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Stereoselective olefin cyclopropanation under aerobic conditions with an artificial enzyme incorporating an iron-chlorin e6 cofactor.

ABSTRACT: Myoglobin has recently emerged as a promising biocatalyst for catalyzing carbene-mediated cyclopropanation, a synthetically valuable transformation not found in nature. Having naturally evolved for binding dioxygen, the carbene transferase activity of this metalloprotein is severely inhibited by it, imposing the need for strictly anaerobic conditions to conduct these reactions. In this report, we describe how substitution of the native heme cofactor with an iron-chlorin e6 complex enabled the development of a biocatalyst capable of promoting the cyclopropanation of vinylarenes with high catalytic efficiency (up to 6,970 TON), turnover rate (>2,000 turnovers/min), and stereoselectivity (up to 99% de and ee) in the presence of oxygen. The artificial metalloenzyme can be recombinantly expressed in bacterial cells, enabling its application also in the context of whole-cell biotransformations. This work makes available a robust and easy-to-use oxygen-tolerant biocatalyst for asymmetric cyclopropanations and demonstrates the value of porphyrin ligand substitution as a strategy for tuning and enhancing the catalytic properties of hemoproteins in the context of abiological reactions.

SUBMITTER: Sreenilayam G

PROVIDER: S-EPMC5863724 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Stereoselective olefin cyclopropanation under aerobic conditions with an artificial enzyme incorporating an iron-chlorin e6 cofactor.

Sreenilayam Gopeekrishnan G Moore Eric J EJ Steck Viktoria V Fasan Rudi R

ACS catalysis 20171009 11

Myoglobin has recently emerged as a promising biocatalyst for catalyzing carbene-mediated cyclopropanation, a synthetically valuable transformation not found in nature. Having naturally evolved for binding dioxygen, the carbene transferase activity of this metalloprotein is severely inhibited by it, imposing the need for strictly anaerobic conditions to conduct these reactions. In this report, we describe how substitution of the native heme cofactor with an iron-chlorin e6 complex enabled the de ...[more]

PMID: 29576911

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Project description:The aim of this study is to prepare redox-sensitive nanophotosensitizers for the targeted delivery of chlorin e6 (Ce6) against cervical cancer. For this purpose, Ce6 was conjugated with β-cyclodextrin (bCD) via a disulfide bond, creating nanophotosensitizers that were fabricated for the redox-sensitive delivery of Ce6 against cancer cells. bCD was treated with succinic anhydride to synthesize succinylated bCD (bCDsu). After that, cystamine was attached to the carboxylic end of bCDsu (bCDsu-ss), and the amine end group of bCDsu-ss was conjugated with Ce6 (bCDsu-ss-Ce6). The chemical composition of bCDsu-ss-Ce6 was confirmed with 1H and 13C NMR spectra. bCDsu-ss-Ce6 nanophotosensitizers were fabricated by a dialysis procedure. They formed small particles with an average particle size of 152.0 ± 23.2 nm. The Ce6 release rate from the bCDsu-ss-Ce6 nanophotosensitizers was accelerated by the addition of glutathione (GSH), indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive photosensitizer delivery capacity. The bCDsu-ss-Ce6 nanophotosensitizers have a low intrinsic cytotoxicity against CCD986Sk human skin fibroblast cells as well as Ce6 alone. However, the bCDsu-ss-Ce6 nanophotosensitizers showed an improved Ce6 uptake ratio, higher reactive oxygen species (ROS) production, and phototoxicity compared to those of Ce6 alone. GSH addition resulted in a higher Ce6 uptake ratio, ROS generation, and phototoxicity than Ce6 alone, indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive biological activity in vitro against HeLa human cervical cancer cells. In a tumor xenograft model using HeLa cells, the bCDsu-ss-Ce6 nanophotosensitizers efficiently accumulated in the tumor rather than in normal organs. In other words, the fluorescence intensity in tumor tissues was significantly higher than that of other organs, while Ce6 alone did not specifically target tumor tissue. These results indicated a higher anticancer activity of bCDsu-ss-Ce6 nanophotosensitizers, as demonstrated by their efficient inhibition of the growth of tumors in an in vivo animal tumor xenograft study.

Dataset Information

Stereoselective olefin cyclopropanation under aerobic conditions with an artificial enzyme incorporating an iron-chlorin e6 cofactor.

Publications

Stereoselective olefin cyclopropanation under aerobic conditions with an artificial enzyme incorporating an iron-chlorin e6 cofactor.

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