Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties.

Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor-related protein-1 (LRP1).

New Angiopep-modified doxorubicin (ANG1007) and etoposide (ANG1009) chemotherapeutics with increased brain penetration.

This report describes the synthesis and preliminary biological characterization of 2 (ANG1007) and 3 (ANG1009), two new chemical entities under development for the treatment of primary and secondary brain cancers. 2 consists of three doxorubicin molecules conjugated to Angiopep-2, a 19-mer peptide that crosses the blood-brain barrier (BBB) by an LRP-1 receptor-mediated transcytosis mechanism. 3 has a similar structure, with the exception that three etoposide moieties are conjugated to Angiopep-2.

A one-pot synthesis of (E)-disubstituted alkenes by a bimetallic [Rh-Pd]-catalyzed hydrosilylation/hiyama cross-coupling sequence.

A bimetallic [Rh-Pd] catalyst was prepared by soaking into an iodide ionic gel an equimolar solution of [RhCl(PPh(3))(3)] and Pd(OAc)(2) in CH(2)Cl(2). Its catalytic activity was evaluated by rhodium-catalyzed hydrosilylation (H), palladium-catalyzed Hiyama coupling (C), and in the one-pot hydrosilylation/Hiyama coupling sequence (H/C). It was found that the homogeneous combination [RhCl(PPh(3))(3)]/NaI was a superior system compared to the polyionic mono- and bimetallic rhodium catalysts in the hydrosilylation of terminal alkynes.

Rh soaked in polyionic gel: an effective catalyst for dehydrogenative silylation of ketones.

[Structure: see text] A polyionic gel-soaked Rh catalyst allows the formation of synthetically useful diphenylsilyl (DPS) enols under mild conditions. The reaction proceeds through dehydrogenative silylation of ketones, affording the kinetic silyl enol ether in good to excellent yields. The in situ formed DPS enols were directly involved, without purification, in one-pot aldol and Mannich condensations.