Autoradiographic studies on the distribution of quaternary ammonium compounds. IV. Adsorption of bisonium ions to rat tissues as revealed by in vitro whole-body adsorption autoradiography.

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

“…It was believed , that the choline-like fragment could have a selective effect because of the interaction between the increased negative surface charge of the cancer cells and the presence of a positively charged quaternary nitrogen atom. The compounds 59 also were expected 120 to have a high affinity for tumors of connective tissues, since quaternary ammonium salts were observed to be strongly adsorbed by these tissues. The synthesis of the quaternary compounds 59 is outlined in Scheme , but no biological activity data was obtainable for these compounds.…”

“…Some undefined polymethylene bisCENUs were reported. 147 The bistertiary 110 and 111, and bisquaternary 112-114 ammonium analogs (Table 4) were synthesized, 148,149 because it was found 125 that the quaternary ammonium cations are capable of selectively accumulating in connective tissue as a result of ionic bonding with sulfate and phosphate anions present in the chondroitin sulfate and cellular DNA, resulting in bridged structures. The synthesis of these compounds is outlined in Scheme 20a,b.…”

“…It was assumed 167,169 that the biochemical decomposition of 125 and 126 would lead to a very reactive bioalkylating species 129 which could cross-link the DNA, whereas 123 and 124 would decompose to a much less reactive monoalkylating species 130 (Chart 4). The two cytotoxic metabolites, the sulfoxide, perimustine (125), and the sulfone, cystemustine (126), were compared 169 with CNCC against 12 cancer models in vivo. Both compounds were found 169 to be at least as active as CNCC against eight of the leukemia lymphomas and solid cancers, but, more importantly, the two metabolites caused a larger percentage of long-term survivors on day 90 than the parent mixture CNCC.…”

“…922 Another example of a metabolic activation is the disulfide-bisCENU analogs CNCC 119-121 (Table 6, section VII.A.2). An in vivo reduction of the disulfide bond to the thiol groups, and a subsequent oxidation of the thiol moiety, produced the biologically active sulfoxide (125) and sulfone (126) metabolites (Table 7). Metabolic routes which deactivate N-nitrosoureas include dechlorination and N-denitrosation.…”

Carbohydrate distribution in mammal; Whole-body autoradiographic approach.

“…Histological and histochemical staining can also be carried out on the whole-body sections. In vitro whole-body autoradiography seems to be applicable for several compounds (26,44,57). Furthermore, samples for biochemical analysis can be obtained from the thick whole-body sections.…”