Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90.
Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90.
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苯醌安莎霉素格尔德霉素及其衍生物是热休克蛋白Hsp 90的抑制剂，热休克蛋白Hsp 90是癌症和神经退行性疾病新型治疗药物的新兴靶点。然而，这些化合物对正常细胞的毒性已被归因于在醌19位与硫醇亲核试剂反应。我们推断，阻断该位置将改善毒性，并且它还可能迫使反式酰胺基团有利地构象转换为蛋白质结合所需的顺式形式。我们在这里报告一个有效的合成这样的19-取代的化合物和实现我们的假设。蛋白质晶体学确定，新化合物与Hsp 90结合，正如预期的那样，顺式酰胺构象。对细胞中Hsp 90抑制的研究证明了Hsp 90抑制剂的分子特征：在人乳腺癌和多巴胺能神经细胞中，客户蛋白减少，而其他热休克蛋白代偿性增加，证明了它们用于治疗癌症或神经退行性疾病的潜力。
The benzoquinone ansamycin geldanamycin and its derivatives are inhibitors of heat shock protein Hsp90, an emerging target for novel therapeutic agents both in cancer and in neurodegeneration. However, toxicity of these compounds to normal cells has been ascribed to reaction with thiol nucleophiles at the quinone 19-position. We reasoned that blocking this position would ameliorate toxicity, and that it might also enforce a favourable conformational switch of the trans-amide group into the cis-form required for protein binding. We report here an efficient synthesis of such 19-substituted compounds and realization of our hypotheses. Protein crystallography established that the new compounds bind to Hsp90 with, as expected, a cis-amide conformation. Studies on Hsp90 inhibition in cells demonstrated the molecular signature of Hsp90 inhibitors: decreases in client proteins with compensatory increases in other heat shock proteins in both human breast cancer and dopaminergic neural cells, demonstrating their potential for use in the therapy of cancer or neurodegenerative diseases.