Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues

J Med Chem. 2001 May 10;44(10):1594-602. doi: 10.1021/jm0004751.

Abstract

Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemical synthesis*
  • Camptothecin / chemistry
  • Camptothecin / pharmacology
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Drug Screening Assays, Antitumor
  • Drug Stability
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • 9,16-diethyl-2,3-dihydro-9-hydroxy-12H-1,4-oxazino(3,2-f)pyrano(3',4'-6,7)indolizino(1,2-b)quinoline-10,13(9H,15H)-dione
  • Antineoplastic Agents
  • Cholinesterase Inhibitors
  • Enzyme Inhibitors
  • Topoisomerase I Inhibitors
  • Camptothecin