Anthranilamide Derivatives Research Articles

Synthesis, antiproliferative activity, and mechanism of action of a series of 2-{[(2 E)-3-phenylprop-2-enoyl]amino}benzamides

Several new 2-{[(2 E)-3-phenylprop-2-enoyl]amino}benzamides 12a–s and 17t–v were synthesized by stirring in pyridine the ( E)-3-(2-R1-3-R2-4-R3-phenyl)acrylic acid chlorides 11c–k and 11t–v with the appropriate anthranilamide derivatives 10a–c or the 5-iodoanthranilic acid 13. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). COMPARE analysis, effects on tubulin polymerization in cells and with purified tubulin, and effects on cell cycle distribution for 17t, the most active of the series, indicate that these new antiproliferative compounds act as antitubulin agents.

Theoretical design of bioinspired macromolecular electrets based on anthranilamide derivatives

Polypeptide helices possess considerable intrinsic dipole moments oriented along their axes. While for proline helices the dipoles originate solely from the ordered orientation of the amide bonds, for 3(10-) and alpha-helices the polarization resultant from the formation of hydrogen-bond network further increases the magnitude of the macromolecular dipoles. The enormous electric-field gradients, generated by the dipoles of alpha-helices (which amount to about 5 D per residue with 0.15 nm residue increments along the helix), play a crucial role in the selectivity and the transport properties of ion channels. The demonstration of dipole-induced rectification of vectorial charge transfer mediated by alpha-helices has opened a range of possibilities for applications of these macromolecules in molecular and biomolecular electronics. These biopolymers, however, possess relatively large bandgaps. As an alternative, we examined a series of synthetic macromolecules, aromatic oligo-ortho-amides, which form extended structures with amide bonds in ordered orientation, supported by a hydrogen-bond network. Unlike their biomolecular counterparts, the extended pi-conjugation of these macromolecules will produce bandgaps significantly smaller than the polypeptide bandgaps. Using ab initio density functional theory calculations, we modeled anthranilamide derivatives that are representative oligo-ortho-amide conjugates. Our calculations, indeed, showed intrinsic dipole moments oriented along the polymer axes and increasing with the increase in the length of the oligomers. Each anthranilamide residue contributed about 3 D to the vectorial macromolecular dipole. When we added electron donating (diethylamine) and electron withdrawing (nitro and trifluoromethyl) groups for n- and p-doping, respectively, we observed that: (1) proper positioning of the electron donating and withdrawing groups further polarized the aromatic residues, increasing the intrinsic dipole to about 4.5 D per residue; and (2) extension of the pi-conjugation over some of the doping groups narrowed the band gaps with as much as 1 eV. The investigated bioinspired systems offer alternatives for the development of broad range of organic electronic materials with nonlinear properties.

Amino acid anthranilamide derivatives as a new class of glycogen phosphorylase inhibitors

A series of amino acid anthranilamide derivatives identified from a high-throughput screening campaign as novel, potent, and glucose-sensitive inhibitors of human liver glycogen phosphorylase a are described. A solid-phase synthesis using Wang resin was also developed which provided efficient access to a variety of analogues, and resulted in the identification of key structure–activity relationships, and the discovery of a potent exemplar (IC 50 = 80 nM). The SAR scope, synthetic strategy, and in vitro results for this series are presented herein.

Synthesis and Cav2.2 Binding Data for Non-Peptide Mimetics of ω-Conotoxin GVIA based on a 5-Amino-Anthranilamide Core

A simple and efficient method has been developed for the synthesis of two anthranilamide-based non-peptide mimetics of ω-conotoxin GVIA. These anthranilamide derivatives aim to mimic the K2, R17, and Y13 residues of the peptide. The synthetic route described enables the rapid synthesis of anthranilamide analogues with identical alkyl chain lengths. The target compounds show affinity to rat N-type voltage gated calcium channels (Cav2.2) with EC50 values of 42 and 75 μM.

A Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) of Anthranilamide Derivatives That Are Multidrug Resistance Modulators

In a continuing effort to develop potent and selective modulators of P-glycoprotein (P-gp) activity overcoming the chemoresistance acquired by tumor cells during cancer chemotherapy, we developed 3D quantitative structure-activity relationship (3D QSAR) models using CoMFA and CoMSIA analyses. This study correlates the P-glycoprotein inhibitory activities of 49 structurally related anthranilamide derivatives to several physicochemical parameters representing steric, electrostatic, acceptor, donor, and hydrophobic fields. Both CoMFA and CoMSIA models using three different alignment conformations gave good internal predictions, and their cross-validated r2 values are between 0.503 and 0.644. These most comprehensive CoMFA and CoMSIA models are useful in understanding the structure-activity relationships of anthranilamide derivatives as well as aid in the design of novel derivatives with enhanced modulation of P-gp activity.

Hydrogen bonding-mediated self-assembly of rigid and planar metallocyclophanes and their recognition for mono- and disaccharides

A hydrogen bonding approach has been developed to facilitate the self-assembly of a new series of rigid and planar metallocyclophanes. Two new anthranilamide derivatives 1 and 2 , which are incorporated with two acetylene units, respectively, have been synthesized and characterized. X-ray analysis (for 1 ), 1D and 2D 1H NMR and IR experiments reveal that, due to the formation of intramolecular three-centered hydrogen bonding, both compounds adopt rigid and planar conformations with the two acetylene units located at the same side of the anthranilamide skeleton. Two new metallocyclophanes 17 and 18 have been constructed in moderate yields from the reaction of 1 and 2 with trans-Pt(PEt 3) 2Cl 2, respectively, in dichloromethane in the presence of diethylamine and cupric chloride. Fluorescent and 1H NMR investigations reveal that both 17 and 18 can efficiently complex mono- and disaccharide derivatives in chloroform, with a binding selectivity for disaccharides, which is driven by intermolecular hydrogen bonding.

Muscarinic M2 antagonists: anthranilamide derivatives with exceptional selectivity and in vivo activity

Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity.

ChemInform Abstract: Reversal of P‐Glycoprotein Mediated Multidrug Resistance by Novel Anthranilamide Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives

We have synthesised and evaluated a series of anthranilamide based modulators of P-glycoprotein. These studies have identified XR9576( 2), a potent inhibitor of P-glycoprotein in vitro and in vivo. The general synthesis and the SAR of these compounds are described.

ChemInform Abstract: NI15501A, a Novel Anthranilamide Derivative from a Marine Fungus Penicillium sp.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

NI15501A, a novel anthranilamide derivative from a marine fungus Penicillium sp.

NI15501A, a novel anthranilamide derivative from a marine fungus Penicillium sp.

Novel Folding Patterns in a Family of Oligoanthranilamides: Non-Peptide Oligomers That Form Extended Helical Secondary Structures

Anthranilamide derivatives are used as the basis for a series of novel oligomers that fold into helical secondary structures in the solid state. When combined with pyridine-2,6-dicarboxylic acid and 4,6-dimethoxy-1,3-diaminobenzene subunits, oligoanthranilamides can be induced to take up a coiled conformation corresponding to two turns of a helix. X-ray crystallography shows that intramolecular hydrogen bonding and π−π stacking interactions are important in stabilizing the extended helical structures. Furthermore, both experimental and calculated 1H NMR methods indicate that related conformations are taken up by the oligomers in chloroform solution.

Mono-N-alkylation of anthranilamides via quinazolinones. An efficient synthesis of G5598, a benzodiazepine dione gpIIbIIIa antagonist

The mono-N-alkylation of an anthranilamide derivative via the reductive ring opening of a quinazolinone precursor, enables the synthesis of benzodiazepine dione derivative G5598, a potent inhibitor of the in vitro binding of GpIIbIIIa to fibrinogen.