Hypoxia-Selective Antitumor Agents. 12. Nitrobenzyl Quaternary Salts as Bioreductive Prodrugs of the Alkylating Agent Mechlorethamine

Abstract

A series of benzene-substituted analogues of the novel hypoxia-selective cytotoxin N,N-bis(2-chloroethyl)-N-methyl-N-(2-nitrobenzyl)ammonium chloride (3a), together with three corresponding tetrahydroisoquinolinium "cyclic" analogues 21a-23a and two naphthalene derivatives (19a and 20a), have been prepared and evaluated for cytotoxicity in cultured mammalian tumor cells under aerobic and hypoxic conditions. The parent compound 3a has a one-electron reduction potential of -358 mV and undergoes reductively-induced fragmentation to release the nitrogen mustard mechlorethamine. The compounds were prepared by halogenation (SOCl2) of the corresponding quaternary diols, which in turn were synthesized from N-methyldiethalnolamine and substituted nitrobenzyl chlorides. The reduction potentials of the benzene-substituted compounds were generally well-predicted by Hammett substituent relationships. All of the compounds were much more toxic toward repair-deficient UV4 cells than the corresponding wild-type AA8 cells, as expected if the active cytotoxic species as a DNA alkylating agent. They were also more toxic toward the human cell lines EMT6 and FME compared to AA8, but the reasons for this are not known. Analogues of 3a substituted in the phenyl ring with electron-donating substituents provided compounds with widely differing selectivities for hypoxic AA8 cells, ranging from no selectivity for the 3-Me compound 9a to 3000-fold (at least as great as that of the parent 3a) for the 4-OMe compound 14a. The naphthalene derivatives 19a and 20a and the tetrahydroisoquinolinium compounds 21a-23a showed no hypoxic selectivity. Selective chemical reduction of 22a and 23a with nickel boride resulted in isolation of the corresponding stable amino derivatives, indicating that reduction of these compounds does not result in fragmentation. The reason(s) for the marked differences in hypoxic selectivity of the nitrobenzyl quaternary mustards is unknown, but may reflect differences in radical chemistry, cell uptake, or sensitivity to enzymatic reduction.

Glucuronidation of Anticancer Prodrug PR-104A: Species Differences, Identification of Human UDP-Glucuronosyltransferases, and Implications for Therapy

“…PR-104, PR-104A, PR-104G, and the corresponding diethyl analog (compound 1; see Supplemental Fig. S6A) were synthesized as described previously , as was 2-chloro-N-(2-chloropropyl)-N-methyl-N-(2-nitrobenzyl)propan-1-ammonium chloride (SN25378) (Tercel et al, 1996), which was used as the internal standard for the quantification of PR-104G by HPLC. Uridine 5Ј-diphosphoglucuronic acid (UDPGA) triammonium salt, magnesium chloride, alamethicin, and D-saccharic acid 1,4-lactone (D-SL; a specific ␤-glucuronidase inhibitor) were from Sigma-Aldrich (St. Louis, MO).…”

Synthesis, characterization and biological activities of mononuclear Co(III) complexes as potential bioreductively activated prodrugs

“…However, some compounds with redox potentials out of this range have presented considerable activities [7][8][9]. Currently, some classes of bioreductively activated agents are known, such as (i) quinone-containing antibodies; (ii) nitroimidazoles; (iii) aromatic N-oxides [10][11][12]; (iv) mustard nitrogens [6,13] and metalcontaining compounds. By 1998, three classes of hypoxia selective prodrugs were already in clinical use including the antibiotics, the nitroimidazoles and the benzotriazines di-N-oxides [14].…”

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

“…Hypoxia-activated nitroheterocyclic phosphoramidates have also been reported, which were unstable in vivo, displaying rapid metabolism and consequent elimination half-lives of only a few minutes (35,36). Similarly, nitroheteroaryl quaternary salts have been synthesized as bioreductive prodrugs of mechlorethamine, but the compounds were too unstable with regard to nonspecific release of mechlorethamine to be of use as bioreductive agents (29,30). Thus, prodrugs showing improved stability toward nonreductive processes are desirable.…”