The effect of a bromide leaving group on the properties of nitro analogs of the duocarmycins as hypoxia-activated prodrugs and phosphate pre-prodrugs for antitumor therapy

Bioorg Med Chem. 2011 Oct 15;19(20):5989-98. doi: 10.1016/j.bmc.2011.08.045. Epub 2011 Aug 25.

Abstract

Nitro seco analogs (nitroCBIs) of the antitumor antibiotic duocarmycins are a new class of hypoxia activated prodrugs. These compounds undergo hypoxia-selective metabolism to form potent DNA alkylating agents. A series of four nitroCBI alcohol prodrugs containing a bromide rather than chloride or sulfonate leaving group was synthesized. In assays for in vitro hypoxia-selective cytotoxicity against human tumor cell lines the two bromides with DNA minor groove binding basic side chains displayed hypoxic cytotoxicity ratios (HCRs) of 52-286 in HT29 cells and 41-43 in SiHa cells. These values compare well with a related previously reported chloride analog. The corresponding more water soluble phosphate pre-prodrugs of the bromides were synthesized and evaluated for in vivo antitumor activity against SiHa human tumor xenografts. All four phosphates, with both neutral and basic side chains, demonstrated activity providing statistically significant hypoxic log(10) cell kills of 0.87-2.80 at non-toxic doses, matching or proving superior to those of their chloride analogs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents, Alkylating / chemistry*
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Bromides / chemistry*
  • Bromides / pharmacology*
  • Cell Hypoxia / physiology
  • Female
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Male
  • Mice
  • Mice, Nude
  • Phosphates / chemistry
  • Phosphates / pharmacology
  • Prodrugs / chemistry*
  • Prodrugs / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Structure-Activity Relationship
  • Uterine Cervical Neoplasms / drug therapy
  • Xenograft Model Antitumor Assays

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents, Alkylating
  • Bromides
  • Indoles
  • Phosphates
  • Prodrugs
  • Pyrroles