ABSTRACT
Due to the rapidly growing bacterial resistance to antibiotics and the scarcity of novel agents under development, bacterial infections are still a pressing global problem, making new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, urgently needed. In this paper, seven series of N-arylsulfonylindole analogs 5-11 bearing rhodanine moieties were synthesized, characterized, and evaluated for antibacterial activity. According to the in vitro antimicrobial results, half of the synthesized compounds showed potent inhibition against four Gram-positive bacteria, with MIC values in the range of 0.5-8 µg/mL. For multidrug-resistant strains, compounds 6a and 6c were the most potent, with MIC values of 0.5 µg/mL, having comparable activity to gatifloxacin, moxiflocaxin and norfloxacin and being 128-fold more potent than oxacillin (MIC = 64 µg/mL) and 64-fold more active than penicillin (MIC = 32 µg/mL) against Staphylococcus aureusATCC 43300.
Subject(s)
Anti-Bacterial Agents/chemistry , Arylsulfonic Acids/chemistry , Escherichia coli/drug effects , Indoles/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Arylsulfonic Acids/chemical synthesis , Arylsulfonic Acids/pharmacology , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Microbial Sensitivity Tests , Rhodanine/chemical synthesis , Rhodanine/chemistry , Rhodanine/pharmacology , Structure-Activity RelationshipABSTRACT
Pancreatic cancer is the leading cause of cancer death worldwide with a poor survival rate. The objective of this study was to determine the mechanism of action of a novel antimitotic and Stat3 inhibitor, LTP-1, on human pancreatic cancer in vitro and in vivo. We found that LTP-1 inhibited pancreatic cancer cell growth and viability with significant G2/M arrest and disruption of microtubule dynamics. LTP-1 also caused G2/M arrest-independent Stat3 dephosphorylation along with ERK activation, which indicated the possible dual function of LTP-1. Long-term treatment of LTP-1 also induced polyploidy, activated caspases, induced subG1 cell population, and therefore, triggered pancreatic cancer cell apoptosis. Finally, we used an in vivo xenograft model to demonstrate that LTP-1 suppressed the growth of pancreatic adenocarcinoma. In summary, our data suggest that LTP-1 may alter microtubule dynamics, which ultimately causes polyploidy and apoptosis, thereby inhibiting pancreatic cancer growth in vitro and in vivo. This study provides evidence that LTP-1 could be a potential therapeutic agent for further development of pancreatic cancer treatment.
Subject(s)
Antimitotic Agents/administration & dosage , Arylsulfonic Acids/administration & dosage , Pancreatic Neoplasms/drug therapy , STAT3 Transcription Factor/metabolism , Animals , Antimitotic Agents/pharmacology , Arylsulfonic Acids/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Pancreatic Neoplasms/metabolism , Phosphorylation/drug effects , Xenograft Model Antitumor Assays , Pancreatic NeoplasmsABSTRACT
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Arylsulfonic Acids/chemical synthesis , Piperazines/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Arylsulfonic Acids/classification , Arylsulfonic Acids/pharmacology , Biological Availability , Cell Line , Crystallography, X-Ray , Enzyme Stability/drug effects , Enzyme Stability/physiology , Humans , Macaca fascicularis , Mice , Piperazines/classification , Piperazines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Carbonic anhydrase inhibitors AZA, EZA, and 4-acetamidobenzsulfonamide were found to inhibit human AQP4-M23 mediated water transport by 80%, 68%, and 23%, respectively, at 20 microM in an in vitro functional assay. AZA was found to have an IC50 against AQP4 of 0.9 microM. Phloretin was inactive under the same conditions.
Subject(s)
Aquaporin 4/antagonists & inhibitors , Arylsulfonic Acids/pharmacology , Sulfonamides/pharmacology , Acetazolamide/pharmacology , Animals , Biological Transport/drug effects , Humans , Inhibitory Concentration 50 , Oocytes , Osmosis , Phloretin/pharmacology , Structure-Activity Relationship , Transfection , Water/metabolismABSTRACT
8-(Sulfostyryl)xanthine derivatives were synthesized as water-soluble A2A-selective adenosine receptor (AR) antagonists. meta- and para-sulfostyryl-DMPX (3,7-dimethyl-1-propargylxanthine) derivatives 11a and 11b exhibited high affinity to rat A2A-AR in submicromolar concentrations, and were 20- to 30-fold selective versus rat A1-AR. Styryl-DMPX derivatives were inactive at human A2B- and A3-AR. 1,3-Dipropyl-8-p-sulfostyrylxanthine (13) or only a 7-methyl derivative (14) showed similar (13) or higher (14) A2A affinity than 11a and 11b but showed no (13) or only a low degree (14) of selectivity versus A1-, A2B-, and A3-AR. The A2A-selective sulfostyryl-DMPX derivatives exhibit high water-solubility and may be useful research tools for in vivo studies.