Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe

Bioorg Med Chem Lett. 2016 Apr 15;26(8):2092-7. doi: 10.1016/j.bmcl.2016.02.051. Epub 2016 Feb 23.


(-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification.

Keywords: Agelastatin A; Diazirine; Photoaffinity probe; Pyrrole-aminoimidazole alkaloid; Structure–activity relationship.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis
  • Alkaloids / chemistry*
  • Alkaloids / pharmacology*
  • Antineoplastic Agents, Phytogenic / chemical synthesis
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Probes / chemical synthesis*
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacology*
  • Molecular Structure
  • Oxazolidinones / chemical synthesis
  • Oxazolidinones / chemistry*
  • Oxazolidinones / pharmacology*
  • Structure-Activity Relationship


  • Alkaloids
  • Antineoplastic Agents, Phytogenic
  • Molecular Probes
  • Oxazolidinones
  • agelastatin A