Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues

Abstract

The studies culminating in the total synthesis of the glutarimide-containing eukaryote translation elongation inhibitor lactimidomycin are described. The optimized synthetic route features a Zn(II)-mediated intramolecular Horner-Wadsworth-Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12-membered macrolactone of lactimidomycin on a 423 mg scale. The presence of the E,Z-diene functionality was found to be key for effective macrocyclizations as a complete removal of these unsaturation units resulted in exclusive formation of the dimer rather than monocyclic enoate. The synthetic route features a late-stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allows for a quick generation of lactimidomycin homolog 55 containing two additional carbons in the glutarimide side chain. Similar to lactimidomycin, this analog was found to possess cytotoxicity against MDA-MB-231 breast cancer cells (GI50 =1-3 μM) using in vitro 2D and 3D assays. Although lactimidomycin was found to be the most potent compound in terms of anticancer activity, 55 as well as truncated analogues 50-52 lacking the glutarimide side-chain were found to be significantly less toxic against human mammary epithelial cells.

Genomics‐Driven Discovery of a Novel Glutarimide Antibiotic from Burkholderia gladioli Reveals an Unusual Polyketide Synthase Chain Release Mechanism

“…HMBC correlations between H-3 and C-1/C-1' and the exchangeable NH proton and C-2/C-2' confirmed the presence of a2 ,6 -piperidine- dione,a nd the chemical shift values for this moiety were in good agreement with the literature. [18,19,37,38] Twonetworks of COSY correlations established the structures of the C-2/C-2' to C-6 and C-8 to C-18 regions of the molecule,a nd HMBC correlations further confirmed the locations of the C-8 Me group and the C-9/C-10 double bond. HMBC correlations also showed that C-6 and C-8 are connected via aketo group and that amethyl ketone is attached to C-18.…”

Bioinformatic study to discover natural molecules with activity against COVID-19

“…3-oxo-glycyrrhetinic acid has antitumor activity and expectorant (antitussive) properties 25 . Lactimidomycin has antifungal, antiviral, and anti-cancer properties apart from acting as a direct inhibitor of protein translation inribosomes which is a glutarimide antibiotic derived from the bacterium Streptomyces amphibiosporus 26 . Cardinalins dinalins 4 exhibit anti-cancer properties.…”

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

“…Lactimidomycin (LTM) prevents the ribosome from leaving the start site and blocks the very first round of translation elongation. This recently established anticancer agent [ 15 ] potently inhibits infections of dengue virus and other RNA viruses in cell culture [ 16 ].…”