Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1991-11-08
1997-06-17
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544287, 564124, 564153, 564156, 560 22, 560 23, C07D48704, C07D23990, A61K 31505, C07B 4302
Patent
active
056398816
ABSTRACT:
Pyrimido[4,5-g]quinazoline quinone derivatives were synthesized as anthranone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediates able to trap nucleophiles (alkylation) and protons. The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation, as the log, versus the quinone reduction potential. The pyrimido[4-5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. A drawback of many quinone antibiotics, particularly the anthracyclines, is the formation of toxic oxygen species by quinone/hydroquinone cycling. In the present invention pyrimido[4,5-g]quinazoline hydroquinones are found to be relatively stable toward oxygen, and thus cause little oxygen toxicity. Antitumor screening revealed that the disclosed pyrimido[4,5-g]quinazoline dione derivatives possess excellent inhibitory activity against selected human cancer cell lines. The pyrimido[4,5g]quinazoline-diones have the following structural formulae: ##STR1## wherein: R is H or CH.sub.3 ; and X is Cl or Br.
REFERENCES:
Von Hoff, Journal of the NC1 82, p. 110 (Jan. 1990).
Von Hoff Journal of NIC 82, p. 96 (Jan. 1990).
Alberts, Proc. of AACR 28, Mar. 1987 p. 420.
Lemus, J. Org. Chem 57, 5649 (1992).
Lemus Robert H.
Skibo Edward B.
Arizona Board of Regents acting on behalf of Arizona State Unive
Berch Mark L.
Mybeck Richard R.
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