Bioreductive alkylating agents

SCHEME 7.2 Examples of potential bioreductive alkylating agents reported by Lin et al.17. 

The bioreductive alkylating agents developed in this laboratory did not afford observable quinone methide species upon quinone reduction and leaving group... 

The UV-Vis spectral detection of an intermediate in the catalytic reductive alkylation reaction provides only circumstantial evidence of the quinone methide species. If the bioreductive alkylating agent has a 13C label at the methide center, then a 13C-NMR could provide chemical shift evidence of the methide intermediate. Although this concept is simple, the synthesis of such 13C-labeled materials may not be trivial. We carried out the synthesis of the 13C-labeled prekinamycin shown in Scheme 7.5 and prepared its quinone methide by catalytic reduction in an N2 glove box. An enriched 13C-NMR spectrum of this reaction mixture was obtained within 100 min of the catalytic reduction (the time of the peak intermediate concentration in Fig. 7.2). This spectrum clearly shows the chemical shift associated with the quinone methide along with those of decomposition products (Fig. 7.3). 

The design of a bioreductive alkylating agent possessing antitumor activity described above validates our approach to rational drug design. Namely, the putative... 

Moore, H. W. Czemiak, R. Naturally occurring quinones as potential bioreductive alkylating agents. Med. Res. Rev. 1981, 1, 249-280. 

Lin, A. J. Shansky, C. W. Sartorelli, A. C. Potential bioreductive alkylating agents. 3. Synthesis and antineoplastic activity of acetoxymethyl and corresponding ethyl carbamate derivatives of benzoquinones. J. Med. Chem. 1974, 17, 558-561. 

S. Rockwell, A.C. Sartorelli, M. Tomasz and K.A. Kennedy, Cellular pharmacology of quinone bioreductive alkylating agents. Cancer Metastasis Revs., 12 (1993) 165. 

NATURALLY OCCURRING QUINONES AS BIOREDUCTIVE ALKYLATING AGENTS... 

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