Synthesis and structure-activity evaluation of isatin-β-thiosemicarbazones with improved selective activity toward multidrug-resistant cells expressing P-glycoprotein

J Med Chem. 2011 Aug 25;54(16):5878-89. doi: 10.1021/jm2006047. Epub 2011 Aug 1.


Cancer multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters presents a significant unresolved clinical challenge. One strategy to resolve MDR is to develop compounds that selectively kill cells overexpressing the efflux transporter P-glycoprotein (MDR1, P-gp, ABCB1). We have previously reported structure-activity studies based around the lead compound NSC73306 (1, 1-isatin-4-(4'-methoxyphenyl)-3-thiosemicarbazone, 4.3-fold selective). Here we sought to extend this work on MDR1-selective analogues by establishing whether 1 showed "robust" activity against a range of cell lines expressing P-gp. We further aimed to synthesize and test analogues with varied substitution at the N4-position, and substitution around the N4-phenyl ring of isatin-β-thiosemicarbazones (IBTs), to identify compounds with increased MDR1-selectivity. Compound 1 demonstrated MDR1-selectivity against all P-gp-expressing cell lines examined. This selectivity was reversed by inhibitors of P-gp ATPase activity. Structural variation at the 4'-phenyl position of 1 yielded compounds of greater MDR1-selectivity. Two of these analogues, 1-isatin-4-(4'-nitrophenyl)-3-thiosemicarbazone (22, 8.3-fold selective) and 1-isatin-4-(4'-tert-butyl phenyl)-3-thiosemicarbazone (32, 14.8-fold selective), were selected for further testing and were found to retain the activity profile of 1. These compounds are the most active IBTs identified to date.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • CHO Cells
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Drug Resistance, Multiple / drug effects*
  • HEK293 Cells
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Isatin / analogs & derivatives*
  • Isatin / chemical synthesis
  • Isatin / pharmacology
  • Mice
  • Models, Chemical
  • Molecular Structure
  • NIH 3T3 Cells
  • Structure-Activity Relationship


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Indoles
  • NSC73306
  • isatin beta-thiosemicarbazone
  • Isatin