Graduate School of Advanced Integrated Studies in Human Survivability , Kyoto University , Sakyo, Kyoto 606-8306 , Japan.
Department of Chemistry, Graduate School of Science , Kyoto University , Sakyo, Kyoto 606-8502 , Japan.
J Am Chem Soc. 2019 Mar 13;141(10):4257-4263. doi: 10.1021/jacs.8b08813. Epub 2019 Mar 4.
The runt-related transcription factor (RUNX) family has been associated with cancer development. The binding of RUNX family members to specific DNA sequences is hypothesized to promote the expression of downstream genes and cause cancer proliferation. On the basis of this proposed mechanism of cancer growth, we developed conjugate 1, which inhibits the binding of RUNX to its target DNA. Conjugate 1 is a DNA-alkylating pyrrole-imidazole (PI) polyamide conjugate containing chlorambucil as an anticancer agent. Conjugate 1 was reported to have a marked anticancer effect in mouse models of acute myeloid leukemia. Although the effectiveness of 1 has been demonstrated in vivo, the detailed mechanism by which it alkylates DNA is unknown. Here, we chemically elucidated the molecular characteristics of conjugate 1 to confirm its potential as a RUNX-inhibiting drug. We also generated an alternative conjugate 2, which targets the same DNA sequence, by replacing one pyrrole with β-alanine. Comparison of the characteristics of conjugates 1 and 2 suggested that reaction selectivity and binding affinity to the RUNX-binding sequence were improved by the introduction of β-alanine. These findings indicate the possibility of DNA-alkylating PI polyamides as candidates for cancer chemotherapeutics.
runt 相关转录因子（RUNX）家族与癌症的发生有关。假设 RUNX 家族成员与特定的 DNA 序列结合会促进下游基因的表达，从而导致癌症增殖。基于这种癌症生长的拟议机制，我们开发了缀合物 1，它可以抑制 RUNX 与其靶 DNA 的结合。缀合物 1 是一种含有苯丁酸氮芥的 DNA 烷化吡咯-咪唑（PI）聚酰胺缀合物，作为一种抗癌药物。据报道，缀合物 1 在急性髓细胞性白血病的小鼠模型中具有显著的抗癌作用。尽管 1 的有效性已在体内得到证实，但它使 DNA 烷化的详细机制尚不清楚。在这里，我们通过化学方法阐明了缀合物 1 的分子特征，以确认其作为 RUNX 抑制剂药物的潜力。我们还通过用 β-丙氨酸替换一个吡咯来生成靶向相同 DNA 序列的替代缀合物 2。比较缀合物 1 和 2 的特征表明，通过引入 β-丙氨酸，反应选择性和与 RUNX 结合序列的结合亲和力得到了提高。这些发现表明，DNA 烷化 PI 聚酰胺有可能成为癌症化疗药物的候选物。
