Synthesis, cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas.

Jiang JD; Roboz J; Weisz I; Deng L; Ma L; Holland JF; Bekesi JG

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Synthesis, cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas.

机译：3-（卤代乙酰胺基）-苯甲酰脲的合成，抗癌和抗微管活性。

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The four title compounds (not hitherto reported) were synthesized from 3-aminobenzoic acid through its trifluoroacetic acid-acid chloride derivative, reaction with urea and aminolytic deprotection to yield 3-aminobenzoylurea, followed by unconventional haloacetylation. Three key factors were found essential for antitumor activity: (i) the cytotoxic nature of the halogen: I > Br > Cl > F (ID90 0.014->10 microM); (ii) the position of the halogen: only the 3-position (meta) expressed relevant activity; and (iii) the presence of the urea group (1-position). The selectivity of the bromo and iodo compounds were higher than those of vinblastine and paclitaxel in terms of cytotoxicity (ID50 ratios in nonmalignant myocardial fibroblasts and CEM leukemia cells) and therapeutic indices (P338 leukemia bearing mice). Relevant mechanisms of bioactivity were mitotic arrest and apoptosis. Complete inhibition of microtubule assembly occurred in cell-free systems (at 2.8 versus 2.1 microM for vinblastine); in contrast to paclitaxel, the target compounds did not interfere with microtubule disassembly. The strong cancericidal and antimicrotubular activities of the bromine and iodine compounds justify further exploration of their potential in antineoplastic chemotherapy.

机译：四种标题化合物（迄今未报道）是由3-氨基苯甲酸通过其三氟乙酸-酰氯衍生物合成的，与尿素反应并进行氨解脱保护，生成3-氨基苯甲酰脲，然后进行非常规的卤代乙酰化。发现三个关键因素对于抗肿瘤活性至关重要：（i）卤素的细胞毒性性质：I> Br> Cl> F（ID90 0.014-> 10 microM）; （ii）卤素的位置：只有3位（元）表示相关活性; （iii）脲基（1-位）的存在。就细胞毒性作用（非恶性心肌成纤维细胞和CEM白血病细胞中的ID50比）和治疗指标（携带P338白血病的小鼠）而言，溴和碘化合物的选择性高于长春碱和紫杉醇。生物活性的相关机制是有丝分裂阻滞和凋亡。在无细胞系统中，完全抑制了微管的组装（长春碱的浓度为2.8对2.1 microM）。与紫杉醇相比，目标化合物不会干扰微管的拆卸。溴和碘化合物具有很强的抗癌和抗微管活性，因此有必要进一步探索其在抗肿瘤化学疗法中的潜力。

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《Anti-Cancer Drug Design》 |1998年第7期|共13页
作者
Jiang JD; Roboz J; Weisz I; Deng L; Ma L; Holland JF; Bekesi JG;
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正文语种 eng
中图分类药学;
关键词
Antineoplastic Agents; Microtubules; Urea; 抗肿瘤药; 微管;

机译：Antineoplastic Agents;Microtubules;Urea;抗肿瘤药;微管;

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1. Synthesis, cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas. [J] . Jiang JD, Roboz J, Weisz I, Anti-Cancer Drug Design . 1998,第7期

机译：3-（卤代乙酰胺基）-苯甲酰脲的合成，抗癌和抗微管活性。
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Synthesis, cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas.

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