35172-44-2Relevant academic research and scientific papers
Selective alkylation of βII-tubulin and thioredoxin-1 by structurally related subsets of aryl chloroethylureas leading to either anti-microtubules or redox modulating agents
Fortin, Jessica S.,Cote, Marie-France,Lacroix, Jacques,Desjardins, Michel,Petitclerc, Eric,C.-Gaudreault, Rene
, p. 7277 - 7290 (2008/12/22)
Aryl chloroethylureas (CEUs) are potent anti-neoplastic agents alkylating specific intracellular proteins such as βII-tubulin. Recently we have identified a new subset of CEU derived from compound 36 that alkylates thioredoxin isoform 1 (Trx-1), inhibits the nuclear translocation of Trx-1, and favors the accumulation of cells in G0/G1 phase. We have evaluated the effects of various substituents and their position on the aromatic ring of a series of derivatives of 36 on (i) the anti-proliferative activity, (ii) the cell cycle progression, (iii) the nuclear translocation of Trx-1, and (iv) their covalent binding to β-tubulin. The same experiments were performed on representative CEU derivatives where the 2-chloroethyl amino moiety is replaced by either an ethyl, a 2-aminooxazolinyl or a 2-chloroacetyl group. On one hand, our results suggest that CEUs substituted on the phenyl ring at position 3 or 4 by cycloalkyl and substituted cycloalkyl or cycloalkoxy groups inhibit the nuclear translocation of Trx-1 and arrest the cell cycle progression in G0/G1. On the other hand, CEUs substituted by a fused aromatic ring, an aliphatic chain, or a fused aliphatic ring are alkylating βII-tubulin but not Trx-1. Beside the expected inactivity of the ethylurea derivatives, none of the modification to the electrophilic moiety led to cross-selectivity of the drugs toward β-tubulin but increased the anti-proliferative activity and resulted in mitigated effects on Trx-1 translocation.
Synthesis and evaluation of 4-alkylanilines as mammary tumor inhibiting aromatase inhibitors
Hartmann,Batzl
, p. 537 - 544 (2007/10/02)
The 4-alkylanilines 1-20 were synthesized to elucidate the importance of the glutarimide moiety for the aromatase inhibiting activity of aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione, AG], the only non-steroidal aromatase inhibitor which is commercially available at present. The most interesting compounds were the (4-aminophenyl)cycloalkanes 4-6 (4, c-pentyl; 5, c-hexyl; 6, c-heptyl) and the 1-alkyl-1-(4-aminophenyl)cyclohexanes 1-3 (1, CH3; 2, C2H5; 3, n-C3H7). Derivatives 1-6 are stronger inhibitors of human placental aromatase than AG exhibiting relative potencies from 1.5 to 2.7 (AG≡1). For selectivity of action, the inhibition of desmolase (cholesterol side chain cleavage enzyme) was determined. Compounds 1-3 showed an inhibition comparable to AG, whereas compounds 4-6 exhibited no effect on desmolase. Being more potent and selective aromatase inhibitors in vitro, compounds 4-6, however, were not superior to AG in vivo, when the reduction of plasma estradiol concentration and the tumor inhibiting activity (PMSG-primed SD rats and DMBA-induced mammary carcinoma of the SD rat, postmenopausal model) were concerned.
