The Preparation of Macrocyclic Calpain Inhibitors by Ring Closing Metathesis and Cross Metathesis

Abstract

Ring closing metathesis and cross metathesis approaches to a new macrocyclic peptidomimetic aldehyde 2 have been developed, with the former route being the most convenient. Aldehyde 2 is a potent inhibitor of calpain II (IC50 of 45 nM) with comparable activity to the benchmark acyclic inhibitor SJA6017 4. Both compounds contain an N-terminal 4-fluorophenylsulfonyl group. The P2 Ile analogue of 2 (16) is significantly less active (IC50 of 2000 nM) which reflects an unusually subtle importance of the P2 residue for active site binding.

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…[782], the related ring system of dissectolide A (RCM exhibits competition from metathesis cyclodimerization) [783], and the total synthesis of 17-deoxyprovidencin [784]; (17) macrocyclic lactonelactams, including those employed in syntheses of PF1163A [785], and radicicol analogs [786]; (18) macrocyclic lactams, including those employed in syntheses of oleate-derived macrocyclic lactams [787]; (19) macrocyclic bis(lactam)s, including those employed in syntheses of p-cyclophane calpain inhibitors [788], a mitochondrial membrane permeabilization preventer [789], and bis(lactam) hepatitis C inhibitors [790]; (20) macrocyclic tetrakis(N-alkoxylactam)s [791]; (21) Attempted stabilization (stapling) of alleno-acetylene oligomers failing due to a competing enyne metathesis pathway [832]. The reversible ring opening and reformation of phenanthroline-bridged catenane systems through metathesis and the effect of copper complexation (for complexation of the phenanthroline parts) on this…”

A mechanistic study on the inhibition of α-chymotrypsin by a macrocyclic peptidomimetic aldehyde

“…The primary alcohol was subsequently oxidized with Dess-Martin periodinane to give the desired macrocyclic aldehyde 7. The 13 C-labelled analogue 8 was similarly prepared by coupling 13 C phenylalaninol 18 with the macrocyclic acid 14, with a final oxidation of the primary alcohol to the aldehyde, see Scheme 2. The alcohol 18 was prepared from commercially available L-phenylalanine-1-13 C 16 as shown in Scheme 2.…”

“…1). [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] This typically involves chemically linking either the P 1 and P 3 or the P 1 ′ and P 3 ′ residues of the inhibitor backbone. For example see compounds 3, 22 4 23,24 and 5 25 (Fig.…”

“…Here we report a combination of NMR and X-ray crystallographic studies to characterize the mode of binding and mechanism of inhibition of this new class of macrocyclic inhibitor. The macrocycle 7 was chosen for this study for ease of solving an α-chymotrypsin-ligand X-ray structure 26 and to allow the incorporation of a 13 C label in the formyl group as shown (compound 8, Fig. 2) for NMR studies as reported here.…”

Roger F. C. Brown Memorial Issue

“…[24] Glen Deacon, David Turner and co-workers (Monash) use hightemperature (solid state) chemistry to achieve an unexpected formation of a biquinolinolate ligand from 8-quinoline and rareearth or transition metals, [25] and Andrew Abell et al (Adelaide) describe a preparation of macrocyclic calpain inhibitors. [26] Steven Langford (Monash) reports on crown ether derivatised pyromellitic diimides, [27] and David Black (UNSW, formerly of Monash) on the synthesis, structures, and conformations of bisglyoxylamides derived from bis-acylisatin. [28] Lawrence Scott (Boston College) and co-workers have investigated the mechanisms of aryl-aryl bond cleavages under FVP conditions, [29] and R. Alan Aitken (St Andrews) describes the FVP of substituted benzo [c]thiopyran and thieno [2,3-c]thiopyran S,S-dioxides.…”