID: mdl-27976892

ABSTRACT

A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.


Subject(s)
Autophagy/drug effects , Cysteamine/pharmacology , Cystic Fibrosis Transmembrane Conductance Regulator/chemistry , Fatty Acids/chemistry , Cysteamine/chemistry , Protein Folding
2.
J Med Chem ; 59(3): 1217-31, 2016 Feb 11.
Article in English | MEDLINE | ID: mdl-26784936

ABSTRACT

This report describes the synthesis and preliminary biological characterization of novel fatty acid niacin conjugates and fatty acid salicylate conjugates. These molecular entities were created by covalently linking two bioactive molecules, either niacin or salicylic acid, to an omega-3 fatty acid. This methodology allows the simultaneous intracellular delivery of two bioactives in order to elicit a pharmacological response that could not be replicated by administering the bioactives individually or in combination. The fatty acid niacin conjugate 5 has been shown to be an inhibitor of the sterol regulatory element binding protein (SREBP), a key regulator of cholesterol metabolism proteins such as PCSK9, HMG-CoA reductase, ATP citrate lyase, and NPC1L1. On the other hand, the fatty acid salicylate conjugate 11 has been shown to have a unique anti-inflammatory profile based on its ability to modulate the NF-κB pathway through the intracellular release of the two bioactives.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Fatty Acids/chemistry , Niacin/chemistry , Niacin/pharmacology , Salicylic Acid/chemistry , Salicylic Acid/pharmacology , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Cell Line , Dogs , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Hydrolysis , Liver/drug effects , Liver/metabolism , Mice , Molecular Structure , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Niacin/administration & dosage , Rats , Rats, Sprague-Dawley , Salicylic Acid/administration & dosage , Sterol Regulatory Element Binding Protein 1/antagonists & inhibitors , Sterol Regulatory Element Binding Protein 1/metabolism , Sterol Regulatory Element Binding Protein 2/antagonists & inhibitors , Sterol Regulatory Element Binding Protein 2/metabolism , Structure-Activity Relationship , Tissue Distribution
3.
Bioorg Med Chem Lett ; 24(24): 5801-5804, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25454272

ABSTRACT

As ENT inhibitors including dilazep have shown efficacy improving oHSV1 targeted oncolytic cancer therapy, a series of dilazep analogues was synthesized and biologically evaluated to examine both ENT1 and ENT2 inhibition. The central diamine core, alkyl chains, ester linkage and substituents on the phenyl ring were all varied. Compounds were screened against ENT1 and ENT2 using a radio-ligand cell-based assay. Dilazep and analogues with minor structural changes are potent and selective ENT1 inhibitors. No selective ENT2 inhibitors were found, although some analogues were more potent against ENT2 than the parent dilazep.


Subject(s)
Dilazep/analogs & derivatives , Equilibrative Nucleoside Transporter 1/antagonists & inhibitors , Equilibrative-Nucleoside Transporter 2/antagonists & inhibitors , Animals , Biological Transport/drug effects , Cell Line , Dilazep/chemical synthesis , Dilazep/pharmacology , Equilibrative Nucleoside Transporter 1/genetics , Equilibrative Nucleoside Transporter 1/metabolism , Equilibrative-Nucleoside Transporter 2/genetics , Equilibrative-Nucleoside Transporter 2/metabolism , Humans , Protein Binding , Rats , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Swine
4.
Beilstein J Org Chem ; 9: 1501-7, 2013.
Article in English | MEDLINE | ID: mdl-23946849

ABSTRACT

The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure-activity relationships led to the discovery of ML212.

5.
ACS Med Chem Lett ; 3(10): 808-813, 2012 Oct 11.
Article in English | MEDLINE | ID: mdl-23074541

ABSTRACT

Macrocyclic Hedgehog (Hh) pathway inhibitors have been discovered with improved potency and maximal inhibition relative to the previously reported macrocycle robotnikinin. Analogues were prepared using a modular and efficient build-couple-pair (BCP) approach, with a ring-closing metathesis step to form the macrocyclic ring. Varying the position of the macrocycle nitrogen and oxygen atoms provided inhibitors with improved activity in cellular assays; the most potent analogue was 29 (BRD-6851), with an IC(50) of 0.4 µM against C3H10T1/2 cells undergoing Hh-induced activation, as measured by Gli1 transcription and alkaline phosphatase induction. Studies with Patched knockout (Ptch(-/-)) cells and competition studies with the Smoothened (Smo) agonists SAG and purmorphamine demonstrate that in contrast to robotnikinin, select analogues are Smo antagonists.

6.
Bioorg Med Chem Lett ; 22(10): 3571-4, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22503247

ABSTRACT

A high-throughput screen (HTS) with the National Institute of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) compound collection identified a class of acyl hydrazones to be selectively lethal to breast cancer stem cell (CSC) enriched populations. Medicinal chemistry efforts were undertaken to optimize potency and selectivity of this class of compounds. The optimized compound was declared as a probe (ML239) with the NIH Molecular Libraries Program and displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control line (HMLE_sh_GFP).


Subject(s)
Breast Neoplasms/drug therapy , Hydrazones/pharmacology , Neoplastic Stem Cells/cytology , Pyrroles/pharmacology , Breast Neoplasms/pathology , Female , Humans
7.
Top Curr Chem ; 291: 145-200, 2010.
Article in English | MEDLINE | ID: mdl-21494951

ABSTRACT

Chiral organic Brønsted bases have emerged as highly efficient catalysts for enantioselective transformations. Since their early use in enantiomeric separation processes, chiral organic Brønsted base catalysis has advanced significantly to include both natural and designed catalysts. Insight into the mode of action of the organocatalysts has promoted modifications in catalyst structures to expand the application to numerous asymmetric reactions. Bifunctional catalysts, containing both Brønsted base and H-activating functionalities, have proven to be very applicable to an array of reaction types. The development of Brønsted base catalysts containing or not containing H-activating moieties, has greatly impacted asymmetric organocatalysis. This overview illustrates the recent developments in this emerging field.


Subject(s)
Alkaloids/chemistry , Amines/chemistry , Imines/chemistry , Catalysis , Guanidine/chemistry , Thiourea/chemistry
8.
Org Lett ; 8(10): 2003-6, 2006 May 11.
Article in English | MEDLINE | ID: mdl-16671767

ABSTRACT

[reaction: see text] The cinchona alkaloids catalyze direct asymmetric Mannich reactions of cyclic 1,3-dicarbonyl compounds with acyl imines to afford alpha-quaternary carbon-bearing reaction products in yields of up to 98%, a diastereomeric excess of 90% or greater, and enantioselectivities up to 99% ee. A model is proposed that accounts for both the observed diastereoselectivities and the enantioselectivities for the reactions.


Subject(s)
Cinchona Alkaloids/chemistry , Imines/chemistry , Ketones/chemistry , Ketones/chemical synthesis , Catalysis , Crystallography, X-Ray , Molecular Conformation , Molecular Structure , Stereoisomerism
9.
J Am Chem Soc ; 127(32): 11256-7, 2005 Aug 17.
Article in English | MEDLINE | ID: mdl-16089450

ABSTRACT

Cinchona alkaloids catalyze the enantioselective Mannich reaction of beta-keto esters with acyl aryl imines. The reaction requires 10 mol % of cinchonine or cinchonidine. The reaction products are obtained in good yields (81-99%), high enantioselectivities (80-96% ee), and in diastereoselectivities that range from 1:1 to >95:5. The cinchonine-catalyzed reaction provides access to highly functionalized building blocks used in the asymmetric synthesis of a dihydropyrimidone and beta-amino alcohol.


Subject(s)
Cinchona Alkaloids/chemistry , Imines/chemistry , Ketones/chemistry , Catalysis , Esters/chemistry , Mannich Bases/chemistry
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