摘要：Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin- 1-yl)benzenesulfonamides (PIB-SAs) are new, potent combretastatin A-4 (CA-4) analogs designed on the basis of their common phenyl 2-imidazolidone moiety. This phenyl 2-imidazolidone group is a bioisosteric equivalent of the trimethoxyphenyl group also found in colchicine, podophyllotoxin and several other ligands of the colchicine-binding site (C-BS). In this study, we investigate the interactions involved in the binding of PIB-SO and PIB-SA into the C-BS. We describe three distinct pockets (I, II, and III) as key structural elements involved in the interactions between the C-BS and PIB-SOs as well as PIB-SAs. We show that PIB-SOs and PIB-SAs adopt 4 and 3 distinct binding conformations, respectively, within the C-BS. The binding conformations I and IV are common to most PIB-SOs and PIB-SAs exhibiting high affinity for the C-BS and high cytocidal potency. In addition, binding conformation I is the main conformation adopted by PIB-SOs, PIB-SAs, T138067, ABT-751, colchicine and CA-4. We also observe that the sulfonate and the sulfonamide moieties of PIB-SOs and PIB-SAs are bioisosteric equivalents. Interestingly, we further find that a large portion of the phenyl 2-imidazolidinone moiety in these analogs does not bind to pocket I unlike the trimethoxyphenyl moiety found in several antimicrotubule agents such as colchicine, CA-4 and podophyllotoxin, suggesting that the phenyl 2-imidazolidinone group may represent a new haptophoric moiety useful for the design of new C-BS inhibitors mimicking the tropolone and the methoxylated phenolic moieties of colchicine and CA-4, respectively.

摘要：[背景]安全的饮用水对于健康至关重要。虽然在全球范围内,微生物污染仍然是饮用水相关疾病发病率和死亡率的最主要原因,但在供水中的化学物也可能导致疾病,而其中一些的人体健康结局的证据有限或缺乏。[目的]旨在总结当前人们对这一问题的了解状况,找出认识差距,并为与饮用水中化学物相关的流行病学研究提供建议。[讨论]评估饮用水中化学物暴露与健康结局十分具有挑战性。暴露通常为低浓度,在水中测量是通常是不够的,化学物以混合物形式存在,暴露时间通常很长,可能涉及多个暴露途径,而能够反映相应暴露阶段的有效生物标志却很少。此外,相对风险的幅度具有变小趋势。[结论]研究应该包括:设计良好的流行病学研究,涵盖能够比较污染程度并具有足够样本量的地区;结合生物分析并整合复杂混合物影响的污染物产生综合评价;足够水中测量次数,以评估地理和时间变异性;有关导致暴露的个人生活习惯的详细信息(例如,摄入、淋浴、游泳和饮食);生物样本的采集,以测量相关的生物标志;先进的统计模型,以评估暴露和相对风险,并应考虑解决测量误差的方法。最后,纳入早期生物效应和遗传易感性的分子标志对于了解化学物作用机制是必不可少的。需要评估大量新出现的污染物的风险和人类暴露,但这些知识仍然缺乏。