Abstract
T regulatory cells (Tregs) are a subset of FoxP3+ lymphocytes that maintain immune homeostasis through immunosuppressive signaling. In many helminth infections, one mechanism of immune ...evasion involves the influx and maintenance of Tregs. Multiple mechanisms can control Treg homeostasis including a Nicotinamide adenine dinucleotide (NAD) dependent apoptotic pathway. In most organisms, the two pathways of NAD synthesis include de novo synthesis from amino acid precursors, and the salvage pathway in which nicotinamide-containing precursors are recycled into NAD. A comparative genome analysis of S. mansoni, the parasite that causes Schistosomiasis, enabled the assembly of a putative NAD biosynthetic pathway. Only orthologues of NAD salvage-specific genes were identified and expression was confirmed by PCR. This suggests that S. mansoni decreases host NAD levels in a salvage-specific manner and rescues Tregs from NAD-dependent cell death. As such, we hypothesized that inhibition of NAD biosynthesis through the salvage pathway would result in impaired NAD uptake by S. mansoni and restoration of NAD-mediated cell death of Tregs. Indeed, co-culture with S. mansoni prevented NAD-induced toxicity and death of Tregs. Blockade of the NAD salvage pathway via the inhibition of Schistosoma mansoni NAD catabolizing enzyme (SmNACE) restored NAD-mediated cell death of Tregs. Furthermore, SmNACE inhibition decreased intracellular NAD levels and reduced metabolism and viability of the parasite. Collectively, our data suggest that inhibition of NAD biosynthesis blocks immune evasion and metabolism of S. mansoni, and that targeting the NAD salvage pathway is a promising therapeutic approach for the treatment of Schistosomiasis.
Due to the interesting pharmacological activity observed for CI-988, a potent and selective CCK-B receptor antagonist, we have continued to study the SAR of this antagonist. This particular study ...examines the importance of the indole moiety for binding affinity. The synthesis and receptor binding affinity for analogs containing functionalized indole derivatives and replacing the indole with various heterocycles are reported.
Due to the interesting pharmacological activity observed for CI-988, a potent and selective CCK-B receptor antagonist, we have continued to study the SAR of this antagonist. This particular study examines the importance of the indole moiety for binding affinity. The synthesis and receptor binding affinity for analogs containing functionalized indole derivatives and replacing the indole with various heterocycles are reported.
A study of structure-activity relationships of substituted beta-ketoamide ACAT inhibitors I and II was performed. The results of this study suggest that whereas the beta-keto group was tolerated with ...no loss in activity, beta-hydroxy and oxime moieties led to significantly reduced activity in vitro and in vivo. The most potent inhibitor from the acyclic series (I) (11, IC50 = 0.006 microM) contained a C-13 alkyl chain. This compound reduced plasma total cholesterol by 38% and 66% at 3 and 30 mg/kg, respectively, in cholesterol-fed rats. Dimethylation alpha to the anilide core (5) and subsequent N-methylation of the amide NH (6) decreased in vitro potency significantly. It was also found that high potency was retained with inhibitors which incorporated the carbonyl into a lactam ring (II).
A study of structure-activity relationships of a series of ‘dipeptoid’ CCK-B receptor antagonists was performed in which variations of the phenyl ring were examined while the ...(2-adamantyloxy)carbonyl-α-methyl-
R)-tryptophan moiety of the potent antagonist CI-988 was kept constant. Since the main focus of this study was phenyl substituent variation, series design techniques were employed to insure an adequate spread of physicochemical properties (lipophilic, steric, electronic), as well as positional substitution. A QSAR analysis on sets of 26 and 16 analogues revealed that CCK-B affinity was related to a combination of the overall size and, marginally, lipophilicity of the phenyl ring substituents (i.e., smaller groups were associated with increased potency with an optimum π near zero, respectively). Further exploration revealed that the dimensions and electronics of the para-phenyl substituent could be related to CCK-B affinity. Increased affinity was seen with short, bulky (branched) electron withdrawing groups. Analogs with small
para-substituents appeared to be about 1000-fold CCK-B selective, indicating that selectivity for CCK-B binding is sensitive to phenyl ring substitution. The 4-F-phenyl dipeptoid, derived from this study, has extraordinary high affinity at the CCK-B receptor (IC
50 = 0.08 nM) and was also very selective (940-fold CCK-B selective). Consistent with previous reports, (
S)-configuration at the substituted phenethylamide center, a carboxylic acid and the presence of a phenyl ring were found to be associated with increased affinity at both CCK-A and CCK-B receptors.
Continued interest in the synthesis of potent, highly selective nonpeptide antagonists for the central (CCK-B) receptor has led to the development of this series of C-terminal analogues of CI-988.
Chapter one. Treatment of hydroxy and amido-containing allylsilanes with ceric ammonium nitrate yielded the corresponding analogs and substituted acyclic diols. All reactions were carried out in a ...1:1 mixture of a one molar aqueous ceric ammonium nitrate solution and acetonitrile at zero degrees. The products were isolated in moderate to high yields and were consistent with a radical cationic intermediate. These reactions, their application to natural product synthesis, the proposed mechanism and structural proofs are discussed. Chapter two. It is well established that the biological activity of vitamin D$\sb3$ is due to metabolic conversion to 1-alpha, 25-dihydroxyvitamin D$\sb3$, a hormone responsible not only for bone growth but for other types of cell division as well. A practical asymmetric synthesis of 1-alpha-OH vitamin D$\sb3$ analogs has been developed which utilizes a new ring A reagent. This new ring A reagent is prepared in optically active form starting from l-menthol. A variety of ketones can then be coupled to this chiral ring A reagent to yield 1-alpha-OH vitamin D$\sb3$ analogs which contain the critical hydroxytriene unit important for binding. These analogs can then be used as probes for the vitamin D$\sb3$ receptors and help to explore the broad range of biological activities of this class of hormones. The synthesis of this chiral ring A synthon and its application to the total synthesis of 1-alpha-OH vitamin D$\sb3$ analogs are discussed.
The synthesis and SAR of a series of (Z)-(±)-1-azabicyclo2.2.1heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are ...highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, ( R )-24Z (CI-1017).
