Recent developments in bisintercalator natural products

Abstract

The bisintercalator natural products are a family of nonribosomal peptides possessing a range of biological properties that include antiviral, antibiotic, and anticancer activities. The name bisintercalator is derived from the ability to directly bind to duplex DNA through two planar intercalating moieties. Although 19 members of this family of compounds have been identified over the past 50 years, the biosynthetic genes responsible for the formation of four of these molecules (thiocoraline, SW‐163, triostin A, and echinomycin) were identified only recently. This recent progress opens an avenue towards understanding how Nature produces these bisintercalating products and provides the potential to develop and identify novel potent analogous lead compounds for clinical applications. This review discusses the mode of action of bisintercalators and summarizes recent genetic and biochemical insights into their biosynthetic production, analog formation, and possible mechanisms by which resistance to these compounds is achieved by their producing organisms. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 777–790, 2010.

Solid-Phase Synthesis of Triostin A Using a Symmetrical Bis(diphenylmethyl) Linker System

“…The solvent was removed under a vacuum, and the residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane as the eluent to afford the desired product 8 (6.1 g, 78% yield). 1 3,5-Bis(2-(4-(hydroxy(phenyl)methyl)phenoxy)ethoxy)benzoic acid (9). The compound 8 (6.0 g, 9.74 mmol) was dissolved in methanol/toluene (2:1) and cooled to 0°C.…”

Synthesis and Antiproliferative Activity Evaluation of the Disulfide-Containing Cyclic Peptide Thiochondrilline C and Derivatives

“…The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 20:80) to give 12 (590 mg, 68%) as a white solid: mp 108−109°C; 1 Boc-N-Me-L-Cys(Trt)-OH (14). To a solution of NaH (60% in mineral oil, 432 mg, 10.8 mmol) in THF (10 mL) was added BocCys(Trt)-OH (2.0 g, 4.32 mmol) in THF (3 mL) dropwise at 0−5°C.…”

“…1 However, clinical advancement of echinomycin for the treatment of cancer has been hindered by significant dose-limiting toxicities. 2 One of the primary obstacles in surpassing this hurdle has been inadequate availability of derivatives that would permit extensive structure−activity relationship (SAR) studies to be conducted in order to optimize the selective toxicity for malignant cells and to improve physiochemical and absorption, distribution metabolism, and excretion (ADME) properties.…”

DNA as a target for antimicrobials

“…Many of these are isolated from Streptomyces spp., but some are produced by other bacteria. All of these contain a peptide core that that is decorated with two intercalating planar aromatic groups, being quinoxaline-2-carboxylic acid in echinomycin and triostin A, or 3-hydroxyquinaldic acid in sandramycin [9].…”