Indolequinone antitumor agents: reductive activation and elimination from (5-methoxy-1-methyl-4,7-dioxoindol-3-yl)methyl derivatives and hypoxia-selective cytotoxicity in vitro.
A series of indolequinones bearing a variety of leaving groups at the (indol-3-yl)methyl position was synthesized by functionalization of the corresponding 3-(hydroxymethyl)indolequinone, and the resulting compounds were evaluated in vitro as bioreductively activated cytotoxins. The elimination of a range of functional groups-carboxylate, phenol, and thiol-was demonstrated upon reductive activation under both chemical and quantitative radiolytic conditions. Only those compounds which eliminated such groups under both sets of conditions exhibited significant hypoxia selectivity, with anoxic:oxic toxicity ratios in the range 10-200. With the exception of the 3-hydroxymethyl derivative, radiolytic generation of semiquinone radicals and HPLC analysis indicated that efficient elimination of the leaving group occurred following one-electron reduction of the parent compound. The active species in leaving group elimination was predominantly the hydroquinone rather than the semiquinone radical. The resulting iminium derivative acted as an alkylating agent and was efficiently trapped by added thiol following chemical reduction and by either water or 2-propanol following radiolytic reduction. A chain reaction in the radical-initiated reduction of these indolequinones (not seen in a simpler benzoquinone) in the presence of a hydrogen donor (2-propanol) was observed. Compounds that were unsubstituted at C-2 were found to be up to 300 times more potent as cytotoxins than their 2-alkyl-substituted analogues in V79-379A cells, but with lower hypoxic cytotoxicity ratios.
Naylor
M A
MA
Gray Laboratory Cancer Research Trust, P.O. Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom.
Swann
E
E
Everett
S A
SA
Jaffar
M
M
Nolan
J
J
Robertson
N
N
Lockyer
S D
SD
Patel
K B
KB
Dennis
M F
MF
Stratford
M R
MR
Wardman
P
P
Adams
G E
GE
Moody
C J
CJ
Stratford
I J
IJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004354:Drug Screening Assays, Antitumor; D005609:Free Radicals / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D007700:Kinetics; D010084:Oxidation-Reduction; D011675:Pulse Radiolysis; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005609:Free Radicals; D007211:Indoles; D011809:Quinones