Imidazo[1,2-a]quinazolines as novel, potent EGFR-TK inhibitors: Design, synthesis, bioactivity evaluation, and in silico studies.

Tyrosine protein kinases (TKs) have been proved to play substantial roles on many cellular processes and their overexpression tend to be found in various types of cancers. Therefore, over recent decades, numerous tyrosine protein kinase inhibitors particularly epidermal growth factor receptor (EGFR) inhibitors have been introduced to treat cancer. Present study describes a novel series of imidazo[1,2-a]quinazolines 18 as potential -inhibitors. These imidazoquinazolines (18a and 18o, in particular) had great anti-proliferative activities with IC50 values in the micromolar (µM) range against PC3, HepG2, HeLa, and MDA-MB-231 comparing with Erlotinib as reference marketed drug. Further evaluations on some derivatives revealed their potential to induce apoptotic cell death and cell growth arrest at G0 phase of the cell cycle. Afterwards, the kinase assay on the most potent compounds 18a and 18o demonstrated their inhibitory potencies and selectivity toward EGFR (with EGFR-IC50 values of 82.0 µM and 12.3 µM, respectively). Additionally, western blot analysis on these compounds 18a and 18o exhibited that they inhibited the phosphorylation of EGFR and its downstream molecule extracellular signal-regulated kinase (ERK1/2). However, the level of B-Actin phosphorylation was not changed. Finally, density functional theory calculations, docking study, and independent gradient model (IGM) were performed to illustrate the structure-activity relationship (SAR) and to assess the interactions between proteins and ligands. The results of molecular docking studies had great agreement with the obtained EGFR inhibitory results through in vitro evaluations.

Thienopyrimidine-based agents bearing diphenylurea: Design, synthesis, and evaluation of antiproliferative and antiangiogenic activity.

An important role has been considered for the vascular endothelial growth factor receptor 2 (VEGFR-2) in the angiogenesis process, so that its inhibition is an important scientific way for cancer treatment. In this work, new thienopyrimidine derivatives were synthesized and evaluated. Compared with sorafenib, the majority of the target compounds had antiproliferative activity against the PC3, HepG2, MCF7, SW480, and HUVEC cell lines, especially 9h with IC50 values of 4.5-15.1 µM, confirming the noticeable cytotoxic effects on the listed cell lines (PC3, HepG2, SW480, and HUVEC). Analyses by flow cytometry on SW480 and HUVEC cells revealed that 9n, 9k, 9h, and 9q led to apoptotic cell death. The result of the chick chorioallantoic membrane assay showed that 9h effectively reduced the number of corresponding blood vessels. Finally, the inhibitory effect on VEGFR-2 phosphorylation was considered as the outcome of Western blot analysis of compound 9h.

Design, synthesis and evaluation of novel tetrahydropyridothienopyrimidin-ureas as cytotoxic and anti-angiogenic agents.

The novel derivatives of tetrahydropyridothienopyrimidine-based compounds have been designed and efficiently synthesized with good yields through seven steps reaction. The anticancer activity of compounds 11a-y has been evaluated against MCF-7, PC-3, HEPG-2, SW-480, and HUVEC cell lines by MTT assay. The target compounds showed IC50 values between 2.81-29.6 µg/mL and were compared with sorafenib as a reference drug. Among them, compound 11n showed high cytotoxic activity against four out of five examined cell lines and was 14 times more selective against MRC5. The flow cytometric analysis confirmed the induction of apoptotic cell death by this compound against HUVEC and MCF-7 cells. In addition, 11n caused sub-G1 phase arrest in the cell cycle arrest. Besides, this compound induced anti-angiogenesis in CAM assay and increased the level of caspase-3 by 5.2 fold. The western-blot analysis of the most active compound, 11n, revealed the inhibition of VEGFR-2 phosphorylation. Molecular docking study also showed the important interactions for compound 11n.

Dynamic (1)H NMR spectroscopic study of the ring inversion in N-sulfonyl morpholines--studies on N-S interactions.

The effect of the exocyclic conjugation, via d-p orbital interaction and/or negative hyperconjugation (anomeric effect) of the N-S bond, on the inversion of the morpholine ring in some N-arylsulfonyl morpholines is studied by variable-temperature (1)H NMR spectroscopy in different solvents. The observed free energy barriers are 9.2-10.3 kcal mol(-1); the lower values were obtained with increasing conjugation (substituents of higher electron withdrawing power) along the series. The barrier to ring inversion of 1e was solvent independent. X-ray data of compounds 1b,d reveal the chair conformation of the six-membered ring, the flattened pyramidal orientation of the ring nitrogen atom, and the sulfonyl group in equatorial position with the plane containing the C(aryl)-S-N bond perpendicular to the plane of the benzene ring. In addition, the sulfonamide group prefers a conformation with the S-C bond antiperiplanar with respect to the nitrogen atom lone pair and the -CH(2)-N-CH(2)- moieties in staggered conformation with the S-O bonds of the SO(2) group.

(31)P and (27)Al NMR studies of aqueous (2-hydroxyethyl) trimethylammonium solutions containing aluminum and phosphorus.

Phosphorus-31 and aluminum-27 nuclear magnetic resonance techniques have been used to characterize the distribution of soluble aluminophosphate species in aqueous solutions of (2-hydroxyethyl) trimethylammonium chloride (2-HETMACl), phosphoric acid, and aluminum sulfate. Soluble aluminophosphate cations obtain from reactions of hexaaqua aluminum cations [A1(H(2)O)(6)](3+), with phosphate ligands (i.e., H(3)PO(4), H(2)PO(4)(-), and acid dimers H(6)P(2)O(8) and H(5)P(2)O(7)(-)). (31)P NMR and (27)Al NMR spectroscopies are very powerful techniques for characterization of the species present in the solution. A number of solutions containing different mole ratio of Al/P were prepared. The assignment of the peaks to aluminate connectivities is attempted, clarifying earlier works and producing information on the equilibrium between various aluminum-containing species (different aluminophosphate complexes). At least seven separated resonances were observed by (31)P NMR spectroscopy indicating presence of different complexes in aluminum phosphate solutions.

Dynamic 1H NMR study of the barrier to rotation about the C-N bond in primary carbamates and its solvent dependence.

The dynamic 1H NMR study of some primary carbamates in the solvents CDCl3 and CD3COCD3 between 183 and 298 K is reported. The free energies of activation, thus obtained (12.4 to 14.3 kcal mol-1), were attributed to the conformational isomerization about the N-C bond. These barriers to rotation show solvent dependence in contrast to the tertiary analogues and are lower in free energy by ca. 2-3 kcal mol-1.

Anticholinesterase activity of some major intermediates in carbacylamidophosphate synthesis: preparation, spectral characterization and inhibitory potency determination.

Carbacylamidophosphates with the general formula RC(O)NHP(O)R1R2 constitute organophosphorus compounds that are used as insecticides, pesticides and ureas inhibitors. In this work, we studied the inhibition potency of CCl3-C(O)NHP(O)Cl21, CHCl2C(O)NHP(O)Cl(2)2, CH2ClC(O)NHP(O)Cl23 and CF3C(O)NHP(O)Cl(2)4, which are the major intermediates for carbacylamidophosphates synthesis towards human erythrocyte acetylcholinesterase (hAChe) activity using Ellman's modified kinetic method. Unexpectedly, it was observed that they were not only hydrolytically unstable but also inhibited hAChE in a similar manner to that produced by organophosphorus insecticides. Enzymatic data, bimolecular inhibition rate constants (ki) and IC50 values for inhibition of hAChE demonstrated that they are irreversible inhibitors and the inhibition potency of compound 2 (IC50 = 88 microM) was the greatest in comparison with compounds 1, 3 and 4. Also the electropositivity of the phosphorus atom and the hydrophobicity of the compounds demonstrated that these two factors play an additional effect and different role in the inhibitory activity of these compounds. Hydrolytic stability of the compounds was determined by 31P NMR monitoring of the loss of the parent molecules with D2O as a function of time. This study considers antiacetylcholinesterase activity according to the structural and the electronic aspects of compounds 1-4, according to IR, 1H, 13C and 31P NMR spectral data.