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1.
Cancers (Basel) ; 12(11)2020 Nov 18.
Article in English | MEDLINE | ID: mdl-33217941

ABSTRACT

Stat5 is of significant interest in the search for new therapeutics for prostate cancer (PC) and hematopoietic disorders. We evaluated the transcriptomic specificity of the Stat5a/b inhibitor IST5-002 (IST5) in PC, defined more closely its mechanisms of action, and investigated the in vivo toxicity of IST5 for further optimization for clinical development. The transcriptomic specificity of IST5 vs. genetic Stat5 knockdown was evaluated by RNA-seq analysis, which showed high similarity with the Pearson correlation coefficient ranging from 0.98-0.99. The potency of IST5 vs. its derivative lacking the phosphate group in suppressing Stat5 was evaluated in two separate but complementary assays. The inhibitory activity of IST5 against kinases was investigated in cell-free assays followed by more focused evaluation in a cell-based assay. IST5 has no specific inhibitory activity against 54 kinases, while suppressing Stat5 phosphorylation and subsequent dimerization in PC cells. The phosphate group was not critical for the biological activity of IST5 in cells. The acute, sub-chronic and chronic toxicity studies of IST5 were carried out in mice. IST5 did not cause any significant toxic effects or changes in the blood profiles. The present work supports further optimization of IST5 for oral bioavailability for clinical development for therapies for solid tumors, hematological and myeloproliferative disorders.

2.
PLoS Negl Trop Dis ; 13(11): e0007826, 2019 11.
Article in English | MEDLINE | ID: mdl-31730614

ABSTRACT

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports on cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines given the anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970's but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ's anti-parasitic target is distinct from the human receptors that drive sedation. Therefore, we have screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of imidazobenzodiazepines that immobilize worms in vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, resulting in extensive vacuole formation beneath the apical membrane. The hit compound series identified has a dramatically lower (~1000×) affinity for the human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects.


Subject(s)
Anthelmintics/pharmacology , Benzodiazepines/pharmacology , Schistosoma mansoni/drug effects , Animals , Drug Evaluation, Preclinical , Locomotion/drug effects , Skin/drug effects , Skin/pathology
3.
J Med Chem ; 61(6): 2422-2446, 2018 03 22.
Article in English | MEDLINE | ID: mdl-29481759

ABSTRACT

Recent reports indicate that α6ß2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6ß2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6ß2/3γ2 GABAARs and were functionally silent at diazepam sensitive α1ß2/3γ2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR α6ß2/3γ2 subtypes.


Subject(s)
GABA Antagonists/chemical synthesis , GABA Antagonists/pharmacology , Receptors, GABA-A/drug effects , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/pharmacology , Behavior, Animal/drug effects , Biological Availability , Deuterium , Drug Design , Female , GABA Antagonists/pharmacokinetics , HEK293 Cells , Humans , Hypnotics and Sedatives/pharmacology , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Microsomes, Liver , Motor Activity/drug effects , Muscle Strength/drug effects , Rats , Rats, Wistar , Substrate Specificity
4.
Bioorg Med Chem ; 21(24): 7830-40, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24200931

ABSTRACT

The alarming increase in bacterial resistance over the last decade along with a dramatic decrease in new treatments for infections has led to problems in the healthcare industry. Tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis which is responsible for 1.4 million deaths per year. A world-wide threat with HIV co-infected with multi and extensively drug-resistant strains of TB has emerged. In this regard, herein, novel acrylic acid ethyl ester derivatives were synthesized in simple, efficient routes and evaluated as potential agents against several Mycobacterium species. These were synthesized via a stereospecific process for structure activity relationship (SAR) studies. Minimum inhibitory concentration (MIC) assays indicated that esters 12, 13, and 20 exhibited greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Based on these studies the acrylic ester 20 has been developed as a potential lead compound which was found to have an MIC value of 0.4 µg/mL against Mycobacterium tuberculosis. The SAR and biological activity of this series is presented; a Michael-acceptor mechanism appears to be important for potent activity of this series of analogs.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Design , Gram-Positive Bacteria/drug effects , Mycobacterium tuberculosis/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
5.
J Org Chem ; 77(1): 300-10, 2012 Jan 06.
Article in English | MEDLINE | ID: mdl-22073965

ABSTRACT

The stereospecific synthesis of aryloxy and amino substituted E- and Z-ethyl-3-acrylates is of interest because of their potential in the polymer industry and in medicinal chemistry. During work on a copper-catalyzed cross-coupling reaction of ethyl (E)- and (Z)-3-iodoacrylates with phenols and N-heterocycles, we discovered a very simple (nonmetallic) method for the stereospecific synthesis of aryloxy and amino substituted acrylates. To study this long-standing problem on the stereoselectivity of aryloxy and amino substituted acrylates, a series of O- and N-substituted nucleophiles was allowed to react with ethyl (E)- and (Z)-3-iodoacrylates. Screening of different bases indicated that DABCO (1,4-diazabicyclo[2.2.2]octane) afforded successful conversion of ethyl (E)- and (Z)-3-iodoacrylates into aryloxy and amino substituted ethyl acrylates in a stereospecific manner. Herein are the details of this DABCO-mediated stereospecific synthesis of aryloxy and amino substituted E- or Z-acrylates.


Subject(s)
Acrylates/chemical synthesis , Copper/chemistry , Cross-Linking Reagents/chemistry , Phenyl Ethers/chemical synthesis , Polymers/chemical synthesis , Acrylates/chemistry , Amination , Catalysis , Molecular Structure , Phenyl Ethers/chemistry , Polymers/chemistry , Stereoisomerism
6.
Bioorg Med Chem ; 18(12): 4178-86, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20537903

ABSTRACT

Novel acrylic acid ethyl ester derivatives were synthesized and evaluated as potential agents against Mycobacterium species. A versatile and efficient copper-catalyzed coupling process was developed and used to prepare a library of substituted acrylic acid ethyl ester analogs. Minimum inhibitory concentration assays indicated that two of these compounds 3 and 4 have greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Moreover, members of this new class of compounds appear to exhibit a specific anti-mycobacterial effect and do not inhibit the growth of the other Gram-positive or Gram-negative species tested.


Subject(s)
Acrylates/chemistry , Acrylates/chemical synthesis , Antitubercular Agents/chemical synthesis , Benzothiazoles/chemical synthesis , Sulfides/chemical synthesis , Acrylates/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Catalysis , Copper/chemistry , Microbial Sensitivity Tests , Mycobacterium/drug effects , Sulfides/chemistry , Sulfides/pharmacology
7.
Eur J Med Chem ; 40(11): 1143-8, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16040160

ABSTRACT

Spiro derivatives of oxindole and isoxazole-5-one were synthesized by using Michael addition reaction, highlighting the regioselective approach towards the synthesis of Michael diadduct followed by condensation of Michael diadduct. The spiro compound 4 showed antitubercular activity against Mycobacterium tuberculosis H37Rv whereas spiro compound 9 possesses pronounced anticancer and antibacterial profile.


Subject(s)
Androstenols/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antitubercular Agents/chemical synthesis , Spiro Compounds/chemical synthesis , Alkylation , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Antineoplastic Agents/pharmacology , Antitubercular Agents/pharmacology , Cell Survival/drug effects , Drug Design , Drug Screening Assays, Antitumor , Indoles/chemical synthesis , Mice , Microbial Sensitivity Tests , Spiro Compounds/pharmacology , Spiro Compounds/toxicity , Tumor Cells, Cultured
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