Synthesis and evaluation of stable bidentate transition metal complexes of 1-(chloromethyl)-5-hydroxy-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline (seco-6-azaCBI-TMI) as hypoxia selective cytotoxins.
A series of metal complexes were prepared as potential prodrugs of the extremely toxic DNA minor groove alkylator 1-(chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline (seco-6-azaCBI-TMI) and close analogues. The pyrrolo[3,2-f]quinoline cytotoxins were prepared from 2-methoxy-4-nitroaniline in a nine-step synthesis involving a Skraup construction of a quinoline intermediate, its appropriate functionalization, and a final radical cyclization. The metal complexes were prepared from these and the labile metal complex synthons [Co(cyclen)(OTf)(2)](+), [Cr(acac)(2)(H(2)O)(2)](+), and [Co(2)(Me(2)dtc)(5)](+). The cobalt complexes were considerably more stable than the free effectors and showed significant attenuation of the cytotoxicity of the latter, with IC(50) ratios (complex/effector) of 50- to 150-fold, and substantial hypoxic cell selectivity, with IC(50) ratios (oxic/hypoxic cells) of 20- to 40-fold. The cobalt complexes were also efficiently activated by ionizing radiation, with G values for loss of the compound close to the theoretical value for one-electron reduction of 0.68 micromol/J. This work extends earlier observations that cobalt cyclen complexes are suitable for both the bioreductive and radiolytic release of potent pyrrolo[3,2-f]quinoline effectors.
Milbank
Jared B J
JB
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Stevenson
Ralph J
RJ
Ware
David C
DC
Chang
John Y C
JY
Tercel
Moana
M
Ahn
G-One
GO
Wilson
William R
WR
Denny
William A
WA
D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D003035:Cobalt; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D011839:Radiation, Ionizing; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; D002614:Chelating Agents; D056831:Coordination Complexes; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; D011804:Quinolines; D003035:Cobalt