Synthesis and activity of novel indirubin derivatives

Abstract

Indirubin is a natural-product-based medication, derived from the traditional Chinese medicine dangguilonghui pill (DLP), which is composed of 11 Chinese herbs and is used clinically to treat chronic myeloid leukemia (Gaboriaud-Kolar, Vougogiannopoulou, & Skaltsounis, 2015). After further research, it has been found that the main chemically active ingredient of DLP is indigo naturalis (qing-dai; Tokuyasu et al., 2018). Although the indigo content in qing-dai is high, the main active ingredient for the treatment of leukemia is indirubin, the isomer of indigo (Gaitanis, Magiatis,

Synthesis and antibacterial activity studies in vitro of indirubin-3′-monoximes

“…1A) is also the active plant ingredient of indigo naturalis (named Sei Tai in Japanese or Qing Dai in Chinese, a dark blue powder prepared from the leaves and branches of various indigo-producing plants) 17,[19][20][21][22][23][24][25][26][27] and Danggui Luhui Wan (a TCM formulation in the treatment of various chronic diseases such as cancer and inammation, and composed of 11 medicinal herbs including indigo naturalis, etc.). [20][21][22][23] Indirubin has the interesting 3,2 0 -bisindole scaffold and shows multiple biological properties, [19][20][21][22][23] including hemostatic, anticancer, antipyretic, anti-inammatory, sedative, antibacterial, and antiviral properties. 22,23 However, due to the existence of a hydrogenbonding framework in the structure of indirubin, the property of extremely poor solubility in most solvents has been observed, which is the main obstacle for the clinical application of indirubin.…”

“…[20][21][22][23] Indirubin has the interesting 3,2 0 -bisindole scaffold and shows multiple biological properties, [19][20][21][22][23] including hemostatic, anticancer, antipyretic, anti-inammatory, sedative, antibacterial, and antiviral properties. 22,23 However, due to the existence of a hydrogenbonding framework in the structure of indirubin, the property of extremely poor solubility in most solvents has been observed, which is the main obstacle for the clinical application of indirubin. 21,[28][29][30][31][32][33][34][35][36] Up to now, much effort has been focused on indirubin and its derivatives; in particular, various cellular targets have been found including CDKs, 19,37,38 GSK-3b, 39 VEGFR-2, 40 c-Src, [41][42][43] Dyrk1A, 44 and other kinases.…”

“…21,[28][29][30][31][32][33][34][35][36]47 At present, although a few examples of the antimicrobial activity of indirubin and indigo extract from indigo naturalis or Wrightia tinctoria have been reported, post-modied indirubin antibacterial agents have not been reported. [48][49][50][51][52][53][54] Indirubin-3 0 -monoxime is a synthetic derivative of indirubin and is usually used as a key intermediate for the synthesis of water-soluble indirubins. 22,28,55 In addition, indirubin-3 0 -monoximes also have various biological properties and can inhibit the activities of CDKs, GSK-3b, 5lipoxygenase, etc.…”

“…14 Similar to bioactive plant constituent artemisinin, indirubin (Fig. 1A) is also the active plant ingredient of indigo naturalis (named Sei Tai in Japanese or Qing Dai in Chinese, a dark blue powder prepared from the leaves and branches of various indigo-producing plants) 17,19–27 and Danggui Luhui Wan (a TCM formulation in the treatment of various chronic diseases such as cancer and inflammation, and composed of 11 medicinal herbs including indigo naturalis, etc. ).…”

Crucial Role of Reactive Oxygen Species (ROS) for the Proapoptotic Effects of Indirubin Derivatives in Cutaneous SCC Cells

“…Clinical results from the 1980s, which have been obtained in chronic myelocytic leukemia patients treated with indirubin, stimulated several studies on this compound [27,28]. Due to the only limited antitumor activity of the native form, the structure of indirubin is presently employed in several laboratories as a skeleton for the synthesis of new derivatives to increase its antitumor effects [29][30][31].…”