Discovery of 5-Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors.

SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors.

Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the Promoter G-Quadruplex and Downregulate .

is one of the most important oncogenes and is overexpressed in the majority of cancers. G-Quadruplexes are noncanonical four-stranded DNA secondary structures that have emerged as attractive cancer-specific molecular targets for drug development. The G-quadruplex formed in the proximal promoter region of the oncogene (MycG4) has been shown to be a transcriptional silencer that is amenable to small-molecule targeting for suppression.

Application of Sequential Palladium Catalysis for the Discovery of Janus Kinase Inhibitors in the Benzo[ c]pyrrolo[2,3- h][1,6]naphthyridin-5-one (BPN) Series.

The present account describes the discovery and development of a new benzo[ c]pyrrolo[2,3- h][1,6]naphthyridin-5-one (BPN) JAK inhibitory chemotype that has produced selective JAK inhibitors. Sequential palladium chemistry was optimized for the rapid access to a focused library of derivatives to explore the structure-activity relationships of the new scaffold. Several compounds from the series displayed potencies in the low nanomolar range against the four members of the JAK family with various selectivity profiles.

Synthesis of Benzo[1,6]naphthyridinones Using the Catellani Reaction.

An intramolecular version of the Catellani reaction was optimized for one-step synthesis of bulky N-substituted benzo[1,6]naphthyridinones with good to excellent yields. The optimized reaction of N-substituted o-bromobenzamides with 4-bromoquinolines features a wide substrate scope and yields of up to 98%. The employment of aryl bromides under carefully optimized conditions instead of the usual aryl iodides enhances the scope of the reaction.

Design, synthesis and molecular modeling study of certain 4-Methylbenzenesulfonamides with CDK2 inhibitory activity as anticancer and radio-sensitizing agents.

Two series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC values of 20.

Novel Fluoroindenoisoquinoline Non-Camptothecin Topoisomerase I Inhibitors.

Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135), and NSC 779134 (LMP134).

Ligand-free, palladacycle-facilitated Suzuki coupling of hindered 2-arylbenzothiazole derivatives yields potent and selective COX-2 inhibitors.

A similarity search and molecular modeling study suggested the 2'-aryl-2-arylbenzothiazole framework as a novel scaffold for the design of COX-2-selective inhibitors. Conventional Suzuki coupling conditions did not furnish the designed compounds in good yield from 2'-bromo-2-arylbenzothiazole as the starting material. A novel ligand-free Suzuki-Miyaura coupling methodology was developed for sterically hindered 2'-bromo-2-arylbenzothiazoles.

Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents That Inhibit Topoisomerase I.

The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model.

Isolation and characterization of Salmonella Enteritidis and Salmonella Typhimurium from chicken meat in Egypt.

Introduction: Salmonella enterica serovars Enteritidis and Typhimurium represent the major serovars associated with human salmonellosis. Contamination of meat products with these serovars is considered the main source of infection.

Methodology: In this study, 100 raw chicken meat samples were investigated for the presence of Salmonella spp.

Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl-DNA Phosphodiesterase 2 (Tdp2).

Tdp1 and Tdp2 are two tyrosyl-DNA phosphodiesterases that can repair damaged DNA resulting from topoisomerase inhibitors and a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase inhibitors. This study reports the successful structure-based design and synthesis of new 7-azaindenoisoquinolines that act as triple inhibitors of Top1, Tdp1, and Tdp2.

Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400).

Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents with two compounds in clinical trials. Recent metabolism studies of indotecan (LMP400) led to the discovery of the biologically active 2-hydroxylated analogue and 3-hydroxylated metabolite, thus providing strategically placed functional groups for the preparation of a variety of potential ester prodrugs of these two compounds. The current study details the design and synthesis of two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity.

Synthesis of indolo[4,3-]phenanthridine-6,11(2,12)-diones using the Schiff base-homophthalic anhydride cyclization reaction.

A novel indolophenanthridine ring system has been synthesized via the Schiff base-homophthalic anhydride cyclization followed by thionyl chloride-mediated dehydrogenation and intramolecular Friedel-Crafts acylation. This adds to the array of heterocyclic systems that are available through the cycloaddition reaction of imines with cyclic dicarboxylic acid anhydrides. The cytotoxicities of the indolophenanthridines were investigated in human cancer cell cultures, and the results documented significant antitumor activity in a variety of human cancer cell lines.

Applying ligands profiling using multiple extended electron distribution based field templates and feature trees similarity searching in the discovery of new generation of urea-based antineoplastic kinase inhibitors.

This study provides a comprehensive computational procedure for the discovery of novel urea-based antineoplastic kinase inhibitors while focusing on diversification of both chemotype and selectivity pattern. It presents a systematic structural analysis of the different binding motifs of urea-based kinase inhibitors and the corresponding configurations of the kinase enzymes. The computational model depends on simultaneous application of two protocols.

Structure-based design and synthesis of novel pseudosaccharine derivatives as antiproliferative agents and kinase inhibitors.

This study is concerned with the implementation of structure-based techniques for the design of new heterocyclic compounds based on pseudosaccharine scaffold with protein kinase inhibition activity. This nucleus was exploited based on the well-known quinazoline core and its interactions with several protein kinases. Two series of compounds employing this new scaffold were synthesized and evaluated at enzymatic and cellular levels.

New inhibitors of VEGFR-2 targeting the extracellular domain dimerization process.

We are reporting the discovery of small molecule inhibitors for vascular endothelial growth factor receptor type 2 (VEGFR-2) extracellular domain. The VEGFR-2 extracellular domain is responsible for the homo-dimerization process, which has been recently reported as a main step in VEGFR signal transduction cascade. This cascade is essential for the vascularization and survival of most types of cancers.