Cytotoxic and Anticancer Activities of Isatin and Its Derivatives: A Comprehensive Review from 2000-2008

Abstract

Isatin (1H-indole-2,3-dione) and its derivatives demonstrate a diverse array of biological and pharmacological activities including anticonvulsant, antibacterial, antifungal, antiviral and anticancer properties. This broad spectrum of biochemical targets has been facilitated by the synthetic versatility of isatin, which has allowed the generation of a large number of structurally diverse derivatives including analogues derived from substitution of the aryl ring, and/or derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. The recent FDA approval of the oxindole sunitinib malate, as a kinase inhibitor for the treatment of advanced renal carcinoma and gastrointestinal stromal tumours, underscores the increasing interest in isatins as a new class of antineoplastic agents. In addition to potent kinase inhibition, the mechanism of action of other isatin derivatives includes the inhibition and/or modulation of proteases, translation initiation, neo-vascularisation and tubulin polymerisation. It was therefore the objective of this review to systematically evaluate the cytotoxic and anticancer properties of various substituted isatins and collate these findings to be used as a guide for future structure-activity relationship and mode of action studies. This is the first review to comprehensively discuss the in vitro and in vivo anticancer activities of isatin and its substituted derivatives.

Synthesis and in vitro Bio-activity Evaluation of N4-benzyl Substituted 5-Chloroisatin- 3-thiosemicarbazones as Urease and Glycation Inhibitors

“…Of the isatin derivatives, isatin-thiosemicarbazones have been found to exhibit a range of biological properties, including antiulcer, 1 anticancer, 1,4,7,12,[21][22][23] antimicrobial, [1][2][3]5,7,22,24,25 antituberculosis, [26][27][28] antiviral 1,2,5,7,12,28 and enzyme inhibitory activities. 1,4,11,17 Incited by these findings and as a part of our synthetic work on bioactive isatin derivatives, we have recently reported the synthesis of numerous N 4 -aryl substituted isatin-3-thiosemicarbazones (thiourea derivatives) as antimicrobial, [36][37][38][39] cytotoxic, [38][39][40][41][42] phytotoxic, [38][39][40][41]43 antileishmanial 44 and more importantly antiurease [36][37][38][39][40]…”

“…1,4,11,17 Incited by these findings and as a part of our synthetic work on bioactive isatin derivatives, we have recently reported the synthesis of numerous N 4 -aryl substituted isatin-3-thiosemicarbazones (thiourea derivatives) as antimicrobial, [36][37][38][39] cytotoxic, [38][39][40][41][42] phytotoxic, [38][39][40][41]43 antileishmanial 44 and more importantly antiurease [36][37][38][39][40]43,45 compounds. SAR studies in the synthesized thiosemicarbazones disclosed that in some cases the nature and location of the substituent on the phenyl ring attached to thiosemicarbazone N 4 and/or the existence of lipophilic/inductively electron-withdrawing functions (Cl, F, F 3 CO, NO 2 ) at position 5 of the isatin moiety played a significant role in inducing and/or increasing certain activities, including urease inhibition. In view of this and as an extension of our earlier studies [36][37][38][39][40][41][42][43][44][45][46][47] aiming to the synthesis of novel isatin derivatives with enhanced or diverse biological activities, we very recently reported the synthesis of a series of N 4 -benzyl substituted 5-nitroisatin-3-thiosemicarbazones (derivatives of thiourea, a substrate-like urease inhibitor) as highly effective urease inhibitors.…”

First Asymmetric Reduction of Isatin by Marine-Derived Fungi

“…2 In addition, diverse pharmacological properties were reported for isatin and its derivatives including anticancer, antioxidant, anti-histaminic, antiviral, anti-inflammatory, anti-Parkinson's, antidiabetic, antiallergic, antimalarial and antimicrobial activities. 3,4 The compound 3-hydroxyindolin-2-one is a derivative of the reduction of isatin and showed pharmacological potential to antiallergic, anti-inflammatory and anticancer activities. 4 In addition, they have been found in many bioactive natural products, such as convolutamydine A, 5 flustraminol A 6 and donaxaridine 7 ( Figure 1).…”

“…3,4 The compound 3-hydroxyindolin-2-one is a derivative of the reduction of isatin and showed pharmacological potential to antiallergic, anti-inflammatory and anticancer activities. 4 In addition, they have been found in many bioactive natural products, such as convolutamydine A, 5 flustraminol A 6 and donaxaridine 7 ( Figure 1). Few studies in the literature have focused on the biotransformation of isatin derivatives by whole cells.…”

5-Nitroisatin-derived thiosemicarbazones: potential antileishmanial agents

“…7,8,[10][11][12][13][15][16][17][18][19]21,23,24,26,28 and 30 exhibited good to excellent antileishmanial activities with IC 50 values ranging from 0.44 AE 0.02 to 32.38 AE 0.66 mg/mL. Of these, 5, 7, 19 and 28 proved to be the most active antileishmanial agents, displaying activities with IC 50 values 1.78 AE 0.35, 0.44 AE 0.02, 1.91 AE 0.04 and 4.28 AE 0.75 mg/mL, respectively, which were even better than the standard drug, pentamidine (IC 50 ¼ 5.09 AE 0.04 mg/mL).…”