Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity

J Med Chem. 1991 Jan;34(1):98-107. doi: 10.1021/jm00105a017.


Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25,26) or by total synthesis (35,42,43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemical synthesis*
  • Camptothecin / pharmacology
  • Camptothecin / therapeutic use
  • Cattle
  • Cell Line
  • Colonic Neoplasms / drug therapy
  • DNA, Superhelical / drug effects
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Humans
  • Indicators and Reagents
  • Leukemia L1210 / drug therapy
  • Lung Neoplasms / drug therapy
  • Melanoma, Experimental / drug therapy
  • Mice
  • Molecular Structure
  • Plasmids
  • Structure-Activity Relationship
  • Thymus Gland / enzymology
  • Topoisomerase I Inhibitors*
  • Transplantation, Heterologous


  • Antineoplastic Agents
  • DNA, Superhelical
  • Indicators and Reagents
  • Topoisomerase I Inhibitors
  • Camptothecin