121706-11-4Relevant academic research and scientific papers
Synthesis, conformation and PKC isozyme surrogate binding of indolinelactam-Vs, new conformationally restricted analogues of (-)-indolactam-V
Nakagawa, Yu,Irie, Kazuhiro,Komiya, Yusuke,Ohigashi, Hajime,Tsuda, Ken-Ichiro
, p. 7077 - 7084 (2004)
New conformationally restricted analogues of tumor promoter (-)-indolactam-V (1), indolinelactam-Vs (8, 11) and their hexyl derivatives at position 1 or 7 (9, 10, 12, 13), were synthesized from 1. (3R)-Indolinelactam-V (8) adopted a conformation similar to the twist form of 1 with a cis amide, while the conformation of (3S)-indolinelactam-V (11) was close to that of the sofa form of 1 with a trans amide. 7-Hexyl derivatives of 8 and 11 (10, 13) showed binding affinities for C1 domains of protein kinase C (PKC) isozymes compared to 1, but exhibited little selectivity among these PKC isozymes. However, introduction of the hexyl group at position 1 of 8 and 11 significantly enhanced their binding selectivity for novel PKC isozymes. The best selectivity for novel PKC isozymes was observed in (3S)-1-hexylindolinelactam-V (12) with a sofa-like conformation. These results suggest that a sofa-restricted analogue of 1 with a hydrophobic chain at an appropriate position would be a promising lead for designing agents with a high selectivity for novel PKC isozymes.
Synthetic Indolactam V Analogues as Inhibitors of PAR2-Induced Calcium Mobilization in Triple-Negative Breast Cancer Cells
Stein, Jan,Stahn, Sonja,Neud?rfl, J?rg-M.,Sperlich, Julia,Schmalz, Hans-Günther,Teusch, Nicole
, p. 147 - 154 (2018/02/06)
Human proteinase-activated receptor 2 (PAR2), a transmembrane G-protein-coupled receptor (GPCR), is an attractive target for a novel anticancer therapy, as it plays a critical role in cell migration and invasion. Selective PAR2 inhibitors therefore have potential as anti-metastatic drugs. Knowing that the natural product teleocidin A2 is able to inhibit PAR2 in tumor cells, the goal of the present study was to elaborate structure–activity relationships and to identify potent PAR2 inhibitors with lower activity against the adverse target, protein kinase C (PKC). For this purpose, an efficient gram-scale total synthesis of indolactam V (i.e., the parent structure of all teleocidins) was developed, and a library of derivatives was prepared. Some compounds were indeed found to exhibit high potency as PAR2 inhibitors at low nanomolar concentrations with improved selectivity (relative to teleocidin A2). The pseudopeptidic fragment bridging the C3 and C4 positions of the indole core proved to be essential for target binding, whereas activity and target selectivity depends on the substituents at N1 or C7. This study revealed novel derivatives that show high efficacy in PAR2 antagonism combined with increased selectivity.
Synthesis and Biological Studies of Simplified Analogues of Lyngbyatoxin A: Use of an Isoxazoline-Based Indole Synthesis. Quest for Protein Kinase C Modulators
Kozikowski, Alan P.,Sato, Kazuo,Basu, Alakananda,Lazo, John S.
, p. 6228 - 6234 (2007/10/02)
Efficient synthetic routes to optically active analogues of lyngbyatoxin A, a potent activator of protein kinase C, have been devised starting from L-valine methyl ester.Access to the indole nucleus of these molecules is gained through the nitrile oxide based annelation of an aromatic ring to a pyrrole ring.The biological action of several of the intermediates and analogues preparated during the course of these studies on protein kinase C activity is also presented.
