Identification of a selective small molecule inhibitor of breast cancer stem cells.

A high-throughput screen (HTS) with the National Institute of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) compound collection identified a class of acyl hydrazones to be selectively lethal to breast cancer stem cell (CSC) enriched populations. Medicinal chemistry efforts were undertaken to optimize potency and selectivity of this class of compounds. The optimized compound was declared as a probe (ML239) with the NIH Molecular Libraries Program and displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control line (HMLE_sh_GFP).

GS-nitroxide (JP4-039)-mediated radioprotection of human Fanconi anemia cell lines.

Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Clinically, FA is associated with high risk for marrow failure, leukemia and head and neck squamous cell carcinoma (HNSCC). Radiosensitivity in FA patients compromises the use of total-body irradiation for hematopoietic stem cell transplantation and radiation therapy for HNSCC.

Synthesis of a novel suppressor of beta-cell apoptosis via diversity-oriented synthesis.

The synthesis of a stereochemically diverse library of medium-sized rings accessible via a 'build/couple/pair' strategy is described. Key aspects of the synthesis include S(N)Ar cycloetherification of a linear amine template to afford eight stereoisomeric 8-membered lactams and subsequent solid-phase diversification of these scaffolds to yield a 6488-membered library. Screening of this compound collection in a cell-based assay for the suppression of cytokine-induced beta-cell apoptosis resulted in the identification of a small-molecule suppressor capable of restoring glucose-stimulated insulin secretion in a rat beta-cell line.

Synthetic studies of heterocyclic natural products.

Recent reports of the syntheses of heterocyclic natural products that are isolated from bacteria, fungi, plants and marine sources are discussed. This review emphasizes new developments in synthetic methodology and strategies for such products, and the potential biological activity of the metabolites that are described is highlighted. Concepts of conformational analysis, stereoelectronic control and reaction mechanism are all used in the development of new methodology.

A regio- and stereoselective approach to quaternary centers from chiral trisubstituted aziridines.

A thorough investigation of a regio- and stereospecific aziridine ring opening reaction presents new synthetic technology for the construction of a variety of quaternary beta-substituted-alpha-amino functional groups. Mild, metal-free reaction conditions allow for application in highly functionalized systems. This reaction has been applied to the challenging stereoselective formation of tertiary alkyl-aryl ethers.

Trisubstituted aziridine ring-opening by phenol derivatives: stereo- and regioselective formation of chiral tertiary alkyl-aryl ethers.

An unprecedented stereo- and regioselective trisubstituted aziridine ring-opening by phenol derivatives was discovered. The reaction features very mild reaction conditions and broad functional group compatibility, which provides a good method for the stereoselective formation of tertiary alkyl-aryl ethers in highly functionalized systems. [reaction: see text]

Total synthesis and biological evaluation of ustiloxin natural products and two analogs.

Synthetic investigations of ustiloxin natural products are described. The first total synthesis of ustiloxin F was completed in 15 steps via ethynyl aziridine ring-opening by a phenol derivative. The results of biological tests of synthetic ustiloxins D and F, and two analogs, O-Me-ustiloxin D and 6-Ile-ustiloxin, demonstrated that the free hydroxyl group ortho to the ether linkage is critical for activity and variations at the Val/Ala site produce changes in the biological activity suggesting the need for further perturbations at this site to more extensively study the tubulin binding.