2-Cyclopropylindoloquinones and Their Analogues as Bioreductively Activated Antitumor Agents:  Structure−Activity in Vitro and Efficacy in Vivo

Abstract

A series of 2-cycloalkyl- and 2-alkyl-3-(hydroxymethyl)-1-methylindoloquinones and corresponding carbamates have been synthesized and substituted in the 5-position with a variety of substituted and unsubstituted aziridines. Cytotoxicity against hypoxic cells in vitro was dependent upon the presence of a 5-aziridinyl or a substituted aziridinyl substituent for 3-hydroxymethyl analogues. The activity of 5-methoxy derivatives was dependent upon the presence of a 3-(carbamoyloxy)methyl substituent. Increasing the steric bulk at the 2-position reduced the compounds' effectiveness against hypoxic cells. A 2-cyclopropyl substituent was up to 2 orders of magnitude more effective than a 2-isopropyl substituent, suggesting possible radical ring-opening reactions contributing to toxicity. Nonfused 2-cyclopropylmitosenes were more effective than related fused cyclopropamitosenes reported previously. The reduction potentials of the quinone/semiquinone one-electron couples were in the range -286 to -380 mV. The semiquinone radicals reacted with oxygen with rate constants 2-8 x 10(8) dm3 mol-1 s-1. The involvement of the two-electron reduced hydroquinone in the mediation of cytotoxicity is implicated. The most effective compounds in vitro were the 2-cyclopropyl and 5-(2-methylaziridinyl) derivatives, and of these, 5-(aziridin-1-yl)-2-cyclopropyl-3-(hydroxymethyl)-1-methylindole-4 ,7-dione (21) and 3-(hydroxymethyl)-5-(2-methylaziridin-1-yl)-1,2-dimethylindole+ ++-4,7-dione (54) were evaluated in vivo. Both compounds showed antitumor activity both as single agents and in combination with radiation, with some substantial improvements over EO9 (3) at maximum tolerated doses and as single agents against the RIF-1 tumor model and comparable efficacy in the KHT tumor model.

Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition

“…The trends in toxicity correlate to a reduced electronaffinity property as a result of the electron donation by the alkoxy substitutent. 22,23 Cyclic amine substituents in 1f-1i led to a general reduction in toxicity values compared to the parent 1a, with the exception of pyrrolo-substituted benzotriazinone 1f. Compound showed the greatest specificity toward the MCF-7 cell line similar to the toxicity of pleurotin.…”

The bromoquinone annulation reaction: a formal total synthesis of EO9

“…Bioreductive alkylating agents exhibit selective toxicity towards hypoxic cells both in vitro and in vivo. 1 Hypoxic cells are resistant to radiotherapy and so drugs that target these cells are of major importance. EO9 was discovered and selected by the new drug development office at the European Organization for Research and Treatment of Cancer (EORTC) as a new bioreductive drug for clinical trials on account of its antitumor properties.…”

New enamine derivatives of lapachol and biological activity

“…Nitrogen containing indoloquinone derivatives have been recently evaluated as novel anticancer agents, and the amine moiety was identified as an important feature for oxic and hipoxic potency and for the ability to act as a substract for reductase enzymes (Naylor et al 1997).…”