Selective alkylation of beta(II)-tubulin and thioredoxin-1 by structurally related subsets of aryl chloroethylureas leading to either anti-microtubules or redox modulating agents.
Aryl chloroethylureas (CEUs) are potent anti-neoplastic agents alkylating specific intracellular proteins such as beta(II)-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 G(0)/G(1) 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 beta-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 G(0)/G(1). On the other hand, CEUs substituted by a fused aromatic ring, an aliphatic chain, or a fused aliphatic ring are alkylating beta(II)-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 beta-tubulin but increased the anti-proliferative activity and resulted in mitigated effects on Trx-1 translocation.
Fortin
Jessica S
JS
Unité des Biotechnologies et de Bioingénierie, CHUQ, Hôpital Saint-François d'Assise, Québec, QC, Canada G1L 3L5. jessica.fortin.1@ulaval.ca
Côté
Marie-France
MF
Lacroix
Jacques
J
Desjardins
Michel
M
Petitclerc
Eric
E
C-Gaudreault
René
R
D000478:Alkylation; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013879:Thioredoxins / Q000378:metabolism*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D014404:Tubulin; D013879:Thioredoxins; D014508:Urea