A tunable synthesis of indigoids: targeting indirubin through temperature.

James A Shriver,Joshua T Cheek,Kaylie S Kaller,Madison K Van Vors,John S Horner,Katelyn R Wang,Summer R Sterrenberg,Ally L Kinsey

doi:10.1039/d2ra00400c

Abstract

The spontaneous conversion of 3-indoxyl to indigo is a well-established process used to produce indigo dyes. It was recently shown that some indoles, when reacted with molybdenum hexacarbonyl and cumyl peroxide, proceed through an indoxyl intermediate to produce significant amounts of indirubin through a competing mechanism. Modulation of this system to lower temperatures allows for careful tuning, leading to selective production of indirubins in a general process. A systematic assay of indoles show that electron deficient indoles work well when substituted at the 5 and 7 positions. In contrast, 6-substituted electron rich indoles give the best results whereas halogeno indoles work well in all cases. This process shows broad functional group tolerance for generally reactive carbonyl-containing compounds such as aldehydes and carboxylic acids.

Highlights

The investigation of indirubin (1) for its potential as a kinase inhibitor has been ongoing, leading to a steady in ux of studies over the past 25 years
The two compounds are distinguished by UV/Vis-different indigos give a maximum absorbance at approximately 590–640 nm, whereas indirubin's maximum absorbance occurs between 500– 560 nm, depending on substituents and their location
While general experimental conditions for indoxyl generation were evaluated in signi cant detail for the Yamamoto method, the role of temperature was not extensively explored

Summary

Introduction

The investigation of indirubin (1) for its potential as a kinase inhibitor has been ongoing, leading to a steady in ux of studies over the past 25 years. It was identi ed as the active component of Danggui Longhui Wan, a traditional Chinese medicinal recipe used to treat Chronic Myelocytic Leukemia (CML).[1] Within the last two years, research has been conducted related to, inter alia, insulin resistance,[2] paraptosis in MDA-MB-231 breast cancer cells,[3] anti-tumor effects in Thyroid Cancer,[4] and inhibition of osteosarcoma cells.[5] A comprehensive review and meta-analysis related to anticancer applications was recently published and demonstrates the potential for the development of selective indirubin moieties.[6] Beyond medical applications, indirubin was recently shown to exhibit photoswitching behavior with red light, which is enhanced when stabilized by supramolecular interactions with a thiourea additive commencing a new line of inquiry for this molecule.[7]. Indirubins can be distinguished by NMR techniques due to their difference in symmetry and a unique down eld absorbance for the hydrogen located at the 4-position on indirubin.[8]

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Conclusion