Relationships between structure and kinetics of cyclization of 2-aminoaryl amides: potential prodrugs of cyclization-activated aromatic mustards

Abstract

2-Nitroaryl amides of general structure I are proposed as bioreducible prodrugs, capable of releasing cytotoxic aminoaniline mustards V on bioactivation by spontaneous cyclization of the resulting 2-aminoarylamides II via a tetrahedral intermediate, III. This concept allows separate optimization of the substituent effects influencing nitro-group reduction and mustard reactivity. A series of model 2-aminoaryl amides has been synthesized, and their rates of cyclization have been studied; these varied by a factor of more than 50,000-fold (kobs from 0.00040 to 21 min-1) at pH 2.4. For three compounds studied in detail, the rates were linearly dependent of pH, indicating that no change in the mechanism of the rate-determining step occurs over the pH range studied. The nucleophilicity of the amino group had a modest influence on the kinetics of cyclization, with electron-withdrawing groups slowing the rate. The geometry of the compound was also important, with structure-activity relationships indicating that the rate of cyclization is greatly enhanced by the preorganization of the molecule. In contrast, 4-substitution on the leaving aniline by a variety of groups had little effect on the cyclization reaction. These results are consistent with the rate-determining step being formation of the tetrahedral intermediate. These model studies suggest that the phenyldimethylacetamide system could be developed as a prodrug system for the bioreductively-triggered release of amines. Further substantial rate enhancements appear possible by alterations in the geometry of the system, whereas substitution of electron-withdrawing groups (required to raise the nitro-group reduction potential into the appropriate range) has only relatively modest retardation effects on rates of cyclization. More rigid systems may also be useful; a nitronaphthaleneacetamide analogue cyclized spontaneously during nitro-group reduction, suggesting a very short half-life for the reduced intermediate (amine or hydroxylamine).

Cyclization-activated Prodrugs

“…Enzymatic cleavage followed by intramolecular aminolysis of DMDC prodrugs [70]. Other two-step prodrugs based on nitrogen nucleophiles have been developed, for instance, by Atwell et al, who proposed 2-nitroaryl amides as bio-reductive two-step prodrugs capable of releasing cytotoxic aminoaniline mustards by spontaneous cyclization of the corresponding 2-aminoaryl amides produced in a previous bio-reduction step [71]. These authors analyzed three factors that could influence the overall cyclization rate: the nucleophilicity of the amine, the geometry of the compound and the nature of the leaving group.…”

“…These authors analyzed three factors that could influence the overall cyclization rate: the nucleophilicity of the amine, the geometry of the compound and the nature of the leaving group. Both the nucleophilicity of the amino group and the 4-substituent of the leaving aniline had little effect on the cyclization rate, whereas the geometry of the compound was a determinant factor, indicating that the rate of cyclization was greatly influenced by the preorganization of the molecule [71]. A series of N-dinitrophenylamino acid amides 20 was also prepared as potential bio-reductive two-step prodrugs and the rates of their intramolecular cyclization after radio-promoted reduction were analyzed.…”

Syntheses and kinetic studies of cyclisation-based self-immolative spacers

“…More generally, the more electron-donors the cycle has at the para position, the faster the cyclisation occurs in line with an enhanced nucleophilicity of the phenol: compared to the H derivative ( para-hydrogen), we observed a relative acceleration with electron-donor groups and a moderate slow-down with electron-withdrawing groups. According to the literature, in both aliphatic 21 and aromatic 22 derivatives, nucleophilicity enhancement is a critical factor for Scheme 4 Kinetic models for disassembly from photoactivation to self-immolation of trimethyl-lock (top) and 2-HPC (bottom) derivatives. the cyclisation rate.…”

Agentes antineoplásicos biorredutíveis: uma nova alternativa para o tratamento de tumores sólidos

“…Em 1986, Denny e Wilson lançaram as bases teóricas do planejamento racional de mostardas nitroaromáticas como potenciais agentes citotóxicos seletivos para células em hipóxia 18 . A partir de então, várias mostardas nitroaromáticas, como as mostardas (16) e (17), vêm sendo extensivamente estudadas como pró-fármacos 18,20,[78][79][80][81][82][83][84] .…”