ChemInform Abstract: HETEROCYCLIC COMPOUNDS. PART IX. SYNTHESES OF N‐NITROSOUREAS AND N‐NITROSOTHIOUREAS AS POSSIBLE ANTITUMOR AGENTS

Abstract

Aus den Harnstoffen (a‐Reihe) werden die entsprechenden Nitroso‐Derivate (b‐Reihe) hergestellt, die Wirkung gegen Leukämie L12lO zeigen.

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

“…Early attempts to prepare sulfonyl ureas 52 , thioureas 53 , alkoxyureas 54 , and nitroureas 55 were unsuccessful, except for 1,3-dimethyl-1-nitroso-2-thiourea ( 56 , Chart ) which was inactive against the ip-inoculated L1210 . Later, several N -nitrosothioureas 57 were synthesized; − however, their antitumor activity was not reported. The nitrosothioureas were synthesized from the respective thioureas, using either sodium nitrite and dilute aqueous hydrochloric acid (0.05−0.1 N), , or in the solvents dichloromethane or chloroform …”

“…Later, several N -nitrosothioureas 57 were synthesized; − however, their antitumor activity was not reported. The nitrosothioureas were synthesized from the respective thioureas, using either sodium nitrite and dilute aqueous hydrochloric acid (0.05−0.1 N), , or in the solvents dichloromethane or chloroform …”

“…A large number of additional heterocyclic N -nitrosourea derivatives related to the previously discussed compounds have been reported in the literature ,,− and some of them are collected in Chart .

11 Structures for Section VII.B

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“…The nitrosothioureas were synthesized from the respective thioureas, using either sodium nitrite and dilute aqueous hydrochloric acid (0.05-0.1 N), 117,118 or in the solvents dichloromethane or chloroform. 119 Dilute acidic conditions were chosen to favor formation of unprotonated nitrous acid and dinitrogen trioxide. These harder acid species were expected to favor electrophilic attack at the harder nitrogen of the thioureas rather than at the competing sulfur atom.…”

“…None of these agents were active against a fibrosarcoma cell line. 151 The CNCC mixture (119)(120)(121) can be considered a prodrug because the disulfide bond is reductively cleaved in vivo, and the resulting thiol groups are oxidized to sulfoxide and sulfone groups (section VII.A.2). The sulfoxide 125 and sulfone 126 metabolites (Table 7) were shown 169 to be at least as active as CNCC against eight of 12 cancer lines and resulted in a larger percentage of 90 day survivors.…”