Lactam NH Research Articles

Synthon Polymorphism and π–π Stacking inN-Phenyl-2-hydroxynicotinanilides

A lactam–lactam dimer (LLD) and lactam NH···O═C (amide) catemer (LAC) are two competing motifs in N-phenyl-2-hydroxynicotinanilides (PHNAs). Steric effects play an important role in determining the...

Synthesis and evaluation of azalamellarin N and its A-ring-modified analogues as non-covalent inhibitors of the EGFR T790M/L858R mutant

Azalamellarin N, a synthetic lactam congener of the marine natural product lamellarin N, and its A-ring-modified analogues were synthesized and evaluated as potent and non-covalent inhibitors of the drug-resistant epidermal growth factor receptor T790M/L858R mutant. An in vitro tyrosine kinase assay indicated that the inhibitory activities of the synthetic azalamellarin analogues were higher than those of the corresponding lamellarins. The azalamellarin analogue bearing two 3-(dimethylamino)propoxy groups at C20- and C21-positions exhibited the highest activity and selectivity against the mutant kinase [IC50 (T790M/L858R) = 1.7 nM; IC50 (WT) = 4.6 nM]. The inhibitory activity was attributed to the hydrogen bonding interaction between the lactam NH group of the B-ring and carbonyl group of a methionine residue.

Synthesis, biological evaluation and molecular docking study of 1,2,3-1H-triazoles having 4H-pyrano[2,3-d]pyrimidine as potential Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors

Some heterocycles, namely 2-amino-4H-pyran-3-carbonitriles, were synthesized in a three-component reaction from substituted benzaldehydes, malononitrile, and ethyl acetoacetate. These heterocycles have been converted subsequently into 4H-pyrano[2,3-d]pyrimidine ring by ring-closing reaction with acetic anhydride in the presence of the concentrated sulfuric acid as catalyst. The successive alkylation reaction of lactam NH bond on pyrimidine-4-one ring was carried out using propargylic bromide in dry acetone in the presence of anhydrous potassium carbonate. The click chemistry of 3-propargyl-4H-pyrano[2,3-d]pyrimidine compounds has been accomplished by reaction with tetra-O-acetyl-α-d-glucopyranosyl azide using the metal-organic framework Cu@MOF-5 as a catalyst in absolute ethanol. All the synthesized 1H-1,2,3-triazoles 8a–y were screened for their in vitro Mycobacterium tuberculosis protein tyrosine phosphatase B (MtbPtpB) inhibition. Kinetic studies of the most active compounds 8v, 8x, and 8y showed their competitive inhibition toward the MtbPtpB enzyme. The detailed structure-activity relationship (SAR) in vitro and in silico studies suggested that the interaction of Arg63 amino acids with anion type of para-hydroxyl group via a salt bridge of iminium cation was essential for strong inhibitory activity against MtbPtpB.

Pterin-based highly selective, ratiometric, and sensitive ‘naked-eye’ sensor for acetate

The design and synthesis of a new pterin-based ratiometric and sensitive ‘naked-eye’ sensor R for highly selective recognition of acetate are reported. The acidic lactam NH and the NH of 2-N-pivaloyl group of receptor R along with 2,4-dinitrophenyl hydrazone group having the other acidic NH moiety lead to the binding of acetate anion in a 1:2 ratio by change of spectroscopic behavior on complexation (UV–vis and 1H NMR studies) which is also proven by Job plot. The sharp color change from light yellow to violet promises R to be a useful chromogenic ratiometric sensor for acetate amongst other common anions.

Exploring the Anticancer Activity of Functionalized Isoindigos: Synthesis, Drug‐like Potential, Mode of Action and Effect on Tumor‐Induced Xenografts

Meisoindigo has been used as an indirubin substitute for the treatment of chronic myeloid leukemia (CML) for several years. In view of its poor solubility and erratic absorption, several investigations have focused on developing analogues with more desirable physicochemical profiles. Here, we investigated the structure-activity relationship (SAR) of meisoindigo with respect to its antiproliferative activity on leukemic K562 cells and found that appending a phenalkyl side chain onto the lactam NH resulted in analogues that retained good activity. Furthermore, analogues in which the phenyl ring was substituted with a basic heterocycle were significantly more soluble than meisoindigo while retaining acceptable antiproliferative profiles. The most promising analogue (E)-1-(2-(4-methylpiperazin-1-yl)ethyl)-[3,3'-biindolinylidene]-2,2'-dione (5-4) is more potent than meisoindigo across a panel of malignant cells, with at least 40 times greater solubility than meisoindigo, little or no tendency to aggregate in solution and capable of significantly extending the lifespans of animals with K562 induced xenografts. Mechanistically, it induced apoptotic cell death and disrupted the progression of K562 cells from the G(1) to G(2) phase. Taken together, our findings highlighted the feasibility of addressing the physicochemical deficits of the isoindigo scaffold by systematic modifications which was achieved without overt loss of growth inhibitory activity.

Synthesis and evaluation of functionalized isoindigos as antiproliferative agents

A series of functionalized isoindigos structurally related to meisoindigo (1-methylisoindigo), a therapeutic agent used for the treatment of a form of leukemia, were synthesized and evaluated for antiproliferative activities on a panel of human cancer cells. Two promising compounds (1-phenpropylisoindigo and 1-( p-methoxy-phenethyl)-isoindigo) that were more potent than meisoindigo and comparable to 6-bromoindirubin-3′-oxime on leukemic K562 and liver HuH7 cells were identified. Structure–activity relationships showed the importance of keeping one of the lactam NH in an unsubstituted state. Substitution of the other lactam NH with aryl or arylalkyl side chains retained or improved activity in most instances. An intact exocyclic double bond was also essential, possibly to maintain planarity and rigidity of the isoindigo scaffold. None of the compounds were found to inhibit CDK2 in an in vitro assay, in spite of reports linking the antiproliferative activities of meisoindigo and other isoindigos to CDK2 inhibition. Hence, these functionalized isoindigos disrupted cell growth and proliferation by other mechanistic pathways that did not involve CDK2 inhibition.

An investigation of the hydrogen-bonding structure in bilirubin by 1H double-quantum magic-angle spinning solid-state NMR spectroscopy.

The complex hydrogen-bonding arrangement in the biologically important molecule bilirubin IXalpha is probed by using 1H double-quantum (DQ) magic-angle spinning (MAS) NMR spectroscopy. Employing fast MAS (30 kHz) and a high magnetic field (16.4 T), three low-field resonances corresponding to the different hydrogen-bonding protons are resolved in a 1H MAS NMR spectrum of bilirubin. These resonances are assigned on the basis of the proton-proton proximities identified from a two-dimensional rotor-synchronized 1H DQ MAS NMR spectrum. An analysis of 1H DQ MAS spinning-sideband patterns for the NH protons in bilirubin allows the quantitative determination of proton-proton distances and the geometry. The validity of this procedure is proven by simulated spectra for a model three-spin system, which show that the shortest distance can be determined to a very high degree of accuracy. The distance between the lactam and pyrrole NH protons in bilirubin is determined to be 0.186 +/- 0.002 nm (corresponding to a dominant dipolar coupling constant of 18.5 +/- 0.5 kHz). The analysis also yields a distance between the lactam NH and carboxylic acid OH protons of 0.230 +/- 0.008 nm (corresponding to a perturbing dipolar coupling constant of 9.9 +/- 1.0 kHz) and an H-H-H angle of 122 +/- 4 degrees. Finally, a comparison of 1H DQ MAS spinning-sideband patterns for bilirubin and its dimethyl ester reveals a significantly longer distance between the two NH protons in the latter case.

Intramolecular hydrogen bonding between remote termini

[10]-Semirubin ( 1) and [20]-semirubin ( 2), with dipyrrinones covalently linked to C 10 and C 20 fatty acid chains, were synthesized following Friedel–Crafts acylation of the parent 9-H dipyrrinone, (4 Z)-2,3,7,8-tetramethyl-(10 H)-dipyrrin-1-one, with the diacid chlorides of decanedioic acid and eicosanedioic acid, respectively. Both of these bright yellow pigments are monomeric in CHCl 3 solvent: MW obs=394±20 for 1 (formula weight 386), and 533±20 for 2 (formula weight 526) as determined by vapor pressure osmometry (VPO) measurements. In contrast, their methyl esters are dimeric in CHCl 3. 1H{ 1H}-Nuclear Overhauser effects are found between the lactam NH and carboxylic acid OH of 1 and 2, consistent with the type of intramolecular hydrogen bonding found in bilirubin (the yellow pigment of jaundice) and its analogs.

Steroidal alkenylphosphonates via palladium-catalyzed coupling reactions

The palladium-catalyzed coupling of various 17-iodo- Δ 16 steroids (17-iodo-androst-16-ene, 17-iodo-4-methyl-4-aza-androst-16-en-3-one, and 17-iodo-4-aza-androst-16-en-3-one) with dialkyl phosphites (dimethyl phosphite, diethyl phosphite, and diisopropyl phosphite) was examined in detail. The only successful condition for homogeneous coupling involved carrying out the reaction in the absence of any solvents. A large excess of dialkyl phosphite was used, which means that the phosphite itself acted as a solvent. Eight new androst-16-ene derivatives with phosphonate groups at C-17 were synthesized and characterized. These steroids are of pharmacological interest as potential 5α-reductase inhibitors. Under the same conditions, methylation of lactam NH was observed using dimethyl phosphite.

Reactivity of pyrrole pigments, part 13: Identification of the reaction product generated from bile pigments by the superoxide anion

The UV/Vis spectra of the conjugated bases (NH deprotonation) of biliverdin IX α (BV), mesobiliverdin IX α (MBV), biliverdin IX α dimethyl ester (BV -DME) and mesobiliverdin IX α dimethyl ester (MBV - DME) are shown. They resemble those obtained for the reaction products of these biliverdins with superoxide anion ( $$o_2^{\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle\cdot}$}}{ - } } $$ ). These results confirm that the bile pigments react with $$o_2^{\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle\cdot}$}}{ - } } $$ giving the lactam NH deprotonated conjugated bases and inducing $$o_2^{\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle\cdot}$}}{ - } } $$ dismutation. The spectrometric titrations ofBV, MBV and their dimehyl esters show that the lactam NH of the vinyl substituted biliverdins is more acidic (ΔpK a ℞0.5). The spectra of the lactam NH bisdeprotonated conjugated bases of the bilatrienes-abc studied (BV 4− andMBV 4−) can be obtained inDMSO/H2O/OH− systems of high basicity function (H−℞23). Because of the low oxidation potentials ofBV 3− and of the corresponding trianion of bilirubin IX α (studied by voltammetry) an alternative metabolic degradative pathway is suggested for bilirubin, involving the interaction in lipophilic media with $$o_2^{\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle\cdot}$}}{ - } } $$ and oxidation of the conjugated base generated by NH deprotonation.

Nuclear magnetic resonance studies of the conformation of bilirubin and its derivatives in solution

Selective and non-selective spin–lattice relaxation times (T1), nuclear Overhauser enhancements (NOE), and rates of exchange of protons in bilirubin and related compounds in chloroform solutions were measured. The NOE observed between methyl and methine protons and between lactam and pyrrole NH protons indicate that the configuration within the pyrromethenone units is exclusively syn-Z. An NOE was also observed between the protons of the carboxylic acid and the lactam NH groups of mesobilirubin. The selective T1 relaxation times, NOE values of the protons, and correlation times calculated from carbon-13 relaxation data were used for the calculation of interproton distances. These distances, as well as the extremely slow rates of exchange of the pyrrole NH protons, establish the presence of hydrogen bonds between the carboxy-residues and the lactam and pyrrole NH groups of mesobilirubin in chloroform solutions. The T1 values, chemical shifts, and rates of proton exchange in bilirubin are similar to those of mesobilirubin, indicating that the same conformation occurs for the two compounds. The conformation of bilirubin dimethyl ester is very different from that of bilirubin and mesobilirubin. It is present as a dimer even at concentrations as high as 0.17M. The proton exchange rates of both the lactam and pyrrole NH groups of bilirubin dimethyl ester are slightly slower than in a model pyrromethenone compound.

Studies on Prototropic Tautomerism in Nitrogen Heterocyclic Compounds. I. The Mannich Reaction of 2(1H)-Pyridone and 3-Hydroxy-2(1H)-pyridone

The Mannich reaction of 3-hydroxy-2 (1H)-pyridone, in which both a phenolic OH and a lactam NH are present in a molecule, was examined, and 3-hydroxy-6-piperidinomethyl-2(1H)-pyridone (IXa) and 3-hydroxy-4, 6-bis (piperidinomethyl)-2(1H)-pyridone (X) were obtained in 82 and 5% yields, respectively. The reaction of IXa with the cyclohexanone pyrrolidine enamine gave 4a, 7-dihydroxy-1, 2, 3, 4, 4a, 10a-hexahydrobenzo [b] indolizin-6 (10H)-one (XVI) in 82% yield.