Utility of copper(II) oxide as a packed reactor in flow injection assembly for rapid analysis of some angiotensin converting enzyme inhibitors

A new simple, sensitive, rapid and precise flow injection (FI) procedure based on the formation of copper complexes with some angiotensin converting enzyme (ACE) inhibitors has been developed and evaluated for the analysis of lisinopril (LN), enalapril maleate (EP), ramipril (RP) and perindopril tert-butylamine (PD). In this method, samples were injected into a flowing stream of distilled-deionized water, carried through the packed reactor of CuO for derivatization followed by ultraviolet (UV) detection. The flow rate was 1.5 ml min⁻¹ and column temperature was ambient (25 °C). Lisinopril was injected directly into the flowing stream and the detector response was measured at 262 nm. The hydrolysis products of enalapril maleate, ramipril and perindopril tert-butylamine in 0.2N NaOH were injected after neutralization with 1N HCl and the detector response was measured at 272, 265 and 252 nm, respectively. The developed method was successfully applied to the determination of tested drugs in pharmaceutical preparations at a sampling rate of 60 samples h⁻¹ and a recovery near 100% for all compounds.     

Synthesis of functionally diverse bicyclic sulfonamides as constrained proline analogues and application to the design of potential thrombin inhibitors

Bicyclic sulfonamides were synthesized from 4-alkenyl N-alkenylsulfonyl l-prolines using a ring-closure metathesis reaction. Three types of bicyclic sulfonamides varying in the size of the second ring (5,5; 5,6; 5,7) were synthesized. A sulfonamide counterpart of an indolizidinone 2-carboxylic acid was synthesized and evaluated for its activity against the enzyme thrombin.     

X=Y=ZH Systems as potential 1,3-dipoles. Part 58: Cycloaddition route to chiral conformationally constrained (R)-pro-(S)-pro peptidomimetics

Imines of (1S,9S)-t-butyl-9-amino-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate undergo thermal (toluene, 110°C) or LiBr-DBU catalysed (MeCN, room temperature) regio- and stereo-specific cycloaddition to a range of chiral dipolarophiles giving enantiopure spiro-cycloadducts in excellent yield. The reactions proceed via intermediate NH azomethine ylides and litho azomethine ylides, respectively and results in the multiplication of chiral centres from 2 (one of which is lost in the process) to 5.     

Reverse zymography using fluorogenic substrates for protease inhibitor detection

A novel, sensitive method for detecting protease inhibitors by using fluorescent protease substrates in gels is described. The protease inhibitors were separated on sodium dodecyl sulfate (SDS)-polyacrylamide gels containing a copolymerized peptide substrate, namely 4-methyl-coumaryl-7-amide (MCA). As the incorporated substrates in the gel, Boc-Phe Ser-Arg-MCA was used for trypsin, Suc-Ala-Ala-Pro-Phe-MCA for alpha-chymotrypsin, and Z-Phe-Arg-MCA for papain. After electrophoresis, washing and incubating the gel with the target protease solutions allowed the substrate to be cleaved by the protease, and the release of the fluorescent 7 amino-4 methyl-coumarin (AMC), which was detected under a UV transilluminator. The uncleaved peptide-MCA substrate remained where the inhibitors were present, and was visualized as dark blue bands on the light-green fluorescent background gel. This new method offers several advantages over other previous methods including: (i) greatly increased sensitivity can be achieved in a shorter period of time, which may be useful for discovering new protease inhibitors in small amounts of crude material; (ii) the procedure is quite simple and quick since the incubation period is very short and no time is needed for staining and destaining steps; (iii) since these probes using substrate specificity/target proteases, they are excellent tools for detection and discrimination of unknown protease inhibitors for various target proteases.     

Lipophilicity in PK design: methyl, ethyl, futile

Lipophilicity, often expressed as distribution coefficients (log D) in octanol/water, is an important physicochemical parameter influencing processes such as oral absorption, brain uptake and various pharmacokinetic (PK) properties. Increasing log D values increases oral absorption, plasma protein binding and volume of distribution. However, more lipophilic compounds also become more vulnerable to P450 metabolism, leading to higher clearance. Molecular size and hydrogen bonding capacity are two other properties often considered as important for membrane permeation and pharmacokinetics. Interrelationships among these physicochemical properties are discussed. Increasing size (molecular weight) often gives higher potency, but inevitably also leads to either higher lipophilicity, and hence poorer dissolution/solubility, or to more hydrogen bonding capacity, which limits oral absorption. Differences in optimal properties between gastrointestinal absorption and uptake into the brain are addressed. Special attention is given to the desired lipophilicity of CNS drugs. In examples using -blockers, Ca channel antagonists and peptidic renin inhibitors we will demonstrate how potency and pharmacokinetic properties need to be balanced.     

2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant

Extensive structure-activity relationships (SARs) study of JND3229 was conducted to yield a series of new reversible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFR^C797S inhibitors. One of the most potent compound 6i potently suppressed EGFR^{L858R/T790M/C797S} kinase with an IC₅₀ value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFR^{L858R/T790M/C797S} and EGFR^{19D/T790M/C797S} mutants with IC₅₀ values of 290 nmol/L and 316 nmol/L, respectively. Further, 6i dose-dependently induced suppression of the phosphorylation of EGFR^{L858R/T790M/C797S} and EGFR^{19D/T790M/C797S} in BaF3 cells. Compound 6i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.     

Total syntheses of hyacinthacine A2 and 7-deoxycasuarine by cycloaddition to a carbohydrate derived nitrone

Practical syntheses of nitrone 8 by two different approaches from sugars are reported. Its use as a versatile intermediate in highly selective 1,3-dipolar cycloaddition reactions constitutes the key step for novel total syntheses of hyacinthacine A₂ (3) and 7-deoxycasuarine (20) by simple transformations of a common isoxazolidine adduct.     

Trihydroxy-2-thiaquinolizidine derivatives as a new class of bicyclic glycosidase inhibitors

Trihydroxy-2-thiaquinolizidines, a new class of bicyclic dideoxy-iminohexitol glycosidase inhibitor derivatives with nominally the d-gluco, l-ido, d-manno and l-gulo configurations were synthesized. X-ray analyses indicated that the preferred conformation for d-gluco and d-manno derivatives was a flat trans-fused system. Unlike deoxynojirimycin, the compound with d-gluco configuration was selective for α-glucosidases (yeast and rice) and showed no inhibitory activity towards β-glucosidase (almond), α-galactosidase (green coffee beans), α-galactosidase (E. coli) and α-mannosidase (jack bean), while the l-ido derivative was specific for β-glucosidase (almond).     

Synthesis of granulatimide analogues bearing a maleimide instead of an imidazole heterocycle

A synthesis in a few steps of a new family of granulatimide analogues was performed. In the new compounds, the aromatic framework of granulatimide is modified by replacement of the imidazole unit by a maleimide moiety. The synthesis of a water-soluble analogue is also presented.